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Xie Z, Lin H, Wu Y, Yu Y, Liu X, Zheng Y, Wang X, Wu J, Xu M, Han Y, Zhang Q, Deng Y, Lin L, Linzhu Y, Qingyun L, Lin X, Huang Y, Chi P. USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer. Cell Death Dis 2025; 16:81. [PMID: 39922805 PMCID: PMC11807140 DOI: 10.1038/s41419-025-07424-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/14/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.
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Affiliation(s)
- Zhongdong Xie
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hanbin Lin
- Central Laboratory, Affiliated Hospital of Putian University, Putian, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Yuecheng Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Yanan Yu
- Guilin Medical University, Guilin, China
| | - Xintong Liu
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yating Zheng
- Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jiashu Wu
- Department of Science and Technology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meifang Xu
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yuting Han
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Qiongying Zhang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yu Deng
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yan Linzhu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Li Qingyun
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
| | - Ying Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
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Xie Z, Lin H, Huang Y, Wang X, Lin H, Xu M, Wu J, Wu Y, Shen H, Zhang Q, Chen J, Deng Y, Xu Z, Chen Z, Lin Y, Han Y, Lin L, Yan L, Li Q, Lin X, Chi P. BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer. Eur J Cancer 2024; 210:114278. [PMID: 39151323 DOI: 10.1016/j.ejca.2024.114278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 07/14/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Despite improvements in colorectal cancer (CRC) treatment, the prognosis for advanced CRC patients remains poor. Disruption of protein stability is one of the important factors in cancer development and progression. In this study, we aim to identify and analyze novel dysregulated proteins in CRC, assessing their significance and the mechanisms. METHODS Using quantitative proteomics, expression pattern analysis, and gain-of-function/loss-of-function experiments, we identify novel functional protein dysregulated by ubiquitin-proteasome axis in CRC. Prognostic significance was evaluated in a training cohort of 546 patients and externally validated in 794 patients. Mechanistic insights are gained through molecular biology experiments, deubiquitinating enzymes (DUBs) expression library screening, and RNA sequencing. RESULTS MAFF protein emerged as the top novel candidate substrate regulated by ubiquitin-proteasome in CRC. MAFF protein was preferentially downregulated in CRC compared to adjacent normal tissues. More importantly, multicenter cohort study identified reduced MAFF protein expression as an independent predictor of overall and disease-free survival in CRC patients. The in vitro and vivo assays showed that MAFF overexpression inhibited CRC growth, while its knockdown had the opposite effect. Intriguingly, we found the abnormal expression of MAFF protein was predominantly regulated via ubiquitination of MAFF, with K48-ubiquitin being dominant. BAP1 as a nuclear deubiquitinating enzyme (DUB), bound to and deubiquitinated MAFF, thereby stabilizing it. Such stabilization upregulated DUSP5 expression, resulting in the inhibition of ERK phosphorylation. CONCLUSIONS This study describes a novel BAP1-MAFF signaling axis which is crucial for CRC growth, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.
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Affiliation(s)
- Zhongdong Xie
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Hanbin Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Ying Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Hongyue Lin
- Department of General Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, China
| | - Meifang Xu
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jiashu Wu
- Department of Science and Technology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuecheng Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Hao Shen
- Department of Navy Environmental and Occupational Health, Naval Medical University, Shanghai, China
| | - Qiongying Zhang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinhua Chen
- Follow up Center, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yu Deng
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Zongbin Xu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Zhiping Chen
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yu Lin
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yuting Han
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
| | - Lin Lin
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Linzhu Yan
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Qingyun Li
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
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Orozco-Castaño C, Mejia-Garcia A, Zambrano Y, Combita AL, Parra-Medina R, Bonilla DA, González A, Odriozola A. Construction of an immune gene expression meta signature to assess the prognostic risk of colorectal cancer patients. ADVANCES IN GENETICS 2024; 112:207-254. [PMID: 39396837 DOI: 10.1016/bs.adgen.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Despite recent advancements in colorectal cancer (CRC) treatment, particularly with the introduction of immunotherapy and checkpoint inhibitors, the efficacy of these therapies remains limited to a subset of patients. To address this challenge, our study aimed to develop a prognostic biomarker based on immune-related genes to predict better outcomes in CRC patients and aid in treatment decision-making. We comprehensively analysed immune gene expression signatures associated with CRC prognosis to construct an immune meta-signature with prognostic potential. Utilising data from The Cancer Genome Atlas (TCGA), we employed Cox regression to identify immune-related genes with prognostic significance from multiple studies. Subsequently, we compared the expression levels of immune genes, levels of immune cell infiltration, and various immune-related molecules between high-risk and low-risk patient groups. Functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses provided insights into the biological pathways associated with the identified prognostic genes. Finally, we validated our findings using a separate CRC cohort from the Gene Expression Omnibus (GEO). Integration of the prognostic genes revealed significant disparities in survival outcomes. Differential expression analysis identified a set of immune-associated genes, which were further refined using LASSO penalisation and Cox regression. Univariate Cox regression analyses confirmed the autonomy of the gene signature as a prognostic indicator for CRC patient survival. Our risk prediction model effectively stratified CRC patients based on their prognosis, with the high-risk group showing enrichment in pro-oncogenic terms and pathways. Immune infiltration analysis revealed an augmented presence of certain immunosuppressive subsets in the high-risk group. Finally, we validated the performance of our prognostic model by applying the risk score equation to a different CRC patient dataset, confirming its prognostic potential in this new cohort. Overall, our study presents a novel immune-related gene signature with promising implications for predicting cancer progression and prognosis, thereby enabling more personalised management strategies for CRC patients.
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Affiliation(s)
- Carlos Orozco-Castaño
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Grupo de Apoyo y Seguimiento para la Investigación GASPI, Instituto Nacional de Cancerología (INC), Bogotá, Colombia.
| | - Alejandro Mejia-Garcia
- Department of Human Genetics, McGill University, Montreal, QC, Canada, McGill University, Genome Centre, Montreal, QC, Canada
| | - Yina Zambrano
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia
| | - Alba Lucia Combita
- Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Grupo de Apoyo y Seguimiento para la Investigación GASPI, Instituto Nacional de Cancerología (INC), Bogotá, Colombia; Departamento de Microbiología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Rafael Parra-Medina
- Research Institute, Fundación Universitaria de Ciencias de la Salud-FUCS, Bogotá, Colombia; Department of Pathology, Instituto Nacional de Cancerología, Electronic address, Bogotá, Colombia
| | - Diego A Bonilla
- Research Division, Dynamical Business & Science Society - DBSS International SAS, Bogotá, Colombia; Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrián Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Fan H, Hu X, Cao F, Zhou L, Wen R, Shen H, Fu Y, Zhu X, Jia H, Liu Z, Wang G, Yu G, Chang W, Zhang W. WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer. NPJ Precis Oncol 2024; 8:144. [PMID: 39014007 PMCID: PMC11252267 DOI: 10.1038/s41698-024-00650-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.
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Affiliation(s)
- Hao Fan
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xuefei Hu
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Leqi Zhou
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Rongbo Wen
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hao Shen
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Yating Fu
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China
| | - Xiaoming Zhu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hang Jia
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zixuan Liu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guimin Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guanyu Yu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
| | - Wenjun Chang
- Department of Navy Environmental and Occupational Health, Faculty of Naval Medicine, Naval Medical University, Shanghai, China.
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
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Huang L, Yuan X, Zhao L, Han Q, Yan H, Yuan J, Guan S, Xu X, Dai G, Wang J, Shi Y. Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer. BJS Open 2023; 7:7169392. [PMID: 37196196 DOI: 10.1093/bjsopen/zrad031] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 01/23/2023] [Accepted: 02/23/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND The aim of this study was to construct a predictive signature integrating tumour-mutation- and copy-number-variation-associated features using machine learning to precisely predict early relapse and survival in patients with resected stage I-II pancreatic ductal adenocarcinoma. METHODS Patients with microscopically confirmed stage I-II pancreatic ductal adenocarcinoma undergoing R0 resection at the Chinese PLA General Hospital between March 2015 and December 2016 were enrolled. Whole exosome sequencing was performed, and genes with different mutation or copy number variation statuses between patients with and without relapse within 1 year were identified using bioinformatics analysis. A support vector machine was used to evaluate the importance of the differential gene features and to develop a signature. Signature validation was performed in an independent cohort. The associations of the support vector machine signature and single gene features with disease-free survival and overall survival were assessed. Biological functions of integrated genes were further analysed. RESULTS Overall, 30 and 40 patients were included in the training and validation cohorts, respectively. Some 11 genes with differential patterns were first identified; using a support vector machine, four features (mutations of DNAH9, TP53, and TUBGCP6, and copy number variation of TMEM132E) were further selected and integrated to construct a predictive signature (the support vector machine classifier). In the training cohort, the 1-year disease-free survival rates were 88 per cent (95 per cent c.i. 73 to 100) and 7 per cent (95 per cent c.i. 1 to 47) in the low-support vector machine subgroup and the high-support vector machine subgroup respectively (P < 0.001). Multivariable analyses showed that high support vector machine was significantly and independently associated with both worse overall survival (HR 29.20 (95 per cent c.i. 4.48 to 190.21); P < 0.001) and disease-free survival (HR 72.04 (95 per cent c.i. 6.74 to 769.96); P < 0.001). The area under the curve of the support vector machine signature for 1-year disease-free survival (0.900) was significantly larger than the area under the curve values of the mutations of DNAH9 (0.733; P = 0.039), TP53 (0.767; P = 0.024), and TUBGCP6 (0.733; P = 0.023), the copy number variation of TMEM132E (0.700; P = 0.014), TNM stage (0.567; P = 0.002), and differentiation grade (0.633; P = 0.005), suggesting higher predictive accuracy for prognosis. The value of the signature was further validated in the validation cohort. The four genes included in the support vector machine signature (DNAH9, TUBGCP6, and TMEM132E were novel in pancreatic ductal adenocarcinoma) were significantly associated with the tumour immune microenvironment, G protein-coupled receptor binding and signalling, cell-cell adhesion, etc. CONCLUSION The newly constructed support vector machine signature precisely and powerfully predicted relapse and survival in patients with stage I-II pancreatic ductal adenocarcinoma after R0 resection.
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Affiliation(s)
- Lei Huang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Medical Centre on Ageing of Ruijin Hospital, MCARJH, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaodong Yuan
- Organ Transplant Center, Department of Hepatobiliary and Transplantation Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Liangchao Zhao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quanli Han
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Huan Yan
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Jing Yuan
- Department of Pathology, Chinese PLA General Hospital, Beijing, China
| | - Shasha Guan
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiaofeng Xu
- Shanghai Chief Technician Studio (Information & Technology), Shanghai, China
| | - Guanghai Dai
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Junqing Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Shi
- Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Jiang YJ, Zhang TT, Zhu YQ, Cai HQ, Chang C, Hao JJ, Cai Y, Wang MR, Liang JW, Zhang Y. Development of novel DNAJB6-KIAA1522-p-mTOR three-protein prognostic prediction models for CRC. Transl Oncol 2023; 28:101609. [PMID: 36571988 PMCID: PMC9803855 DOI: 10.1016/j.tranon.2022.101609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/28/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND To evaluate the prognostic value of DNAJB6, KIAA1522, and p-mTOR expression for colorectal cancer (CRC) and to develop effective prognostic models for CRC patients. METHODS The expression of DNAJB6, KIAA1522, and p-mTOR (Ser2448) was detected using immunohistochemistry in 329 CRC specimens. The prognostic values of the three proteins in the training cohort were assessed using Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models. Prediction nomogram models integrating the three proteins and TNM stage were constructed. Subsequently, calibration curves, receiver operating characteristic (ROC) curves, the concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the performance of the nomograms in the training and validation cohorts. RESULTS The three proteins DNAJB6, KIAA1522, and p-mTOR were significantly overexpressed in CRC tissues (each P < 0.01), and their expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) (each P < 0.05). The area under the ROC curves (AUC) and C-index values were approximately 0.7. Additionally, the calibration curves showed that the predicted values and the actual values fit well. Furthermore, DCA curves indicated that the clinical value of the nomogram models was higher than that of TNM stage. Overall, the novel prediction models have good discriminability, sensitivity, specificity and clinical utility. CONCLUSION The nomograms containing DNAJB6, KIAA1522, and p-mTOR may be promising models for predicting postoperative survival in CRC.
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Affiliation(s)
- Yu-Juan Jiang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tong-Tong Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, 610031, China
| | - Yi-Qing Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hong-Qing Cai
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chen Chang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jia-Jie Hao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ming-Rong Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jian-Wei Liang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Yu Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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7
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Yu G, Xu M, Zhou L, Zheng K, Zhu X, Sui J, Xin C, Chang W, Zhang W, Cao F. High expression of phosphorylated focal adhesion kinase predicts a poor prognosis in human colorectal cancer. Front Pharmacol 2022; 13:989999. [PMID: 36176444 PMCID: PMC9513477 DOI: 10.3389/fphar.2022.989999] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 08/04/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Phosphorylated Focal adhesion kinase (FAK) has been reported to be intimately involved in various malignant tumors. The effect of p-FAK on colorectal cancer (CRC) is still disputable. The purpose of this study is to investigate the role of p-FAK in the prognosis of colorectal cancer. Methods: The clinical significance of p-FAK expression in CRC was evaluated by immunohistochemistry in a large cohort, including carcinoma and para-carcinoma tissues from 908 patients, and normal tissues, adenoma, and metastasis tissues. The correlation between p-FAK expression and CRC occurrence was investigated in tumor and other tissues. Factors contributing to prognosis were evaluated using Kaplan-Meier survival analysis and Cox regression model. Results: p-FAK is apparently overexpressed in CRC and metastasis tissues. Compared with low p-FAK expression, patients with high p-FAK expression had shorter overall survival [hazard ratio (HR), 2.200; 95% confidence interval (CI), 1.265-3.452; p < 0.01] and disease-free survival (HR, 2.004; 95% CI 1.262-3.382; p < 0.01) in multivariate Cox analysis after adjusting other prognostic factors. High p-FAK expression was also related to a worse chemotherapeutic response in patients who achieved adjuvant chemotherapy (p < 0.01). Conclusion: Expression level of p-FAK is an independent risk factor and can serve as a prognostic biomarker for CRC. High p-FAK expression predicts an unfavorable prognosis of CRC as well as poor chemotherapeutic response.
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Affiliation(s)
- Guanyu Yu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mengnan Xu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Leqi Zhou
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Kuo Zheng
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaoming Zhu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jinke Sui
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Cheng Xin
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wenjun Chang
- Department of Environmental Health, Naval Medical University, Shanghai, China
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
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Pond KW, Morris JM, Alkhimenok O, Varghese RP, Cabel CR, Ellis NA, Chakrabarti J, Zavros Y, Merchant JL, Thorne CA, Paek AL. Live-cell imaging in human colonic monolayers reveals ERK waves limit the stem cell compartment to maintain epithelial homeostasis. eLife 2022; 11:e78837. [PMID: 36094159 PMCID: PMC9499537 DOI: 10.7554/elife.78837] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 09/11/2022] [Indexed: 11/13/2022] Open
Abstract
The establishment and maintenance of different cellular compartments in tissues is a universal requirement across all metazoans. Maintaining the correct ratio of cell types in time and space allows tissues to form patterned compartments and perform complex functions. Patterning is especially evident in the human colon, where tissue homeostasis is maintained by stem cells in crypt structures that balance proliferation and differentiation. Here, we developed a human 2D patient derived organoid screening platform to study tissue patterning and kinase pathway dynamics in single cells. Using this system, we discovered that waves of ERK signaling induced by apoptotic cells play a critical role in maintaining tissue patterning and homeostasis. If ERK is activated acutely across all cells instead of in wave-like patterns, then tissue patterning and stem cells are lost. Conversely, if ERK activity is inhibited, then stem cells become unrestricted and expand dramatically. This work demonstrates that the colonic epithelium requires coordinated ERK signaling dynamics to maintain patterning and tissue homeostasis. Our work reveals how ERK can antagonize stem cells while supporting cell replacement and the function of the gut.
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Affiliation(s)
- Kelvin W Pond
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- Department of Molecular and Cellular Biology, The University of ArizonaTucsonUnited States
- University of Arizona Cancer CenterTucsonUnited States
| | - Julia M Morris
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
| | - Olga Alkhimenok
- Department of Molecular and Cellular Biology, The University of ArizonaTucsonUnited States
| | - Reeba P Varghese
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- Cancer Biology Graduate Interdisciplinary Program, University of ArizonaTucsonUnited States
| | - Carly R Cabel
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- Cancer Biology Graduate Interdisciplinary Program, University of ArizonaTucsonUnited States
| | - Nathan A Ellis
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- University of Arizona Cancer CenterTucsonUnited States
| | - Jayati Chakrabarti
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
| | - Yana Zavros
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- University of Arizona Cancer CenterTucsonUnited States
| | | | - Curtis A Thorne
- Department of Cellular and Molecular Medicine, University of ArizonaTucsonUnited States
- University of Arizona Cancer CenterTucsonUnited States
| | - Andrew L Paek
- Department of Molecular and Cellular Biology, The University of ArizonaTucsonUnited States
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9
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Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer. Cell Oncol (Dordr) 2022; 45:1019-1036. [PMID: 36036881 DOI: 10.1007/s13402-022-00707-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2022] [Indexed: 11/03/2022] Open
Abstract
PURPOSE We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance. METHODS PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing. RESULTS Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days, p = 2.28 × 10-13). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness- and epithelial-mesenchymal transition (EMT)-related gene sets were found to be upregulated, whereas liver development- and liver specific molecule-related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis. CONCLUSIONS HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.
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10
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Liu W, Cai S, Pu R, Li Z, Liu D, Zhou X, Yin J, Chen X, Chen L, Wu J, Tan X, Wang X, Cao G. HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling. Cancers (Basel) 2022; 14:cancers14133274. [PMID: 35805045 PMCID: PMC9265300 DOI: 10.3390/cancers14133274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Viral mutations at the preS region of hepatitis B virus (HBV) significantly increase the risk of developing hepatocellular carcinoma (HCC). Compared to HBV preS deletion, the oncogenic effect of preS combo mutation has rarely been investigated. With a cohort including 2114 subjects, we demonstrated that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased the risk of HCC in patients without antiviral treatment, whereas preS2 deletion significantly increased the risk of HCC in patients with antiviral treatment. The prevalence of C3116T/T31C (43.61%) was higher than preS2 deletion (7.16%). By using Sleeping Beauty mouse models and in vitro experiments, we found G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promoted hepatocarcinogenesis by increasing levels of inflammatory cytokines, activating STAT3 pathway, enhancing endoplasmic reticulum stress, and altering gene expression profiles in inflammation- and metabolism-related pathways. These results suggest that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C had similar oncogenic effects of preS2 deletion and should also be monitored. Abstract This study aimed to elucidate the effects and underlying mechanisms of hepatitis B virus (HBV) preS mutations on hepatocarcinogenesis. The effect of the preS mutations on hepatocellular carcinoma (HCC) occurrence was evaluated using a prospective cohort study with 2114 HBV-infected patients, of whom 612 received antiviral treatments. The oncogenic functions of HBV preS mutations were investigated using cancer cell lines and Sleeping Beauty (SB) mouse models. RNA-sequencing and microarray were applied to identify key molecules involved in the mutant-induced carcinogenesis. Combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased HCC risk in patients without antiviral treatment, whereas the preS2 deletion significantly increased HCC risk in patients with antiviral treatment. In SB mice, the preS1/preS2/S mutants induced a higher rate of tumor and higher serum levels of inflammatory cytokines than did wild-type counterpart. The preS1/preS2/S mutants induced altered gene expression profiles in the inflammation- and metabolism-related pathways, activated pathways of endoplasmic reticulum (ER) stress, affected the response to hypoxia, and upregulated the protein level of STAT3. Inhibiting the STAT3 pathway attenuated the effects of the preS1/preS2/S mutants on cell proliferation. G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promote hepatocarcinogenesis via inducing ER stress, metabolism alteration, and STAT3 pathways, which might be translated into HCC prophylaxis.
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Affiliation(s)
- Wenbin Liu
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Shiliang Cai
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Rui Pu
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Zixiong Li
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Donghong Liu
- Department of Liver Cancer Surgery, Third Affiliated Hospital, Second Military Medical University, Shanghai 200433, China;
| | - Xinyu Zhou
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Xi Chen
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Liping Chen
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Jianfeng Wu
- Department of Pathology, Xijing Hospital, Xi’an 710032, China;
| | - Xiaojie Tan
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
| | - Xin Wang
- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200433, China;
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China; (W.L.); (S.C.); (R.P.); (Z.L.); (X.Z.); (J.Y.); (X.C.); (L.C.); (X.T.)
- Correspondence: ; Tel.: +86-21-8187-1060
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11
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Liu W, Deng Y, Li Z, Chen Y, Zhu X, Tan X, Cao G. Cancer Evo-Dev: A Theory of Inflammation-Induced Oncogenesis. Front Immunol 2021; 12:768098. [PMID: 34880864 PMCID: PMC8645856 DOI: 10.3389/fimmu.2021.768098] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/04/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil-DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of "mutation-selection-adaptation". Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.
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Affiliation(s)
- Wenbin Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yang Deng
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, China
| | - Zishuai Li
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yifan Chen
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Xiaoqiong Zhu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiaojie Tan
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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12
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Li Y, Yuan Y, Zhang F, Guo A, Cao F, Song M, Fu Y, Xu X, Shen H, Zheng S, Pan Y, Chang W. Therapeutic Suppression of FAK-AKT Signaling Overcomes Resistance to SHP2 Inhibition in Colorectal Carcinoma. Front Pharmacol 2021; 12:739501. [PMID: 34790119 PMCID: PMC8591248 DOI: 10.3389/fphar.2021.739501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
SHP2 mediates signaling from multiple receptor tyrosine kinases (RTKs) to extracellular signal-regulated kinase (ERK) and Ser and Thr kinase AKT, and its inhibitors offer an unprecedented opportunity for cancer treatment. Although the ERK signaling variation after SHP2 inhibition has been well investigated, the AKT signaling variation in colorectal carcinoma (CRC) is still unknown. Therefore, we performed immunohistochemistry and bioinformatics analyses to explore the significance of p-SHP2 in CRC. A panel of CRC cell lines with the SHP2 inhibitor, SHP099, was used to assess the effects on viability and signaling. The inhibitors of AKT and focal adhesion kinase (FAK) signaling were examined in combination with SHP099 as potential strategies to enhance the efficacy and overcome resistance. Frequent resistance to the SHP2 inhibitor was observed in CRC cells, even in those without RAS mutations. We observed rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition, possibly driven by the reactivation of RTKs or released p-FAK. High baseline p-FAK may also be associated with CRC cell resistance to SHP2 inhibition. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition. Moreover, the combined inhibition of SHP2 with AKT or FAK resulted in sustained AKT pathway suppression and improved antitumor efficacy in vitro and in vivo. Our study found that reactivation of the AKT pathway is a key mechanism of adaptive resistance to SHP2 inhibition, highlighting the potential significance of AKT and FAK inhibition strategies to enhance the efficacy of SHP2 inhibitors in CRC treatment.
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Affiliation(s)
- Ye Li
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Yuncang Yuan
- Laboratory of Animal Tumor Models, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fan Zhang
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Aizhen Guo
- Department of General Practice, Yangpu Center Hospital, Medical School of Tongji University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Mengmeng Song
- Department of Gastrointestinal Surgery/Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yating Fu
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Xiaowen Xu
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Shen
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | | | - Yamin Pan
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Chang
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
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13
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Peng Y, Zhao J, Yin F, Sharen G, Wu Q, Chen Q, Sun X, Yang J, Wang H, Zhang D. A methylation-driven gene panel predicts survival in patients with colon cancer. FEBS Open Bio 2021; 11:2490-2506. [PMID: 34184409 PMCID: PMC8409306 DOI: 10.1002/2211-5463.13242] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/14/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
The accumulation of various genetic and epigenetic changes in colonic epithelial cells has been identified as one of the fundamental processes that drive the initiation and progression of colorectal cancer (CRC). This study aimed to explore functional genes regulated by DNA methylation and their potential utilization as biomarkers for the prediction of CRC prognoses. Methylation‐driven genes (MDGs) were explored by applying the integrative analysis tool (methylmix) to The Cancer Genome Atlas CRC project. The prognostic MDG panel was identified by combining the Cox regression model with the least absolute shrinkage and selection operator regularization. Gene set enrichment analysis was used to determine the pathways associated with the six‐MDG panel. Cluster of differentiation 40 (CD40) expression and methylation in CRC samples were validated by using additional datasets from the Gene Expression Omnibus. Methylation‐specific PCR and bisulfite sequencing were used to confirm DNA methylation in CRC cell lines. A prognostic MDG panel consisting of six gene members was identified: TMEM88, HOXB2, FGD1, TOGARAM1, ARHGDIB and CD40. The high‐risk phenotype classified by the six‐MDG panel was associated with cancer‐related biological processes, including invasion and metastasis, angiogenesis and the tumor immune microenvironment. The prognostic value of the six‐MDG panel was found to be independent of tumor node metastasis stage and, in combination with tumor node metastasis stage and age, could help improve survival prediction. In addition, the expression of CD40 was confirmed to be regulated by promoter region methylation in CRC samples and cell lines. The proposed six‐MDG panel represents a promising signature for estimating the prognosis of patients with CRC.
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Affiliation(s)
- Yaojun Peng
- Emergency Department, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,College of Graduate, Chinese PLA General Hospital, Beijing, China
| | - Jing Zhao
- Department of Scientific Research Administration, Chinese PLA General Hospital, Beijing, China
| | - Fan Yin
- Department of Oncology, The Second Medical Center & National Clinical Research Center of Geriatric Disease, Chinese PLA General Hospital, Beijing, China
| | - Gaowa Sharen
- Department of Pathology, The First Affiliated Hospital of Inner Mongolia Medical University, Hohhot City, China
| | - Qiyan Wu
- Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qi Chen
- Department of Traditional Chinese Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoxuan Sun
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, China.,Department of Oncology Surgery, Tianjin Cancer Hospital Airport Free Trade Zone Hospital, China
| | - Juan Yang
- Department of Cardiothoracic Surgery, Tianjin Fourth Center Hospital, China
| | - Huan Wang
- Department of Scientific Research Administration, Chinese PLA General Hospital, Beijing, China
| | - Dong Zhang
- Department of Oncology, The Second Medical Center & National Clinical Research Center of Geriatric Disease, Chinese PLA General Hospital, Beijing, China
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14
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Wang L, Jiang X, Zhang X, Shu P. Prognostic implications of an autophagy-based signature in colorectal cancer. Medicine (Baltimore) 2021; 100:e25148. [PMID: 33787596 PMCID: PMC8021367 DOI: 10.1097/md.0000000000025148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The heterogeneity of colorectal cancer (CRC) poses a significant challenge to the precise treatment of patients. CRC has been divided into 4 consensus molecular subtypes (CMSs) with distinct biological and clinical characteristics, of which CMS4 has the mesenchymal identity and the highest relapse rate. Autophagy plays a vital role in CRC development and therapeutic response. METHODS The gene expression profiles collected from 6 datasets were applied to this study. Network analysis was applied to integrate the subtype-specific molecular modalities and autophagy signature to establish an autophagy-based prognostic signature for CRC (APSCRC). RESULTS Network analysis revealed that 6 prognostic autophagy genes (VAMP7, DLC1, FKBP1B, PEA15, PEX14, and DNAJB1) predominantly regulated the mesenchymal modalities of CRC. The APSCRC was constructed by these 6 core genes and applied for risk calculation. Patients were divided into high- and low-risk groups based on APSCRC score in all cohorts. Patients within the high-risk group showed an unfavorable prognosis. In multivariate analysis, the APSCRC remained an independent predictor of prognosis. Moreover, the APSCRC achieved higher prognostic power than commercialized multigene signatures. CONCLUSIONS We proposed and validated an autophagy-based signature, which is a promising prognostic biomarker of CRC patients. Further prospective studies are warranted to test and validate its efficiency for clinical application.
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Affiliation(s)
- Liangbin Wang
- Department of Anorectal Surgery, Beilun People's Hospital, Ningbo
| | - Xinlei Jiang
- Tianjin Key Laboratory of Aquatic Science and Technology, School of Environmental and Municipal Engineering, Tianjin Chengjian University, Tianjin
| | - Xingguo Zhang
- Molecular Laboratory, Beilun People's Hospital, Ningbo, P.R. China
| | - Peng Shu
- Molecular Laboratory, Beilun People's Hospital, Ningbo, P.R. China
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15
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Zhang F, Shen H, Fu Y, Yu G, Cao F, Chang W, Xie Z. Vacuolar Membrane ATPase Activity 21 Predicts a Favorable Outcome and Acts as a Suppressor in Colorectal Cancer. Front Oncol 2021; 10:605801. [PMID: 33680927 PMCID: PMC7933500 DOI: 10.3389/fonc.2020.605801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 12/31/2020] [Indexed: 12/14/2022] Open
Abstract
Extracellular and/or intracellular manipulation of pH in tumor may have noticeable potential in cancer treatment. Although the assembly factor genes of V0 domain of the V-ATPase complex are required for intracellular pH homeostasis, their significance in colorectal cancer (CRC) remains largely unknown. Here, we used bioinformatics to identify the candidates from known assembly factor genes of the V0 domain, which were further evaluated by immunohistochemistry (IHC) in CRC and adjacent normal specimens from 661 patients. Univariate and multivariate Cox analyses were used to evaluate factors contributing to prognosis. The effects of variations in the expression of VMA21 on tumor growth were assessed in vitro and in vivo. Of five known assembly factors, only VMA21 showed differential expression between CRC and adjacent normal tissues at both mRNA and protein levels. Patients with high VMA21 expression had higher differentiation grade and longer disease-specific survival (DSS) at stages I–III disease. High VMA21 expression in tumors was also an independent predictor of DSS (hazard ratio, 0.345; 95% confidence interval, 0.123–0.976), with covariates included TNM stage and differentiation grade. VMA21 overexpression decreased CRC growth, whereas VMA21 knockdown increased CRC growth in vitro and in vivo. VMA21 expression suppresses CRC growth and predicts a favorable DSS in patients with stage I-III disease.
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Affiliation(s)
- Fan Zhang
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Hao Shen
- School of Medicine, Yunnan University, Kunming, China.,Department of Gastrointestinal Surgery, First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Yating Fu
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Guanyu Yu
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Wenjun Chang
- Department of Environmental and Occupational Health, Second Military Medical University, Shanghai, China
| | - Zhongdong Xie
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.,Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
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16
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Ahluwalia P, Kolhe R, Gahlay GK. The clinical relevance of gene expression based prognostic signatures in colorectal cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188513. [PMID: 33493614 DOI: 10.1016/j.bbcan.2021.188513] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers, with more than one million new cases every year. In the last few decades, several advancements in therapeutic and preventative levels have reduced the mortality rate, but new biomarkers are required for improved prognosis. The alterations at the genetic and epigenetic level have been recognized as major players in tumorigenesis. The products of gene expression in the form of mRNA, microRNA, and long-noncoding RNA, have started to emerge as important regulatory molecules, playing an important role in cancer. Gene-expression based prognostic risk scores, which quantify and compare their expression, have emerged as promising biomarkers with enormous clinical value. These composite multi-gene models in which more than one gene is used to predict prognosis have been shown to be significantly effective in identifying patients with multiple clinico-pathological risks like overall mortality, response to chemotherapy, risk of metastasis, etc. The advent of microarray and advanced sequencing technologies have led to the generation of large datasets like TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), which have fueled the search for new biomarkers. Continuous evaluation of these candidate biomarkers in clinical settings is promising to improve the management of CRC. These composite gene signatures provide potential in identifying high-risk patients, which might help clinicians to better manage these patients and design appropriate personalized therapeutic interventions. In this review, we emphasize on composite prognostic scores from diverse resources with clinical utility in CRC.
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Affiliation(s)
- Pankaj Ahluwalia
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Gagandeep K Gahlay
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, India.
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17
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Jiang P, Li Y, Xu Z, He S. A signature of 17 immune-related gene pairs predicts prognosis and immune status in HNSCC patients. Transl Oncol 2021; 14:100924. [PMID: 33221687 PMCID: PMC7689340 DOI: 10.1016/j.tranon.2020.100924] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/04/2020] [Accepted: 10/16/2020] [Indexed: 02/08/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an invasive malignancy with high worldwide mortality. Growing evidence has indicated a pivotal correlation between HNSCC prognosis and immune signature. This study investigated an immune-related gene pairs (IRGPs) signature to predict the prognostic value of HNSCC patients. We constructed IRGPs via integrating multiple IRG expression data sets. Moreover, we established the predictive model base on the IRGPs for HNSCC, and utilized multidimensional bioinformatics methods to validate the robustness of prognostic value of the IRGPs signature. In addition, we explored the relationship between the IRGPs model and immune status. Seventeen IRGPs signature was built as the predictive model which predicted prognosis independently and reliably for HNSCC. Compared to the high-risk group, the low-risk group demonstrated a distinctly favorable prognosis including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). The low-risk group showed higher-immune score and lower-tumor purity than the high-risk group. In addition, the low-risk group exhibited higher expression of Programmed cell death 1 ligand 1 (PD-L1) and Microsatellite instability (MSI) score, and lower expression of Tumor Immune Dysfunction and Exclusion (TIDE), which indicated the low-risk group was much more sensitive to immunotherapy. Lastly, the IRGs signature has achieved a higher accuracy than clinical properties for estimation of survival. The IRGPs model is an independent biomarker for estimating the prognosis, and could be also used to predict immunotherapeutic response in HNSCC patients. These findings may provide new ideas for novel biomarkers and may be helpful to formulate personalized immunotherapy strategy.
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Affiliation(s)
- Pan Jiang
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China.
| | - Yanli Li
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China
| | - Zheng Xu
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China
| | - Shengteng He
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China.
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Yang Y, Zheng J, Wang M, Zhang J, Tian T, Wang Z, Yuan S, Liu L, Zhu P, Gu F, Fu S, Shan Y, Pan Z, Zhou W. NQO1 promotes an aggressive phenotype in hepatocellular carcinoma via amplifying ERK-NRF2 signaling. Cancer Sci 2020; 112:641-654. [PMID: 33222332 PMCID: PMC7894015 DOI: 10.1111/cas.14744] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 10/31/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
Patients with hepatocellular carcinoma (HCC) are usually diagnosed at the later stages and have poor survival outcomes. New molecules are urgently needed for the prognostic predication and individual treatment. Our study showed that high levels of NQO1 expression frequently exist in HCC with an obvious cancer‐specific pattern. Patients with NQO1‐high tumors are significantly associated with poor survival outcomes and serve as independent predictors. Functional experiments showed that NQO1 promotes the growth and aggressiveness of HCC in both in vitro and in vivo models, and the underlying mechanism involved NQO1‐derived amplification of ERK/p38‐NRF2 signaling. Combined block of ERK and NRF2 signaling generated stronger growth inhibition compared with any single block, especially for HCC with high‐NQO1. Therefore, NQO1 is a potential biomarker for HCC early diagnosis and prognosis prediction, and also attractive for cancer‐specific targets for HCC treatment.
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Affiliation(s)
- Yun Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Jie Zheng
- Department of Intervention, First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China
| | - Mengchao Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,The Center for Liver Disease and Transplantation, General Hospital of Guangzhou Military Command of People's Liberation Army, Guangzhou, China
| | - Jin Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Tao Tian
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zhiheng Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lei Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Peng Zhu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Fangming Gu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Siyuan Fu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yunfeng Shan
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China
| | - Zeya Pan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, China
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Sueyama T, Kajiwara Y, Mochizuki S, Shimazaki H, Shinto E, Hase K, Ueno H. Periostin as a key molecule defining desmoplastic environment in colorectal cancer. Virchows Arch 2020; 478:865-874. [PMID: 33215229 DOI: 10.1007/s00428-020-02965-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 10/26/2020] [Accepted: 11/01/2020] [Indexed: 11/30/2022]
Abstract
Categorizing desmoplastic reaction (DR) based on the histological findings of cancer-associated fibroblasts is shown to be a promising novel method to predict prognosis of patients with colorectal cancer (CRC). Periostin (POSTN) in cancer-associated stroma is reportedly associated with poor clinical outcomes. Immunohistochemical staining with an anti-POSTN antibody was performed in 73 patients with pStage III CRC (cohort 1). In addition, to evaluate mRNA and protein expression levels of POSTN, we analyzed paired normal and invasive cancer frozen specimens by quantitative real-time polymerase chain reaction and western blot analysis in 41 patients (cohort 2). In cohort 1, according to the DR categorization, 18, 22, and 33 patients were classified as immature, intermediate, and mature, respectively. High immunoreactivity of POSTN was observed 100%, 68.2%, and 27.3%, respectively (p < 0.0001). The 5-year relapse-free survival rates were 56.8% and 82.7% in high and low POSTN expression subgroups, respectively (p = 0.015). In cohort 2, the POSTN mRNA and protein levels were significantly higher in the immature stroma as compared to the stroma characterized as other DR patterns. POSTN expression was closely associated with DR categorization. POSTN may be a key molecule that contributes to the malignant potential of CRC.
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Affiliation(s)
- Takahiro Sueyama
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Yoshiki Kajiwara
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Satsuki Mochizuki
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideyuki Shimazaki
- Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Kazuo Hase
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan
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20
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Kubota S, Yoshida T, Kageyama S, Isono T, Yuasa T, Yonese J, Kushima R, Kawauchi A, Chano T. A risk stratification model based on four novel biomarkers predicts prognosis for patients with renal cell carcinoma. World J Surg Oncol 2020; 18:270. [PMID: 33092599 PMCID: PMC7584101 DOI: 10.1186/s12957-020-02046-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Accurate prediction of the prognosis of RCC using a single biomarker is challenging due to the genetic heterogeneity of the disease. However, it is essential to develop an accurate system to allow better patient selection for optimal treatment strategies. ARL4C, ECT2, SOD2, and STEAP3 are novel molecular biomarkers identified in earlier studies as survival-related genes by comprehensive analyses of 43 primary RCC tissues and RCC cell lines. METHODS To develop a prognostic model based on these multiple biomarkers, the expression of four biomarkers ARL4C, ECT2, SOD2, and STEAP3 in primary RCC tissue were semi-quantitatively investigated by immunohistochemical analysis in an independent cohort of 97 patients who underwent nephrectomy, and the clinical significance of these biomarkers were analyzed by survival analysis using Kaplan-Meier curves. The prognostic model was constructed by calculation of the contribution score to prognosis of each biomarker on Cox regression analysis, and its prognostic performance was validated. RESULTS Patients whose tumors had high expression of the individual biomarkers had shorter cancer-specific survival (CSS) from the time of primary nephrectomy. The prognostic model based on four biomarkers segregated the patients into a high- and low-risk scored group according to defined cut-off value. This approach was more robust in predicting CSS compared to each single biomarker alone in the total of 97 patients with RCC. Especially in the 36 metastatic RCC patients, our prognostic model could more accurately predict early events within 2 years of diagnosis of metastasis. In addition, high risk-scored patients with particular strong SOD2 expression had a much worse prognosis in 25 patients with metastatic RCC who were treated with molecular targeting agents. CONCLUSIONS Our findings indicate that a prognostic model based on four novel biomarkers provides valuable data for prediction of clinical prognosis and useful information for considering the follow-up conditions and therapeutic strategies for patients with primary and metastatic RCC.
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Affiliation(s)
- Shigehisa Kubota
- Department of Urology, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Tetsuya Yoshida
- Department of Urology, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Susumu Kageyama
- Department of Urology, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Takahiro Isono
- Central Research Laboratory, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Takeshi Yuasa
- Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Koto, Tokyo, 135-8550 Japan
| | - Junji Yonese
- Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Koto, Tokyo, 135-8550 Japan
| | - Ryoji Kushima
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Akihiro Kawauchi
- Department of Urology, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Tokuhiro Chano
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
- Department of Medical Genetics, Shiga University of Medical Science, SetaTshukinowa-cho, Otsu, Shiga 520-2192 Japan
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21
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Zhang B, Wang L, Liu Z, Shao B, Jiang W, Shu P. Integrated analysis identifies an immune-based prognostic signature for the mesenchymal identity in colorectal cancer. Medicine (Baltimore) 2020; 99:e20617. [PMID: 32569190 PMCID: PMC7310905 DOI: 10.1097/md.0000000000020617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has been divided into 4 consensus molecular subtypes (CMSs), of which CMS4 has the mesenchymal identity and the highest relapse rate. Our goal is to develop a prognostic signature by integrating the immune system and mesenchymal modalities involved in CMS4. METHODS The gene expression profiles collected from 5 public datasets were applied to this study, including 1280 samples totally. Network analysis was applied to integrate the mesenchymal modalities and immune signature to establish an immune-based prognostic signature for CRC (IPSCRC). RESULTS We identified 6 immune genes as key factors of CMS4 and established the IPSCRC. The IPSCRC could significantly divide patients into high- and low- risk groups in terms of relapse-free survival (RFS) and overall survival (OS) and in discovery (RFS: P < .0001) and 4 independent validation sets (RFS range: P = .01 to <.0001; OS range: P = .02-.0004). After stage stratification, the IPSCRC could still distinguish poor prognosis patients in discovery (RFS: P = .04) and validation cohorts (RFS range: P = .04-.007) within stage II in terms of RFS. Further, in multivariate analysis, the IPSCRC remained an independent predictor of prognosis. Moreover, Macrophage M2 was significantly enriched in the high-risk group, while plasma cells enriched in the low-risk group. CONCLUSION We propose an immune-based signature identified by network analysis, which is a promising prognostic biomarker and help for the selection of CRC patients who might benefit from more rigorous therapies. Further prospective studies are warranted to test and validate its efficiency for clinical application.
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Affiliation(s)
| | | | | | | | | | - Peng Shu
- Molecular Laboratory, Beilun People's Hospital, Ningbo, China
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22
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Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment. Cancer Immunol Immunother 2020; 69:1477-1492. [PMID: 32285172 DOI: 10.1007/s00262-020-02542-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 03/03/2020] [Indexed: 12/14/2022]
Abstract
The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-β1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-β1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-β1 and GM-CSF had the highest increase. Based on the above results, TGF-β1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-β1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.
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23
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Mao Y, Lv M, Zhang Y, Nie G, Cui J, Wang Y, Wang Y, Cao W, Liu X, Wang X, Wang H. APOBEC3B expression and its prognostic potential in breast cancer. Oncol Lett 2020; 19:3205-3214. [PMID: 32256817 PMCID: PMC7074638 DOI: 10.3892/ol.2020.11433] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 01/03/2020] [Indexed: 12/24/2022] Open
Abstract
Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) mRNA expression is associated with the poor prognosis of estrogen receptor positive (ER+) breast cancer. However, the clinical relevance of APOBEC3B protein expression in patients with breast cancer remains unclear. The present study evaluated the association of APOBEC3B protein expression with clinicopathological features, as well as survival outcomes of patients with breast cancer. Furthermore, the association between APOBEC3B protein expression and tumor infiltrating lymphocytes (TILs) was investigated. APOBEC3B protein expression in 120 patients with breast cancer was evaluated via immunohistochemistry, using a constructed tumor microarray, and TILs were analyzed by hematoxylin and eosin staining. The relevance of APOBEC3B mRNA expression in breast cancer was assessed using a Kaplan-Meier Plotter online tool, as well as the Tumor Immune Estimation Response and The Cancer Genome Atlas databases. The present study assessed APOBEC3B expression in 116 patients with breast cancer and demonstrated that protein expression was significantly associated with ER and progesterone receptor expression, as well as different subtypes of breast cancer. Notably, APOEBC3B protein expression was significantly associated with TILs. Overall, high expression levels of APOBEC3B protein and high levels of TILs were indicative of longer disease-free survival rate. High APOBEC3B mRNA expression was associated with poor relapse-free survival rate, overall survival rate and distant metastasis-free survival rate in patients with breast cancer, particularly for the Luminal A subtype. APOBEC3B mRNA expression was also indicated to be associated with the immune status of patients with breast cancer. Overall, the results of the present study demonstrated that APOBEC3B mRNA and protein expression levels presented different prognostic values in the survival of patients with breast cancer. However, both APOBEC3B mRNA and protein expression levels were associated with TILs in breast cancer. Therefore, APOBEC3B may be a prognostic biomarker for breast cancer.
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Affiliation(s)
- Yan Mao
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Meng Lv
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yuzi Zhang
- 3D Medicines Inc., Shanghai 200025, P.R. China
| | - Gang Nie
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jian Cui
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yongmei Wang
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yuanyuan Wang
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Weihong Cao
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xiaoyi Liu
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xingang Wang
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Haibo Wang
- Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Xu L, Zhou C, Pan R, Tang J, Wang J, Li B, Huang T, Duan S, Xu C. PTPN11 hypomethylation is associated with gastric cancer progression. Oncol Lett 2020; 19:1693-1700. [PMID: 32194661 PMCID: PMC7039138 DOI: 10.3892/ol.2020.11250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 10/14/2019] [Indexed: 11/06/2022] Open
Abstract
Protein tyrosine phosphatase non-receptor type 11 (PTPN11) encodes the tyrosine phosphatase SHP-2 that is overexpressed in gastric cancer (GC). In the present study, the association of PTPN11 methylation levels with the incidence of GC and its correlation with SHP-2 overexpression were investigated. The methylation levels of PTPN11 in tumor and adjacent normal tissues of 112 GC patients were assessed by quantitative methylation specific PCR (qMSP). The Cancer Genome Atlas (TCGA) public database was used to analyze the association between PTPN11 methylation and PTPN11 expression. Survival analyses were conducted in order to evaluate the prognostic value of PTPN11 methylation for GC. The results of the qMSP analysis indicated that the methylation levels of PTPN11 in GC tumor tissues were significantly decreased compared with those noted in the normal adjacent tissues (mean with standard deviation: 40.91±26.33 vs. 51.99±37.37, P=0.007). An inverse correlation between PTPN11 methylation levels and PTPN11 mRNA expression levels (P=4×10-6, r=-0.237) was noted. Subgroup analyses indicated that the association of PTPN11 hypomethylation with the incidence of GC was specific to male subjects (P=0.015), heavy drinking patients (P=0.019), patients with poor tumor differentiation (P=0.010) and patients with tumor node and metastasis (TNM) stage III+IV (P=0.008). Kaplan-Meier analyses and log-rank test suggested that PTPN11 hypomethylation was not associated with GC patient overall survival (P=0.605) and recurrence (P=0.485), although it could predict the recurrence of GC patients up to and including 60 years (≤60, P=0.049). The results indicated that PTPN11 levels were hypomethylated in GC patients. TCGA data analysis suggested that PTPN11 hypomethylation could cause an upregulation in the transcription levels of PTPN11. Although, this may explain the pattern of SHP-2 overexpression in GC, additional studies are required to verify this hypothesis. The association of PTPN11 hypomethylation with GC incidence may be specific to male patients, heavy drinking patients, patients with poor tumor differentiation and patients with TNM stage of III+IV. PTPN11 hypomethylation can be considered a biomarker for the recurrence of GC patients with an age of 60 years or lower.
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Affiliation(s)
- Lele Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215200, P.R. China
| | - Cong Zhou
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Ranran Pan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Junjian Tang
- Department of Vascular Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, P.R. China
| | - Jinzhi Wang
- Department of Cell Biology, School of Medicine, Soochow University, Suzhou, Jiangsu 215007, P.R. China
| | - Bin Li
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Tianyi Huang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215200, P.R. China
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Lu W, Fu D, Kong X, Huang Z, Hwang M, Zhu Y, Chen L, Jiang K, Li X, Wu Y, Li J, Yuan Y, Ding K. FOLFOX treatment response prediction in metastatic or recurrent colorectal cancer patients via machine learning algorithms. Cancer Med 2020; 9:1419-1429. [PMID: 31893575 PMCID: PMC7013065 DOI: 10.1002/cam4.2786] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 11/19/2019] [Accepted: 12/04/2019] [Indexed: 12/21/2022] Open
Abstract
Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5-FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta-analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy.
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Affiliation(s)
- Wei Lu
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Dongliang Fu
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Xiangxing Kong
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Zhiheng Huang
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Maxwell Hwang
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Yingshuang Zhu
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Liubo Chen
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Kai Jiang
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Xinlin Li
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Yihua Wu
- Department of ToxicologySchool of Public HealthZhejiang UniversityHangzhouZhejiangChina
| | - Jun Li
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Ying Yuan
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Department of Medical OncologyThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
| | - Kefeng Ding
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China)The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
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Song M, Li Y, Miao M, Zhang F, Yuan H, Cao F, Chang W, Shi H, Song C. High stromal nicotinamide N-methyltransferase (NNMT) indicates poor prognosis in colorectal cancer. Cancer Med 2020; 9:2030-2038. [PMID: 31989785 PMCID: PMC7064029 DOI: 10.1002/cam4.2890] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/24/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Nicotinamide n-methyltransferase (NNMT) has good biochemical activity and epigenetic regulation, and has been reported as a major metabolic regulator of cancer. The goal of this study was to investigate the significance of stromal NNMT expression in colorectal cancer (CRC). PATIENTS AND METHODS Stromal expression of NNMT in primary CRC, metastasis CRC, and their non-cancerous tissues from 1088 CRC patients was examined by immunohistochemistry. The associations between stromal NNMT expression and survival outcomes in 967 patients with stage I-III CRC were further evaluated with Kaplan-Meier curve and Cox model analyses. RESULTS NNMT expression was mainly sourced from stromal compartments and also elevated in CRC. Patients with high stromal NNMT (IHC-score ≥ 106) have a worse survival than those patients with low stromal NNMT. In multiple Cox analyses, high expression of stromal NNMT remained as an independent risk factor in CRC for disease-free survival with a hazard ratio (HR) of 1.415 (95% confidence interval [CI], 1.015-1.972) and disease-specific survival with a HR of 5.004 (95% CI, 2.301-10.883). In addition, high stromal NNMT expression in CRC also indicates the poor survival outcomes in patients with early stage CRC (stage I and II) and in patients who undergo chemotherapy. CONCLUSION NNMT is mainly located in CRC stromal compartment. High stromal NNMT expression predicts an unfavorable postoperative prognosis.
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Affiliation(s)
- Mengmeng Song
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Ye Li
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingyong Miao
- Department of Biochemistry, Second Military Medical University, Shanghai, China
| | - Fan Zhang
- Department of Environmental Health, Second Military Medical University, Shanghai, China
| | - Hao Yuan
- Department of Environmental Health, Second Military Medical University, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Wenjun Chang
- Department of Environmental Health, Second Military Medical University, Shanghai, China
| | - Hanping Shi
- Department of Gastrointestinal Surgery/Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Chunhua Song
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou, China
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Jiang Y, Xie J, Huang W, Chen H, Xi S, Han Z, Huang L, Lin T, Zhao LY, Hu YF, Yu J, Cai SR, Li T, Li G. Tumor Immune Microenvironment and Chemosensitivity Signature for Predicting Response to Chemotherapy in Gastric Cancer. Cancer Immunol Res 2019; 7:2065-2073. [PMID: 31615816 DOI: 10.1158/2326-6066.cir-19-0311] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 08/08/2019] [Accepted: 10/10/2019] [Indexed: 12/29/2022]
Abstract
Current gastric cancer staging alone cannot predict prognosis and adjuvant chemotherapy benefits in stage II and III gastric cancer. Tumor immune microenvironment biomarkers and tumor-cell chemosensitivity might add predictive value to staging. This study aimed to construct a predictive signature integrating tumor immune microenvironment and chemosensitivity-related features to improve the prediction of survival and adjuvant chemotherapy benefits in patients with stage II to III gastric cancer. We used IHC to assess 26 features related to tumor, stroma, and chemosensitivity in tumors from 223 patients and evaluated the association of the features with disease-free survival (DFS) and overall survival (OS). Support vector machine (SVM)-based methods were used to develop the predictive signature, which we call the SVM signature. Validation of the signature was performed in two independent cohorts of 445 patients. The diagnostic signature integrated seven features: CD3+ cells at the invasive margin (CD3 IM), CD8+ cells at the IM (CD8 IM), CD45RO+ cells in the center of tumors (CD45RO CT), CD66b+ cells at the IM (CD66b IM), CD34+ cells, periostin, and cyclooxygenase-2. Patients fell into low- and high-SVM groups with significant differences in 5-year DFS and OS in the training and validation cohorts (all P < 0.001). The signature was an independent prognosis indicator in multivariate analysis in each cohort. The signature had better prognostic value than various clinicopathologic risk factors and single features. High-SVM patients exhibited a favorable response to adjuvant chemotherapy. Thus, this SVM signature predicted survival and has the potential for identifying patients with stage II and III gastric cancer who could benefit from adjuvant chemotherapy.
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Affiliation(s)
- Yuming Jiang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingjing Xie
- Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weicai Huang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sujuan Xi
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhen Han
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Huang
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tian Lin
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li-Ying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan-Feng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shi-Rong Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Tuanjie Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Yang WJ, Wang HB, Wang WD, Bai PY, Lu HX, Sun CH, Liu ZS, Guan DK, Yang GW, Zhang GL. A network-based predictive gene expression signature for recurrence risks in stage II colorectal cancer. Cancer Med 2019; 9:179-193. [PMID: 31724326 PMCID: PMC6943157 DOI: 10.1002/cam4.2642] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 08/07/2019] [Accepted: 10/10/2019] [Indexed: 12/11/2022] Open
Abstract
The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four‐gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease‐free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein‐protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients.
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Affiliation(s)
- Wen-Jing Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hai-Bo Wang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, China
| | - Wen-Da Wang
- Department of Anorectal Surgery, Shanxi Cancer Hospital, Taiyuan, China
| | - Peng-Yu Bai
- Department of Anorectal Surgery, Shanxi Cancer Hospital, Taiyuan, China
| | - Hong-Xia Lu
- Department of Gastroenterology, Shanxi Cancer Hospital, Taiyuan, China
| | - Chang-He Sun
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zi-Shen Liu
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ding-Kun Guan
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Guo-Wang Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Gan-Lin Zhang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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29
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Ye L, Zhang T, Kang Z, Guo G, Sun Y, Lin K, Huang Q, Shi X, Ni Z, Ding N, Zhao KN, Chang W, Wang J, Lin F, Xue X. Tumor-Infiltrating Immune Cells Act as a Marker for Prognosis in Colorectal Cancer. Front Immunol 2019; 10:2368. [PMID: 31681276 PMCID: PMC6811516 DOI: 10.3389/fimmu.2019.02368] [Citation(s) in RCA: 220] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/20/2019] [Indexed: 12/31/2022] Open
Abstract
Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (PDFS ≤ 0.001; POS ≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-indexDFS&OS = 0.86; AICDFS = 448.43; AICOS = 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers.
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Affiliation(s)
- Lele Ye
- Department of Gynecologic Oncology, Wenzhou Central Hospital, Wenzhou, China.,Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Teming Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Zhengchun Kang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Gangqiang Guo
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yongji Sun
- First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Kangming Lin
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Qunjia Huang
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Xinyu Shi
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Zhonglin Ni
- Department of General Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ning Ding
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Kong-Nan Zhao
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Wenjun Chang
- Department of Environmental Health, Naval Medical University, Shanghai, China
| | - Junjie Wang
- Department of Critical Care Medicine, Shanghai Tenth People's Hosptial, Tongji University School of Medicine, Shanghai, China
| | - Feng Lin
- Department of General Surgery, Taizhou First People's Hospital, Taizhou, China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China
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Tian MX, Zhou YF, Qu WF, Liu WR, Jin L, Jiang XF, Wang H, Tao CY, Zhou PY, Fang Y, Ding ZB, Peng YF, Zhou J, Fan J, Shi YH. Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy. Cancer Immunol Immunother 2019; 68:1369-1378. [PMID: 31338558 PMCID: PMC11028083 DOI: 10.1007/s00262-019-02371-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 07/14/2019] [Indexed: 02/06/2023]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan-Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P < 0.001) and the validation cohort (P = 0.014), respectively. Multivariate analysis demonstrated that serum γ-glutamyl transpeptidase, carbohydrate antigen 19-9, lymphoid metastasis, tumor numbers, and the HRI score were independent risk factors associated with recurrence-free survival (RFS). The combination of Shen's model and HRI score provided better performance in recurrence prediction compared with traditional staging systems. The HRI score might serve as a promising RFS predictor for ICC with prognostic values.
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Affiliation(s)
- Meng-Xin Tian
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yu-Fu Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Wei-Feng Qu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Wei-Ren Liu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Lei Jin
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Xi-Fei Jiang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Han Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Chen-Yang Tao
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Pei-Yun Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yuan Fang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zhen-Bin Ding
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yuan-Fei Peng
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Ying-Hong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
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Deng X, Ao S, Hou J, Li Z, Lei Y, Lyu G. Prognostic significance of periostin in colorectal cancer. Chin J Cancer Res 2019; 31:547-556. [PMID: 31354223 PMCID: PMC6613499 DOI: 10.21147/j.issn.1000-9604.2019.03.16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 06/05/2019] [Indexed: 12/11/2022] Open
Abstract
Accumulating evidence suggests that periostin is frequently upregulated in tissue injury, inflammation, fibrosis and tumor progression. Periostin expression in cancer cells can promote metastatic potential of colorectal cancer (CRC) via activating PI3K/Akt signaling pathway. Moreover, periostin is observed mainly in tumor stroma and cytoplasm of cancer cells, which may facilitate aggressiveness of CRC. In this review, we summarize information regarding periostin to emphasize its role as a prognostic marker of CRC.
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Affiliation(s)
- Xingming Deng
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Sheng Ao
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jianing Hou
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Zhuofei Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yunpeng Lei
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Guoqing Lyu
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
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Low tumour PPM1H indicates poor prognosis in colorectal cancer via activation of cancer-associated fibroblasts. Br J Cancer 2019; 120:987-995. [PMID: 30988394 PMCID: PMC6734651 DOI: 10.1038/s41416-019-0450-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Vimentin (VIM) is considered a prognostic marker in colorectal cancer (CRC). Our aim is to identify genes that fulfil a "X-low implies VIM-high" Boolean relationship and to evaluate their prognostic value and potential mechanism. METHODS Potential biomarkers related to VIM expression were searched using a bioinformatics approach across gene-expression arrays. Based on subgroup analysis of 2 CRC cohorts, the selected gene was tested for its association with patient's survival outcomes. The regulatory link between the selected gene and VIM was further examined with in vitro models. RESULTS PPM1H was identified as the top candidate in our search. Patients with PPM1H-low tumours have a lower 5-year disease-free survival rate than patients with PPM1H-high tumours in 2 independent cohorts. In multivariate Cox analysis, patients with PPM1H-low tumours were independently associated with relapse in both the discovery cohort (hazard ratio [HR], 1.362; 95% confidence interval [CI], 1.015-1.826; P = 0.039) and the validation cohort (HR for DFS, 4.052; 95% CI, 2.634-6.234; P < 0.001). PPM1H knockdown in CRC cells and growth in the corresponding conditional medium increased VIM expression and colon fibroblast proliferation, indicating a transformation of cancer-association fibroblasts (CAFs). Conversely, educated CAFs also facilitated the growth of CRC cells with low PPM1H expression. CONCLUSIONS Lack of tumour PPM1H expression identifies a patient subgroup with a high relapse risk, and CRC cells with low expression of PPM1H activate CAFs and inversely get promoted by CAFs.
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Wu J, Zhao Y, Zhang J, Wu Q, Wang W. Development and validation of an immune-related gene pairs signature in colorectal cancer. Oncoimmunology 2019; 8:1596715. [PMID: 31143520 PMCID: PMC6527298 DOI: 10.1080/2162402x.2019.1596715] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 03/05/2019] [Accepted: 03/15/2019] [Indexed: 12/22/2022] Open
Abstract
Although the outcome of colorectal cancer (CRC) patients has improved significantly with the recent implementation of annual screening programs, reliable prognostic biomarkers are still needed due to the disease heterogeneity. Increasing pieces of evidence revealed an association between immune signature and CRC prognosis. Thus, we aim to build a robust immune-related gene pairs (IRGPs) signature that can estimate prognosis for CRC. Gene expression profiles and clinical information of CRC patients were collected from six public cohorts, divided into training cohort (n = 565) and five independent validation cohorts (n = 572, 290, 90 177 and 68, respectively). Within 1534 immune genes, a 19 IRGPs signature consisting of 36 unique genes was constructed which was significantly associated with the survival. In the validation cohorts, the IRGPs signature significantly stratified patients into high- vs low-risk groups in terms of prognosis across and within subpopulations with early stages disease and was prognostic in univariate and multivariate analyses. Several biological processes, including response to bacterium, were enriched among genes in the IRGPs signature. Macrophage M2 and mast cells were significantly higher in the high-risk risk group compared with the low-risk group. The IRGPs signature achieved a higher accuracy than commercialized multigene signatures for estimation of survival. When integrated with clinical factors such as sex and stage, the composite clinical and IRGPs signature showed improved prognostic accuracy relative to IRGPs signatures alone. In short, we developed a robust IRGPs signature for estimating prognosis in CRC, including early-stage disease, providing new insights into the identification of CRC patients with a high risk of mortality.
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Affiliation(s)
- Jianping Wu
- Department of Clinical Laboratory, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying Zhao
- Department of Clinical Laboratory, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Juanwen Zhang
- Department of Clinical Laboratory, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qianxia Wu
- Department of Clinical Laboratory, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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34
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Duan L, Yang W, Wang X, Zhou W, Zhang Y, Liu J, Zhang H, Zhao Q, Hong L, Fan D. Advances in prognostic markers for colorectal cancer. Expert Rev Mol Diagn 2019; 19:313-324. [PMID: 30907673 DOI: 10.1080/14737159.2019.1592679] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Lili Duan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Wanli Yang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Xiaoqian Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Wei Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Yujie Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Jinqiang Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Hongwei Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Qingchuan Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, China
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35
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Yuan Y, Qi G, Shen H, Guo A, Cao F, Zhu Y, Xiao C, Chang W, Zheng S. Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer. Int J Cancer 2018; 144:1584-1595. [PMID: 29987896 DOI: 10.1002/ijc.31736] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/29/2018] [Accepted: 06/20/2018] [Indexed: 01/23/2023]
Abstract
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.
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Affiliation(s)
- Yuncang Yuan
- School of Medicine, Yunnan University, Kunming, China
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, China
| | - Guoxiang Qi
- School of Medicine, Yunnan University, Kunming, China
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, China
| | - Hao Shen
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, China
| | - Aizhen Guo
- Department of General Practice, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fuao Cao
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yan Zhu
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chunjie Xiao
- School of Medicine, Yunnan University, Kunming, China
| | - Wenjun Chang
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, China
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Liu G, Chen L, Ren H, Liu F, Dong C, Wu A, Liu Z, Zheng Y, Cheng X, Liu L. Seven Genes Based Novel Signature Predicts Clinical Outcome and Platinum Sensitivity of High Grade IIIc Serous Ovarian Carcinoma. Int J Biol Sci 2018; 14:2012-2022. [PMID: 30585265 PMCID: PMC6299362 DOI: 10.7150/ijbs.28249] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 08/30/2018] [Indexed: 02/06/2023] Open
Abstract
Background: As a major subtype of ovarian cancer, high grade FIGO stage IIIc serous ovarian carcinoma (HG3cSOC), has various prognosis due to genetic heterogeneity. Methods: The transcriptome of 401 primary FIGO IIIc serous ovarian samples was screened, seven genes based prognostic model was developed. The prognostic valueof risk score in four different cohorts (TCGA-cohort, Poland-cohort, Japan-cohort and USA-cohort) was validated. The relationship between risk score and other clinical indicators were analyzed. The guide value of risk score for platinum-taxol chemotherapy was also assayed. Tissue microenvironment difference among samples with different risk scores was investigated. Results: High-risk group (N=200, median survival months: 39.6, 95% CI: 35.9-46.3 months) had a significantly worse prognosis than low-risk group (N=201, median survival months: 52.6, 95% CI: 45.2-64.9 months;). The risk score's performance was validated in Japan-cohort (N=90, Poland-cohort (N=48) and USA-cohort (N=84). The risk score is independent from age, primary tumor size, grade and treatment methods and the performance of risk score is uniform in subgroups. Furthermore, the risk score predicted the response of HG3cSOC to platinum-based regimen after surgery, and this finding was further validated in newly collected China-cohort (N=102). Gene Set Enrichment Analysis (GSEA) and tumor infiltration analysis revealed that risk score reflected the immune infiltration and cell-cell interaction status, and the migration function of candidate genes were also verified. Conclusions: The optimized seven genes-based model is a valuable and robust model in predicting the survival of HG3cSOC, and served as a valuable marker for the response to platinum-based chemotherapy.
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Affiliation(s)
- Gang Liu
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
| | - Lihua Chen
- Department of Gynecology Oncology, Fudan University Shanghai Cancer Centre, Fudan University, 200032, Shanghai, P.R.China
| | - He Ren
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
| | - Fei Liu
- Department of Gynecology Oncology, Fudan University Shanghai Cancer Centre, Fudan University, 200032, Shanghai, P.R.China
| | - Chuanpeng Dong
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University, Indianapolis, IN, US
| | - Aosen Wu
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
| | - Zhenhao Liu
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
| | - Yu Zheng
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
| | - Xi Cheng
- Department of Gynecology Oncology, Fudan University Shanghai Cancer Centre, Fudan University, 200032, Shanghai, P.R.China
| | - Lei Liu
- Shanghai Public Health Clinical Center, Department of Medical System Biology, School of Basic Medical Sciences and Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, P.R.China
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A molecular and staging model predicts survival in patients with resected non-small cell lung cancer. BMC Cancer 2018; 18:966. [PMID: 30305064 PMCID: PMC6180609 DOI: 10.1186/s12885-018-4881-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 10/01/2018] [Indexed: 01/16/2023] Open
Abstract
Background The current TNM staging system is far from perfect in predicting the survival of individual non-small cell lung cancer (NSCLC) patients. In this study, we aim to combine clinical variables and molecular biomarkers to develop a prognostic model for patients with NSCLC. Methods Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on multivariable Cox regression analysis in a cohort of 152 NSCLC patients. The predictive performance of the model was assessed by the Area under the Receiver Operating Characteristic Curve (AUC) and Kaplan–Meier survival analysis. Results The survival prediction model consisting of two genes (TPX2 and MMP12) and two clinicopathological factors (tumor stage and grade) was developed. The patients could be divided into either high-risk group or low-risk group. Both disease-free survival and overall survival were significantly different among the diverse groups (P < 0.05). The AUC of the prognostic model was higher than that of the TNM staging system for predicting survival. Conclusions We developed a novel prognostic model which can accurately predict outcomes for patients with NSCLC after surgery. Electronic supplementary material The online version of this article (10.1186/s12885-018-4881-9) contains supplementary material, which is available to authorized users.
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Abstract
BACKGROUND The identification of high-risk colorectal cancer (CRC) patient is key to individualized treatment after surgery and reliable prognostic biomarkers are needed identifying high-risk CRC patients. METHODS We developed a gene pair based prognostic signature that could can the prognosis risk in patients with CRC. This study retrospectively analyzed 4 public CRC datasets, and 1123 patients with CRC were divided into a training cohort (n = 300) and 3 independent validation cohorts (n = 507, 226, and 90 patients). RESULTS A signature of 9 prognosis-related gene pairs (PRGPs) consisting of 17 unique genes was constructed. Then, a PRGP index (PRGPI) was constructed and divided patients into high- and low-risk groups according to the signature score. Patients in the high-risk group showed a poorer relapse-free survival than the low-risk group in both the training cohort [hazard ratio (HR) range, 4.6, 95% confidence interval (95% CI), 2.55-8.32; P < .0001] and meta-validation set (hazard ratio range, 4.09, 95% CI, 1.99-8.39; P < .0001). The PRGPI signature achieved a higher accuracy [mean concordance index (C-index): 0.6∼0.74] than a commercialized molecular signature (mean C-index, 0.48∼0.56) for estimation of relapse-free survival in comparable validation sets. CONCLUSION The gene pair based prognostic signature is a promising biomarker for estimating relapse-free survival of CRC.
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Affiliation(s)
- Peng Shu
- Beilun People's Hospital, Ningbo
| | - Jianping Wu
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yao Tong
- College of Agriculture and Life Sciences, Cornell University, Ithaca, NY
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Li P, Ren H, Zhang Y, Zhou Z. Fifteen-gene expression based model predicts the survival of clear cell renal cell carcinoma. Medicine (Baltimore) 2018; 97:e11839. [PMID: 30113474 PMCID: PMC6113007 DOI: 10.1097/md.0000000000011839] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Clear-cell renal cell carcinoma (ccRCC) is the major renal cell carcinoma subtype, but its postsurgical prognosis varies among individual patients.We used gene expression, machine learning (random forest variable hunting), and Cox regression analysis to develop a risk score model based on 15 genes to predict survival of patients with ccRCC in the The Cancer Genome Atlas dataset (N = 533). We validated this model in another cohort, and analyzed correlations between risk score and other clinical indicators.Patients in the high-risk group had significantly worse overall survival (OS) than did those in the low-risk group (P = 5.6e-16); recurrence-free survival showed a similar pattern. This result was reproducible in another dataset, E-MTAB-1980 (N = 101, P = .00029). We evaluated correlations between risk score and other clinical indicators. Risk was independent of age and sex, but was significantly associated with hemoglobin level, primary tumor size, and grade. Radiation therapy also had no effect on the prognostic value of the risk score. Cox multivariate regression showed risk score to be an important indicator for ccRCC prognosis. We plotted a nomogram for 3-year OS to facilitate use of risk score and other indicators.The risk score model based on expression of the 15 selected genes can predict survival of patients with ccRCC.
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Affiliation(s)
- Ping Li
- Shanghai University of Medicine & Health Sciences School of Optical-electrical and Computer Engineer of University of Shanghai for Science and Technology Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine & Health Science Department of Pharmacology, School of Pharmacy, Shanghai University of Medicine & Health Science, Shanghai, China
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Chu J, Li N, Gai W. Identification of genes that predict the biochemical recurrence of prostate cancer. Oncol Lett 2018; 16:3447-3452. [PMID: 30127947 PMCID: PMC6096182 DOI: 10.3892/ol.2018.9106] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 12/05/2017] [Indexed: 01/03/2023] Open
Abstract
Prostate cancer (PCa) is one of the most prevalent cancer types in men. Biochemical recurrence continues to occur in a large proportion of patients after radical prostatectomy. Thus, prognostic biomarkers are required to determine which treatment is suitable. In the present study, RNA-sequencing gene expression data from The Cancer Genome Atlas was used in order to develop a risk-score staging system based on the expression of eight genes. Cox multivariate regression was used to predict the outcome of patients with PCa. The biomedical recurrence-free survival of patients with low-risk scores was significantly longer compared with patients with high-risk scores (P=5×10−7). This result was further validated using another dataset, GSE70769, from the National Center for Biotechnology Information. The prognostic values of other clinical information and risk scores were evaluated for 5-year biochemical recurrence. The prognostic value of the risk score was determined using an area under curve value of 0.819, predicting the 5-year biochemical recurrence of patients with PCa. The risk score was identified to be significantly associated with primary tumor stage (P<0.01), Gleason score (P<0.01), and lymph node invasion (P<0.05), but was independent of age. Cox multivariate regression revealed that the risk score was an indicator for prediction of biochemical recurrence. Thus, the risk score is a valuable and robust indicator for predicting the biochemical recurrence of patients with PCa.
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Affiliation(s)
- Jianfeng Chu
- Department of Urology, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Ning Li
- Department of Urology, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Wentao Gai
- Department of Urology, Yantai Municipal Laiyang Central Hospital, Yantai, Shandong, 265200, P.R. China
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Du Y, Tao X, Wu J, Yu H, Yu Y, Zhao H. APOBEC3B up-regulation independently predicts ovarian cancer prognosis: a cohort study. Cancer Cell Int 2018; 18:78. [PMID: 29853799 PMCID: PMC5975489 DOI: 10.1186/s12935-018-0572-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 05/23/2018] [Indexed: 01/22/2023] Open
Abstract
Background Ovarian cancer is a heterogeneous disease with a high degree of genomic instability, pro-/antitumor immunity and inflammation, and remains the most lethal gynecologic cancer worldwide. APOBEC3B, a member of the AID/APOBEC family, is part of the innate immune system which plays a key role in combating exogenous infection especially viral infection. Studies have shown that APOBEC3B expression is elevated in a variety of cancer tissues and cell lines, and plays a prominent role in the genesis and evolution of various cancers. However, the clinical relevance of APOBEC3B in ovarian cancer needs to be further investigated. The current study aimed to evaluate the predictive value of APOBEC3B in ovarian cancer clinical outcome, and to explore possible molecular mechanisms contributing to ovarian cancer progression. Methods The expression of APOBEC3B in biopsy tissue specimens from 88 ovarian cancer patients was examined using immunohistochemistry. In addition, ovarian cancer cell lines were transfected with APOBEC3B siRNA or pLenti-APOBEC3B construct. Western blotting and SRB assay were performed to explore the role of APOBEC3B in ovarian cancer. Results Patients were followed for a median of 74.77 months following the time of surgery. Forty-two patients had died, 5 had relapsed but were still alive at the end of study, and 41 patients remained alive and had no recurrence. Over-expression of APOBEC3B was associated with advanced FIGO stage and elevated CA125 (both p< 0.05). Univariate analysis result showed that histological subtype, FIGO stage, intravascular tumor thrombus, CA125 and APOBEC3B expression were associated with overall survival and disease-free survival of ovarian cancer patients. Multivariate analysis result showed that higher APOBEC3B expression were an independent prognostic factor to predict both worse overall survival (hazard ratio: 5.18, 95% confidence interval: 1.40–11.95, p= 0.003) and disease-free survival (hazard ratio: 4.23, 95% confidence interval: 1.60–11.17, p= 0.004) of ovarian cancer patients. Furthermore, knockdown of APOBEC3B expression in ovarian cancer cells caused an decrease in cell line viability. Conclusions APOBEC3B expression is an independent prognostic factor in ovarian cancer patients. Knockdown of APOBEC3B expression affects ovarian cancer viability.
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Affiliation(s)
- Yan Du
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,2The Academy of Integrative Medicine of Fudan University, 200011 Shanghai, People's Republic of China
| | - Xiang Tao
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, People's Republic of China
| | - Jing Wu
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, People's Republic of China
| | - Huandi Yu
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, People's Republic of China
| | - Yinhua Yu
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, People's Republic of China
| | - Hongbo Zhao
- 1Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, 200011 Shanghai, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, People's Republic of China
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Xiong Y, You W, Hou M, Peng L, Zhou H, Fu Z. Nomogram Integrating Genomics with Clinicopathologic Features Improves Prognosis Prediction for Colorectal Cancer. Mol Cancer Res 2018; 16:1373-1384. [PMID: 29784666 DOI: 10.1158/1541-7786.mcr-18-0063] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/05/2018] [Accepted: 05/02/2018] [Indexed: 11/16/2022]
Abstract
The current tumor staging system is insufficient for predicting the outcomes for patients with colorectal cancer because of its phenotypic and genomic heterogeneity. Integrating gene expression signatures with clinicopathologic factors may yield a predictive accuracy exceeding that of the currently available system. Twenty-seven signatures that used gene expression data to predict colorectal cancer prognosis were identified and re-analyzed using bioinformatic methods. Next, clinically annotated colorectal cancer samples (n = 1710) with the corresponding expression profiles, that predicted a patient's probability of cancer recurrence, were pooled to evaluate their prognostic values and establish a clinicopathologic-genomic nomogram. Only 2 of the 27 signatures evaluated showed a significant association with prognosis and provided a reasonable prediction accuracy in the pooled cohort (HR, 2.46; 95% CI, 1.183-5.132, P < 0.001; AUC, 60.83; HR, 2.33; 95% CI, 1.218-4.453, P < 0.001; AUC, 71.34). By integrating the above signatures with prognostic clinicopathologic features, a clinicopathologic-genomic nomogram was cautiously constructed. The nomogram successfully stratified colorectal cancer patients into three risk groups with remarkably different DFS rates and further stratified stage II and III patients into distinct risk subgroups. Importantly, among patients receiving chemotherapy, the nomogram determined that those in the intermediate- (HR, 0.98; 95% CI, 0.255-0.679, P < 0.001) and high-risk (HR, 0.67; 95% CI, 0.469-0.957, P = 0.028) groups had favorable responses.Implications: These findings offer evidence that genomic data provide independent and complementary prognostic information, and incorporation of this information refines the prognosis of colorectal cancer. Mol Cancer Res; 16(9); 1373-84. ©2018 AACR.
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Affiliation(s)
- Yongfu Xiong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenxian You
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Hou
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Linglong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - He Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongxue Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Wang W, Wang Z, Zhao J, Wei M, Zhu X, He Q, Ling T, Chen X, Cao Z, Zhang Y, Liu L, Shi M. A novel molecular and clinical staging model to predict survival for patients with esophageal squamous cell carcinoma. Oncotarget 2018; 7:63526-63536. [PMID: 27556859 PMCID: PMC5325382 DOI: 10.18632/oncotarget.11362] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 07/26/2016] [Indexed: 01/15/2023] Open
Abstract
Current prognostic factors fail to accurately determine prognosis for patients with esophageal squamous cell carcinoma (ESCC) after surgery. Here, we constructed a survival prediction model for prognostication in patients with ESCC. Candidate molecular biomarkers were extracted from the Gene Expression Omnibus (GEO), and Cox regression analysis was performed to determine significant prognostic factors. The survival prediction model was constructed based on cluster and discriminant analyses in a training cohort (N=205), and validated in a test cohort (N=207). The survival prediction model consisting of two genes (UBE2C and MGP) and two clinicopathological factors (tumor stage and grade) was developed. This model could be used to accurately categorize patients into three groups in the test cohort. Both disease-free survival and overall survival differed among the diverse groups (P<0.05). In summary, we have developed and validated a predictive model that is based on two gene markers in conjunction with two clinicopathological variables, and which can accurately predict outcomes for ESCC patients after surgery.
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Affiliation(s)
- Wei Wang
- Department of Surgery, The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Zhiwei Wang
- Department of Breast, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Thoracic Surgery, Shanghai Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhao
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Min Wei
- Department of Breast, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xinghua Zhu
- Department of Pathology, The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Qi He
- Department of Breast, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Tianlong Ling
- Department of Thoracic Surgery, Shanghai Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Chen
- Department of Pathology, Shanghai Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziang Cao
- Department of Thoracic Surgery, Shanghai Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yixin Zhang
- Department of Surgery, The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Lei Liu
- Department of Surgery, The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Minxin Shi
- Department of Surgery, The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
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Deng X, Xiao Q, Liu F, Zheng C. A gene expression-based risk model reveals prognosis of gastric cancer. PeerJ 2018; 6:e4204. [PMID: 29441228 PMCID: PMC5807894 DOI: 10.7717/peerj.4204] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/08/2017] [Indexed: 12/11/2022] Open
Abstract
Background The prognosis of gastric cancer is difficult to determine, although clinical indicators provide valuable evidence. Methods In this study, using screened biomarkers of gastric cancer in combination with random forest variable hunting and multivariable Cox regression, a risk score model was developed to predict the survival of gastric cancer. Survival difference between high/low-risk groups were compared. The relationship between risk score and other clinicopathological indicators was evaluated. Gene set enrichment analysis (GSEA) was used to identify pathways associated with risk scores. Results The patients with high risk scores (median overall survival: 20.2 months, 95% CI [16.9–26.0] months) tend to exhibit early events compared with those with low risk scores (median survival: 70.0 months, 95% CI [46.9–101] months, p = 1.80e–5). Further validation was implemented in another three independent datasets (GSE15459, GSE26253, GSE62254). Correlation analyses between clinical observations and risk scores were performed, and the results indicated that the risk score was not significantly associated with gender, age and primary tumor size but was significantly associated with grade and tumor stage. In addition, the risk score was also not influenced by radiation therapy. Cox multivariate regression and three-year survival nomogram suggest that the risk score is an important indicator of gastric cancer prognosis. GSEA was used to identified KEGG pathways significantly associated with risk score, and signaling pathways involved in focal adhesion and the TGF-beta signaling pathway were identified. Conclusion The risk score model successfully predicted the survival of 1,294 gastric cancer samples from four independent datasets and is among the most important indicators in clinical clinicopathological information for the prognosis of gastric cancer. To our knowledge, it is the first report to predict the survival of gastric cancer using optimized expression panel.
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Affiliation(s)
- Xiaorong Deng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qun Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan College of Traditional Chinese Medicine, Zhuzhou, Hunan, China
| | - Feng Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Cihua Zheng
- Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi, China
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Huang Y, Wang J, Cao F, Jiang H, Li A, Li J, Qiu L, Shen H, Chang W, Zhou C, Pan Y, Lu Y. SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer. Sci Rep 2017; 7:17597. [PMID: 29242509 PMCID: PMC5730547 DOI: 10.1038/s41598-017-17604-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022] Open
Abstract
Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.
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Affiliation(s)
- Yan Huang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jie Wang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Fuao Cao
- Department of colorectal surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Hailong Jiang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - An Li
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jianzhong Li
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Lei Qiu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Hao Shen
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, 200433, China
| | - Wenjun Chang
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, 200433, China
| | - Chuanxiang Zhou
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
| | - Yamin Pan
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yiming Lu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
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Liu G, Dong C, Wang X, Hou G, Zheng Y, Xu H, Zhan X, Liu L. Regulatory activity based risk model identifies survival of stage II and III colorectal carcinoma. Oncotarget 2017; 8:98360-98370. [PMID: 29228695 PMCID: PMC5716735 DOI: 10.18632/oncotarget.21312] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 08/26/2017] [Indexed: 02/07/2023] Open
Abstract
Clinical and pathological indicators are inadequate for prognosis of stage II and III colorectal carcinoma (CRC). In this study, we utilized the activity of regulatory factors, univariate Cox regression and random forest for variable selection and developed a multivariate Cox model to predict the overall survival of Stage II/III colorectal carcinoma in GSE39582 datasets (469 samples). Patients in low-risk group showed a significant longer overall survival and recurrence-free survival time than those in high-risk group. This finding was further validated in five other independent datasets (GSE14333, GSE17536, GSE17537, GSE33113, and GSE37892). Besides, associations between clinicopathological information and risk score were analyzed. A nomogram including risk score was plotted to facilitate the utilization of risk score. The risk score model is also demonstrated to be effective on predicting both overall and recurrence-free survival of chemotherapy received patients. After performing Gene Set Enrichment Analysis (GSEA) between high and low risk groups, we found that several cell-cell interaction KEGG pathways were identified. Funnel plot results showed that there was no publication bias in these datasets. In summary, by utilizing the regulatory activity in stage II and III colorectal carcinoma, the risk score successfully predicts the survival of 1021 stage II/III CRC patients in six independent datasets.
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Affiliation(s)
- Gang Liu
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chuanpeng Dong
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xing Wang
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Guojun Hou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu Zheng
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Huilin Xu
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaohui Zhan
- CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lei Liu
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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Pan Y, Zhang H, Zhang M, Zhu J, Yu J, Wang B, Qiu J, Zhang J. A five-gene based risk score with high prognostic value in colorectal cancer. Oncol Lett 2017; 14:6724-6734. [PMID: 29344121 PMCID: PMC5754913 DOI: 10.3892/ol.2017.7097] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 08/31/2017] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancies worldwide. The outcomes of patients with similar clinical symptoms or at similar pathological stages remain unpredictable. This inherent clinical diversity is most likely due to the genetic heterogeneity. The present study aimed to create a predicting tool to evaluate patient survival based on genetic profile. Firstly, three Gene Expression Omnibus (GEO) datasets (GSE9348, GSE44076 and GSE44861) were utilized to identify and validate differentially expressed genes (DEGs) in CRC. The GSE14333 dataset containing survival information was then introduced in order to screen and verify prognosis-associated genes. Of the 66 DEGs, the present study screened out 46 biomarkers closely associated to patient overall survival. By Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, it was demonstrated that these genes participated in multiple biological processes which were highly associated with cancer proliferation, drug-resistance and metastasis, thus further affecting patient survival. The five most important genes, MET proto-oncogene, receptor tyrosine kinase, carboxypeptidase M, serine hydroxymethyltransferase 2, guanylate cyclase activator 2B and sodium voltage-gated channel a subunit 9 were selected by a random survival forests algorithm, and were further made up to a linear risk score formula by multivariable cox regression. Finally, the present study tested and verified this risk score within three independent GEO datasets (GSE14333, GSE17536 and GSE29621), and observed that patients with a high risk score had a lower overall survival (P<0.05). Furthermore, this risk score was the most significant compared with other predicting factors including age and American Joint Committee on Cancer stage, in the model, and was able to predict patient survival independently and directly. The findings suggest that this survival associated DEGs-based risk score is a powerful and accurate prognostic tool and is promisingly implemented in a clinical setting.
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Affiliation(s)
- Yida Pan
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Hongyang Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Mingming Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing 210008, P.R. China
| | - Jie Zhu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jianghong Yu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Bangting Wang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jigang Qiu
- Department of General Surgery, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jun Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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谭 婉, 熊 枝. SHP-2在结直肠癌组织中的表达及临床意义. Shijie Huaren Xiaohua Zazhi 2017; 25:2039-2044. [DOI: 10.11569/wcjd.v25.i22.2039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
目的 探讨SHP-2蛋白在结直肠癌中的表达情况及其与病理特征的关系.
方法 采用免疫组织化学法和Western blot方法检测SHP-2蛋白在人结直肠癌组织中的表达情况, 分析其与患者临床病理因素的关系.
结果 结直肠癌组织中SHP-2阳性表达率为25.6%(43/168), 与正常结直肠组织比较, 差异有统计学意义(P<0.05). 结直肠癌组织中SHP-2的蛋白水平为0.2396±0.0655, 与配对正常结直肠组织比较(0.7665±0.1133), 差异有统计学意义(P<0.0001). SHP-2蛋白的低表达与分化程度和淋巴结转移有关, 与性别、年龄、浸润程度、远处转移、TNM分期无关.
结论 SHP-2可能在结直肠癌的发生发展过程中起抑制作用, 并可能成为潜在的治疗靶点.
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Zhan X, Jiao J, Zhang H, Li C, Zhao J, Liao L, Wu J, Wu B, Wu Z, Wang S, Du Z, Shen J, Zou H, Neufeld G, Xu L, Li E. A three-gene signature from protein-protein interaction network of LOXL2- and actin-related proteins for esophageal squamous cell carcinoma prognosis. Cancer Med 2017; 6:1707-1719. [PMID: 28556501 PMCID: PMC5504325 DOI: 10.1002/cam4.1096] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/06/2017] [Accepted: 04/18/2017] [Indexed: 02/05/2023] Open
Abstract
Current staging is inadequate for predicting clinical outcome of esophageal squamous cell carcinoma (ESCC). Aberrant expression of LOXL2 and actin-related proteins plays important roles in ESCC. Here, we aimed to develop a novel molecular signature that exceeds the power of the current staging system in predicting ESCC prognosis. We found that LOXL2 colocalized with filamentous actin in ESCC cells, and gene set enrichment analysis (GSEA) showed that LOXL2 is related to the actin cytoskeleton. An ESCC-specific protein-protein interaction (PPI) network involving LOXL2 and actin-related proteins was generated based on genome-wide RNA-seq in 15 paired ESCC samples, and the prognostic significance of 14 core genes was analyzed. Using risk score calculation, a three-gene signature comprising LOXL2, CDH1, and FN1 was derived from transcriptome data of patients with ESCC. The high-risk three-gene signature strongly correlated with poor prognosis in a training cohort of 60 patients (P = 0.003). In mRNA and protein levels, the prognostic values of this signature were further validated in 243 patients from a testing cohort (P = 0.001) and two validation cohorts (P = 0.021, P = 0.007). Furthermore, Cox regression analysis revealed that the signature was an independent prognostic factor. Compared with using the signature or TNM stage alone, the combined model significantly enhanced the accuracy in evaluating ESCC prognosis. In conclusion, our data reveal that the tumor-promoting role of LOXL2 in ESCC is mediated by perturbing the architecture of actin cytoskeleton through its PPIs. We generated a novel three-gene signature (PPI interfaces) that robustly predicts poor clinical outcome in ESCC patients.
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Affiliation(s)
- Xiu‐hui Zhan
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Ji‐wei Jiao
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Hai‐feng Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Chun‐quan Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
- College of Medical InformaticsDaqing CampusHarbin Medical UniversityDaqingHeilongjiangChina
| | - Jian‐mei Zhao
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Lian‐di Liao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
- Institute of Oncologic PathologyShantou University Medical CollegeShantouGuangdongChina
| | - Jian‐yi Wu
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Bing‐li Wu
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Zhi‐yong Wu
- Department of Tumor SurgeryShantou Central HospitalAffiliated Shantou Hospital of Sun Yat‐sen UniversityShantouGuangdongChina
| | - Shao‐hong Wang
- Department of PathologyShantou Central HospitalAffiliated Shantou Hospital of Sun Yat‐sen UniversityShantouGuangdongChina
| | - Ze‐peng Du
- Department of PathologyShantou Central HospitalAffiliated Shantou Hospital of Sun Yat‐sen UniversityShantouGuangdongChina
| | - Jin‐hui Shen
- Department of PathologyShantou Central HospitalAffiliated Shantou Hospital of Sun Yat‐sen UniversityShantouGuangdongChina
| | - Hai‐ying Zou
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
| | - Gera Neufeld
- Cancer Research and Vascular Biology CenterThe Bruce Rappaport Faculty of MedicineTechnionIsrael Institute of TechnologyHaifaIsrael
| | - Li‐yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
- Institute of Oncologic PathologyShantou University Medical CollegeShantouGuangdongChina
| | - En‐min Li
- Department of Biochemistry and Molecular BiologyShantou University Medical CollegeShantouGuangdongChina
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan AreaShantou University Medical CollegeShantouGuangdongChina
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Liu Q, Diao R, Feng G, Mu X, Li A. Risk score based on three mRNA expression predicts the survival of bladder cancer. Oncotarget 2017; 8:61583-61591. [PMID: 28977887 PMCID: PMC5617447 DOI: 10.18632/oncotarget.18642] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 05/23/2017] [Indexed: 01/08/2023] Open
Abstract
Bladder cancer (BLCA) is one of the most malignant cancers worldwide, and its prognosis varies. 1214 BLCA samples in five different datasets and 2 platforms were enrolled in this study. By utilizing the gene expression in The Cancer Genome Atlas (TCGA) dataset, and another two datasets, in GSE13507 and GSE31684, we constructed a risk score staging system with Cox multivariate regression to evaluate predict the outcome of BLCA patients. Three genes consist of RCOR1, ST3GAL5, and COL10A1 were used to predict the survival of BLCA patients. The patients with low risk score have a better survival rate than those with high risk score, significantly. The survival profiles of another two datasets (GSE13507 and GSE31684), which were used for candidate gene selection, were similar as the training dataset (TCGA). Furthermore, survival prediction effect of risk score staging system in another 2 independent datasets, GSE40875 and E-TABM-4321, were also validated. Compared with other clinical observations, and the risk score performs better in evaluating the survival of BLCA patients. Moreover, the correlation between radiation were also evaluated, and we found that patients have a poor survival in high risk group, regardless of radiation. Gene Set Enrichment Analysis was also implemented to find the difference between high-risk and low-risk groups on biological pathways, and focal adhesion and JAK signaling pathway were significantly enriched. In summary, we developed a risk staging model for BLCA patients with three gene expression. The model is independent from and performs better than other clinical information.
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Affiliation(s)
- Qingzuo Liu
- Yantai Yuhuangding Hospital, Zhifu District, Yantai 264000, China
| | - Ruigang Diao
- Yantai Yuhuangding Hospital, Zhifu District, Yantai 264000, China
| | - Guoyan Feng
- Yantai Yuhuangding Hospital, Zhifu District, Yantai 264000, China
| | - Xiaodong Mu
- Yantai Yuhuangding Hospital, Zhifu District, Yantai 264000, China
| | - Aiqun Li
- Yantai Affiliated Hospital of Binzhou Medical University, Muping District, Yantai 264003, China
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