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Park S, Lee SS, Kim S, Lee Y, Park G, Kim JO, Choi J. The PTTG1/VASP axis promotes oral squamous cell carcinoma metastasis by modulating focal adhesion and actin filaments. Mol Oncol 2025; 19:1517-1531. [PMID: 39792809 PMCID: PMC12077276 DOI: 10.1002/1878-0261.13779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/29/2024] [Accepted: 11/28/2024] [Indexed: 01/12/2025] Open
Abstract
The dynamics of focal adhesions (FAs) are essential physiological processes involved in cell spreading, metastasis, and regulation of the actin cytoskeleton. FAs are complex structures comprising proteins, such as paxillin and zyxin, which interact with extracellular membranes and influence cell motility and morphology. Although related studies have been reported in various cancers, the function and molecular mechanisms of oral squamous cell carcinoma (OSCC) remain unknown. We investigated the coordination between the actin cytoskeleton and FA proteins, specifically introducing pituitary tumor-transforming gene 1 (PTTG1; also known as PTTG1 regulator of sister chromatid separation, securin) into OSCC. Furthermore, we explored the co-localization of several FAs and PTTG1 through small interfering RNA (siRNA) control or siRNA-vasodilator-stimulated phosphoprotein (VASP) and -PTTG1, examining the mechanisms mediated by the induced changes in OSCC both in vitro and in vivo. The knockdown of VASP and PTTG1 regulates the dynamic actin cytoskeleton, restricting cell protrusion and motility from the front to the rear of OSCC cells. Our findings may provide new insights into how cells interact with each other on the surface of FAs in OSCC, influencing metastatic properties.
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Affiliation(s)
- Suyeon Park
- Department of Oral Pathology, College of DentistryGangneung‐Wonju National UniversityKorea
| | - Sang Shin Lee
- Department of Oral Pathology, College of DentistryGangneung‐Wonju National UniversityKorea
| | - Shihyun Kim
- Department of Oral Pathology, College of DentistryGangneung‐Wonju National UniversityKorea
| | - Yeonjun Lee
- Research Institute of Oral Science, College of DentistryGangneung‐Wonju National UniversityKorea
| | - Gyeonwon Park
- Research Institute of Oral Science, College of DentistryGangneung‐Wonju National UniversityKorea
| | | | - Jongho Choi
- Department of Oral Pathology, College of DentistryGangneung‐Wonju National UniversityKorea
- Research Institute of Oral Science, College of DentistryGangneung‐Wonju National UniversityKorea
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Zou L, Xu S, Wang C, Wu P, Xu C, Shi H. Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell. Transl Stroke Res 2025; 16:350-367. [PMID: 38095841 DOI: 10.1007/s12975-023-01217-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/31/2023] [Accepted: 11/09/2023] [Indexed: 04/08/2025]
Abstract
BACKGROUND Spontaneous subarachnoid hemorrhage (SAH) is a relatively common clinical hemorrhagic stroke crisis. The important role of early brain injury (EBI) and autophagy in SAH has been increasingly recognized in recent years. This study aims to investigate the function and the undergoing mechanism of MFGE8 in EBI after SAH. METHODS SAH model was established using C57BL/6 mice, and the SAH cell model was constructed by oxy-hemoglobin (Oxy-Hb) induced BV2 and SH-SY5Y co-culture system. Various methods were used to detect EBI and autophagy after SAH in mouse/cell lines, including mouse neurological function score, wet/dry method, HE and Evans blue staining, etc. The effect on EBI was explored after knockdown or overexpression of key genes DNMT1, MFGE8, and P2X7R. MSP was used to detect the methylation of MFGE8 promoter region, and ChIP was used to detect the binding relationship between DNMT1 and MFGE8 promoter region. RESULTS The results showed that the activation of autophagy attenuates EBI in SAH mice. Increased level of DNMT1 and decreased level of MFGE8 were observed in brain tissues of SAH mice. Knockdown of DNMT1 or overexpression of MFGE8 attenuates EBI in mice by promoting autophagy. At the same time, we found that DNMT1 promotes methylation of MFGE8 promoter region and suppresses its protein levels. MFGE8 downregulates P2X7R levels and subsequently activates PI3k/Akt/mTOR axis, promotes autophagy, and attenuates EBI in SAH mice. CONCLUSION DNMT1 promotes the methylation of MFGE8 promoter region and downregulates MFGE8 level; restoring MFGE8 downregulates P2X7R, and promotes autophagy by limiting the activation of PI3k/Akt/mTOR, thus exerting a protective effect on brain tissue of SAH mice. HIGHLIGHTS • High expression of DNMT1 and P2X7R and low expression of MFGE8 were observed in SAH mice. • Activation of autophagy reduces EBI after SAH in mice. • DNMT1/MFGE8 reduces autophagy in EBI after SAH in both mouse and cell models. • DNMT1 targets the MFGE8 promoter to upregulate its methylation level. • MFGE8 inhibits P2X7R to activate PI3k/AKT/mTOR pathway and autophagy, thus inhibiting EBI after SAH.
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Affiliation(s)
- Liang Zou
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Shancai Xu
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chunlei Wang
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Pei Wu
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Chao Xu
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China
| | - Huaizhang Shi
- The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang Province, People's Republic of China.
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Guo E, Li L, Yang J, Zhou Y, Bai L, Zhu W, Hu Q, Wang H, Liu H. HOXB4/METTL7B cascade mediates malignant phenotypes of hepatocellular carcinoma through TKT m6A modification. Biol Direct 2025; 20:26. [PMID: 40045399 PMCID: PMC11884015 DOI: 10.1186/s13062-025-00620-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 02/17/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a fatal malignancy that lacking specific therapies. Homeobox B4 (HOXB4) was negatively correlated with poor prognosis in cancers, but its role in hepatocellular carcinoma has not been elucidated. RESULTS We confirmed that HOXB4 was downregulated in hepatocellular carcinoma tissues and lower HOXB4 expression associated with poor prognosis. Gain- and loss-of function experiments were performed to understand the functional consequences. We revealed that HOXB4 overexpression inhibited proliferation and metastasis of hepatocellular carcinoma cells, accompanied with the decrease in epithelial-mesenchymal transition and increase in cell apoptosis. Database analysis showed that HOXB4 was positively correlated with the immune infiltration. PD-L1 expression was decreased in HOXB4 overexpressed hepatocellular carcinoma cells. HOXB4 overexpression was confirmed to inhibit the progression of hepatocellular carcinoma and promote T cell infiltration in vivo. N6-methyladenosine (m6A) modification was implicated in the tumorigenesis. RNA-seq analysis showed that HOXB4 overexpression modulated METTL7B expression. With the performance of dual-luciferase reporter, ChIP, and DNA pulldown assays, we revealed that HOXB4 binding to METTL7B promoter and inhibited its mRNA expression. The increased aggressiveness of hepatocellular carcinoma cells and the enhanced immune escape, triggered by HOXB4 knockdown, were inhibited via METTL7B downregulation. Methylated RNA immunoprecipitation assay displayed that METTL7B controlled the mRNA decay of TKT in m6A methylation. METTL7B overexpression increase the expression of TKT, ultimately promoting hepatocellular carcinoma progression and immune evasion. CONCLUSIONS HOXB4 mediated the malignant phenotypes and modulated the immune evasion via METTL7B/TKT axis. The HOXB4/METTL7B cascade and its downstream changes might be novel targets for blocking hepatocellular carcinoma progression.
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Affiliation(s)
- Enshuang Guo
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Lei Li
- Department of Osteology, Yellow River Central Hospital of the Yellow River Conservancy Commission, Zhengzhou, 450003, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yongjian Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lu Bai
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Weiwei Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qiuyue Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Huifen Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Precision Medicine Center, Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hongqiang Liu
- Department of Emergency, Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou, 450002, China
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Chen W, Tan M, Zhang H, Gao T, Ren J, Cheng S, Chen J. Signaling molecules in the microenvironment of hepatocellular carcinoma. Funct Integr Genomics 2024; 24:146. [PMID: 39207523 DOI: 10.1007/s10142-024-01427-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Hepatocellular carcinoma (HCC) is a major fatal cancer that is known for its high recurrence and metastasis. An increasing number of studies have shown that the tumor microenvironment is closely related to the metastasis and invasion of HCC. The HCC microenvironment is a complex integrated system composed of cellular components, the extracellular matrix (ECM), and signaling molecules such as chemokines, growth factors, and cytokines, which are generally regarded as crucial molecules that regulate a series of important processes, such as the migration and invasion of HCC cells. Considering the crucial role of signaling molecules, this review aims to elucidate the regulatory effects of chemokines, growth factors, and cytokines on HCC cells in their microenvironment to provide important references for clarifying the development of HCC and exploring effective therapeutic targets.
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Affiliation(s)
- Wanjin Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Ming Tan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Hui Zhang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Tingting Gao
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Jihua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Shengtao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
- College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China.
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Li K, Yang B, Du Y, Ding Y, Shen S, Sun Z, Liu Y, Wang Y, Cao S, Ren W, Wang X, Li M, Zhang Y, Wu J, Zheng W, Yan W, Li L. The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer. Bone Res 2024; 12:47. [PMID: 39191757 PMCID: PMC11349752 DOI: 10.1038/s41413-024-00350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 06/09/2024] [Accepted: 07/12/2024] [Indexed: 08/29/2024] Open
Abstract
While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.
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Affiliation(s)
- Kun Li
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Health Science Center, East China Normal University, Shanghai, 200241, China
- Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China
| | - Bo Yang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Du
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yi Ding
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Shihui Shen
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
- Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China
| | - Zhengwang Sun
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yun Liu
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yuhan Wang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Siyuan Cao
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Wenjie Ren
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiangyu Wang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mengjuan Li
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yunpeng Zhang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Juan Wu
- Department of Pharmacy The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Wei Zheng
- Orthopaedic Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
- Department of Orthopedics, General Hospital of Western Theater Command, Chengdu, 610000, China.
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, P. R. China.
| | - Wangjun Yan
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Lei Li
- Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China.
- School of Life Sciences, East China Normal University, Shanghai, 200241, China.
- Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China.
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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Cheng X, Luo J, Cao J. Identification of HOXC Gene Family as Prognostic and Immune-Related Biomarkers in Breast Cancer Through mRNA Transcriptional Profile and Experimental Validation. Biochem Genet 2024:10.1007/s10528-024-10884-5. [PMID: 38995528 DOI: 10.1007/s10528-024-10884-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Breast cancer (BC) is the most common malignancy in women worldwide, and more effective biomarkers are urgently needed for the prevention and treatment of BC. Our study aimed to investigate the role of the HOXC gene family (HOXCs) and its relationship with the immune response in BC. The differential expression of HOXCs and its clinical prognostic significance in BC were explored using bioinformatics analysis, and the cBioPortal database was used to evaluate the genetic mutation profile of the HOXCs in BC. The results indicated that the expression levels of HOXC4, 10, 11, 12, and 13 were significantly increased in BC tissues compared with the normal tissues, and expressions of these genes were closely associated with BC stage, among them, high expression levels of HOXC10 and HOXC13 predicted poor outcome in BC patients. In addition, to elucidate the essential role of HOXCs in the tumor microenvironment and immunotherapeutic response of BC, the impact of HOXCs on the regulation of immune infiltration in BC was comprehensively assessed. The result showed that HOXC10 and HOXC13 expressions were significantly positively linked with the infiltration levels of CD8+T cell and M1 macrophage, while they were negatively related to Mast and Natural killer cells, suggesting the important influence of HOXCs on regulating tumor immunity in BC patients. Lastly, the RT-qPCR assay was employed to validate HOXCs expression in samples of BC patients. In conclusion, HOXCs may be a promising prognostic indicator and could regulate the immune infiltration in BC patients, thus being a promising targeted immunotherapy for BC.
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Affiliation(s)
- Xiongtao Cheng
- Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jie Luo
- Department of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, China
| | - Jianxiong Cao
- Department of Oncology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
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Liu C, Li K, Ding W, Tang X, Wu Z, Zhu X, Gong W, Zhao H. LINC01535 promotes hepatocellular carcinoma proliferation and metastasis by regulating the miR-214-3p/VASP axis. J Cancer 2024; 15:3809-3824. [PMID: 38911365 PMCID: PMC11190762 DOI: 10.7150/jca.91756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/02/2024] [Indexed: 06/25/2024] Open
Abstract
Background: Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are associated with the development and progression of several carcinomas, including hepatocellular carcinoma (HCC). However, the role of LINC01535 in HCC is still unknown. Materials and methods: In this study, RNA-seq, CCK-8, colony formation, wound healing, Transwell and tumor xenograft assays were used to explore the function of LINC01535 in the proliferation and metastasis of HCC in vitro and in vivo. Fluorescence in situ hybridization (FISH) assay, bioinformatics analysis, dual-luciferase assay, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis were used to reveal the interactions of LINC01535, miR-214-3p and VASP. Results: LINC01535 was overexpressed in HCC tissues and HCC cell lines. Gain- and loss-of-function studies revealed that LINC01535 could promote HCC cell proliferation, migration and invasion both in vitro and in vivo. In addition, upregulation of LINC01535 significantly decreased the expression of microRNA-214-3p (miR-214-3p), which was found closely associated with suppressing tumor progression. Moreover, VASP was identified as a direct downstream target gene of miR-214-3p. LINC01535 positively regulated VASP expression by sponging miR-214-3p, and VASP overexpression activated the PI3K/AKT signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT) in HCC. Conclusions: Our study first found that LINC01535 promoted HCC progression by regulating its downstream target, the miR-214-3p/VASP axis, via the PI3K/AKT signaling pathway. The function and novel regulatory mechanism of LINC01535 may provide a valuable target for the diagnosis and treatment of HCC patients.
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Affiliation(s)
- Chunjiang Liu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Kuan Li
- Department of Hepatobiliary Surgery, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, 215000, China
| | - Wenzhou Ding
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
| | - Xiaoqi Tang
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Zhifeng Wu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Xin Zhu
- Department of General Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Wanwan Gong
- Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, 214002, China
| | - Hui Zhao
- Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, 214002, China
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Khawkhiaw K, Panaampon J, Imemkamon T, Saengboonmee C. Interleukin-1β: Friend or foe for gastrointestinal cancers. World J Gastrointest Oncol 2024; 16:1676-1682. [PMID: 38764841 PMCID: PMC11099428 DOI: 10.4251/wjgo.v16.i5.1676] [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] [Received: 12/27/2023] [Revised: 02/17/2024] [Accepted: 03/19/2024] [Indexed: 05/09/2024] Open
Abstract
Gastrointestinal (GI) cancer is a malignancy arising in the digestive system and accounts for approximately a third of increasing global cancer-related mortality, especially in the colorectum, esophagus, stomach, and liver. Interleukin-1β (IL-1β) is a leukocytic pyrogen recognized as a tumor progression-related cytokine. IL-1β secretion and maturation in inflammatory responses could be regulated by nuclear factor-kappaB-dependent expression of NLR family pyrin domain containing 3, inflammasome formation, and activation of IL-1 converting enzyme. Several studies have documented the pro-tumorigenic effects of IL-1β in tumor microenvironments, promoting proliferation and metastatic potential of cancer cells in vitro and tumorigenesis in vivo. The application of IL-1β inhibitors is also promising for targeted therapy development in some cancer types. However, as a leukocytic pro-inflammatory cytokine, IL-1β may also possess anti-tumorigenic effects and be type-specific in different cancers. This editorial discusses the up-to-date roles of IL-1β in GI cancers, including underlying mechanisms and downstream signaling pathways. Understanding and clarifying the roles of IL-1β would significantly benefit future therapeutic targeting and help improve therapeutic outcomes in patients suffering from GI cancer.
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Affiliation(s)
- Kullanat Khawkhiaw
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Jutatip Panaampon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, United States
- Department of Medicine, Harvard Medical School, Boston, MA 02215, United States
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Thanit Imemkamon
- Department of Medicine, Faculty of Medicine, Khon Kaen Univsersity, Khon Kaen 40002, Thailand
| | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
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10
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Su QY, Li HC, Jiang XJ, Jiang ZQ, Zhang Y, Zhang HY, Zhang SX. Exploring the therapeutic potential of regulatory T cell in rheumatoid arthritis: Insights into subsets, markers, and signaling pathways. Biomed Pharmacother 2024; 174:116440. [PMID: 38518605 DOI: 10.1016/j.biopha.2024.116440] [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: 01/21/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 03/24/2024] Open
Abstract
Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.
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Affiliation(s)
- Qin-Yi Su
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Huan-Cheng Li
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Xiao-Jing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Zhong-Qing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Yan Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - He-Yi Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Sheng-Xiao Zhang
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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Wang L, Qiao C, Han L, Wang X, Miao J, Cao L, Huang C, Wang J. HOXD3 promotes the migration and angiogenesis of hepatocellular carcinoma via modifying hepatocellular carcinoma cells exosome-delivered CCR6 and regulating chromatin conformation of CCL20. Cell Death Dis 2024; 15:221. [PMID: 38493218 PMCID: PMC10944507 DOI: 10.1038/s41419-024-06593-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 03/18/2024]
Abstract
Angiogenesis plays an essential role in the microenvironment of hepatocellular carcinoma (HCC). HOXD3 is involved in the metastasis and invasion of HCC cells; Whereas the underlying molecular mechanisms in the microenvironment of HCC remain unknown. Wound healing, transwell invasion, tube formation and spheroid sprouting assays were carried out to identify the effects of HCC-HOXD3-exosomes and genes on the migration of HCC cells. ChIP-PCR was applied to test the binding region of HOXD3 on CCR6, Med15, and CREBBP promoter. Exosome isolation and mRNA-seq were applied to examine the morphological characteristics of exosomes and the contained mRNA in exosomes. Co-IP and Immunofluorescence assays were used to demonstrate the role of CREBBP in the chromatin conformation of CCL20. The nude mice were used to identify the function of genes in regulating migration of HCC in vivo. In this study, integrated cellular and bioinformatic analyses revealed that HOXD3 targeted the promoter region of CCR6 and induced its transcription. CCR6 was delivered by exosomes to endothelial cells and promoted tumour migration. Overexpression of CCR6 promoted metastasis, invasion in HCCs and angiogenesis in endothelial cells (ECs), whereas its downregulation suppressed these functions. The role of HOXD3 in the metastasis and invasion of HCC cells was reversed after the suppression of CCR6. Furthermore, CCL20 was demonstrated as the ligand of CCR6, and its high expression was found in HCC tissues and cells, which was clinically associated with the poor prognosis of HCC. Mechanistically, HOXD3 targets the promoter regions of CREBBP and Med15, which affect CCL20 chromatin conformation by regulating histone acetylation and expression of Pol II to enhance the migration of HCCs. This study demonstrated the function of the HOXD3-CREBBP/Med15-CCL20-CCR6 axis in regulating invasion and migration in HCC, thus providing new therapeutic targets for HCC.
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Affiliation(s)
- Lumin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, P. R. China.
| | - Chenyang Qiao
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, P. R. China
| | - Lili Han
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, P. R. China
| | - Xiaofei Wang
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, P. R. China
| | - Jiyu Miao
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, P. R. China
| | - Li Cao
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, P. R. China
| | - Chen Huang
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, P. R. China.
| | - Jinhai Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, P. R. China.
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Zhou Y, Huang Q, Wu C, Xu Y, Guo Y, Yuan X, Xu C, Zhou L. m 6A‑modified HOXC10 promotes HNSCC progression via co‑activation of ADAM17/EGFR and Wnt/β‑catenin signaling. Int J Oncol 2024; 64:10. [PMID: 38063205 PMCID: PMC10734666 DOI: 10.3892/ijo.2023.5598] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/12/2023] [Indexed: 12/18/2023] Open
Abstract
The homeobox (HOX) gene family plays a fundamental role in carcinogenesis. However, the oncogenic mechanism of HOXC10 in head and neck squamous cell carcinoma (HNSCC) remains unclear. In the present study, it was revealed that HOXC10 expression was significantly higher in HNSCC tissues than in adjacent tissues, and a high level of HOXC10 was closely associated with worse clinical outcomes. HOXC10 overexpression promoted HNSCC cell proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, chromatin immunoprecipitation sequencing revealed that HOXC10 drove the transcriptional activation of a disintegrin and metalloproteinase 17 (ADAM17), and the ADAM17/epidermal growth factor receptor (EGFR)/ERK1/2 signaling pathway facilitating the proliferation of HNSCC. Furthermore, mass spectrometric analysis indicated that HOXC10 interacted with ribosomal protein S15A (RPS15A) and enhanced RPS15A protein expression, activating the Wnt/β‑catenin pathway and contributing to invasion and metastasis of HNSCC. Additionally, the methylated RNA immune precipitation and RNA antisense purification assays showed that N6‑methyladenosine (m6A) writer, methyltransferase‑like 3, catalyzed m6A modification of the HOXC10 transcript, m6A reader insulin like growth factor 2 mRNA binding protein (IGF2BP)1 and IGF2BP3 involved in recognizing and stabilizing m6A‑tagged HOXC10 mRNA. In summary, the present study identified HOXC10 as a promising candidate oncogene in HNSCC. The m6A modification‑mediated HOXC10 promoted proliferation, migration, and invasion of HNSCC through co‑activation of ADAM17/EGFR and Wnt/β‑catenin signaling, providing a novel diagnostic and prognostic biomarker and a potential therapeutic target for HNSCC.
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Affiliation(s)
- Yujuan Zhou
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Qiang Huang
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Chunping Wu
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Ye Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Yang Guo
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Xiaohui Yuan
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Chengzhi Xu
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
| | - Liang Zhou
- Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai 200031, P.R. China
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Fang W, Liu J, Zhang F, Pang C, Li X. A novel cholesterol metabolism-related ferroptosis pathway in hepatocellular carcinoma. Discov Oncol 2024; 15:7. [PMID: 38191842 PMCID: PMC10774324 DOI: 10.1007/s12672-023-00822-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 11/09/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Emerging studies have reported the contribution of cholesterol to hepatocellular carcinoma (HCC) progression. However, the specific role and mechanism of cholesterol metabolism on spontaneous and progressive HCC development from the point of view of ferroptosis are still worth exploring. The present study aimed to reveal a novel mechanism of cholesterol metabolism-related ferroptosis in hepatocellular carcinoma cells. METHODS Two microarray datasets (GSE25097, GSE22058) related to HCC were downloaded from Gene Expression Omnibus (GEO) datasets. Metabolomics analysis was performed by ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). The cholesterol-related proteins were downloaded from HMBD. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE25097 was used to identify ferroptosis-related genes, and GSE22058 was used to verify results. During these processes, chemical-protein interaction (CPI), protein-protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Multivariate logistic regression analysis was used to test the associated pathway. RESULTS We identified 8 differentially expressed ferroptosis-related genes (HAMP, PTGS2, IL1B, ALOX15B, CDKN2A, RRM2, NQO1 and KIF20A) and 4 differentially expressed cholesterol-related genes (LCAT, CH25H, CEL and CYP7A1). Furthermore, based on the predicted results with STITCH, we identified indomethacin and IL1B as the essential node for cholesterol-mediated ferroptosis in hepatocellular carcinoma cell. Multivariate logistic regression analysis showed the activities of plasma IL1B in liver cancer patients enrolled have been significantly affected by the level of plasma cholesterol (P < 0.001) and the test result of IL1B is a predictor variable causing the changes of serum Fe levels (P < 0.001). CONCLUSIONS Our findings shed new light on the association between cholesterol metabolism and ferroptosis in HCC, and suggest that IL1B is the necessary node for cholesterol to lead to ferroptosis process in HCC. Also, we identified the potential role of indomethacin in adjuvant therapy of HCC with complications of abnormal cholesterol metabolism.
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Affiliation(s)
- Weiwei Fang
- Department of Blood Transfusion, State Key Laboratory of Molecular Oncology, National Clinical Research Center for Cancer/Cancer Hospital, Institute/University, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Nanli Road, Pan Jia Yuan, Beijing, 100021, China
| | - Jianyong Liu
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Institute/University/Hospital, Chinese Academy of Medical Sciences, No.1, Dahua Road, Dong Dan, 100730, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Fanguo Zhang
- Excellence Future International Consulting Co, Ltd, Beijing, 101100, China
| | - Cheng Pang
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Institute/University/Hospital, Chinese Academy of Medical Sciences, No.1, Dahua Road, Dong Dan, 100730, Beijing, China.
| | - Xiying Li
- Department of Blood Transfusion, State Key Laboratory of Molecular Oncology, National Clinical Research Center for Cancer/Cancer Hospital, Institute/University, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Nanli Road, Pan Jia Yuan, Beijing, 100021, China.
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Gui J, Zhou H, Wan H, Yang D, Liu Q, Zhu L, Mi Y. The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors. Curr Cancer Drug Targets 2024; 24:477-489. [PMID: 37962042 PMCID: PMC11092557 DOI: 10.2174/0115680096262439231023110106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/06/2023] [Accepted: 09/06/2023] [Indexed: 11/15/2023]
Abstract
Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.
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Affiliation(s)
- Jiandong Gui
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Hangsheng Zhou
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Hongyuan Wan
- Wuxi School of Medicine, Jiangnan University, 1800 Lihudadao, Wuxi, 214122, Jiangsu Province, China
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Dongjie Yang
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Qing Liu
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
- Huadong Sanatorium, 67 Dajishan, Wuxi 214122, Jiangsu Province, China
| | - Lijie Zhu
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
| | - Yuanyuan Mi
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, 214122, Jiangsu Province, China
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15
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Tan X, Li Z, Xie H, Chen J, Xiao J, Zhi Y, Mo H, Huang Y, Liu A. Pan-cancer analysis of homeodomain-containing gene C10 and its carcinogenesis in lung adenocarcinoma. Aging (Albany NY) 2023; 15:15243-15266. [PMID: 38154103 PMCID: PMC10781453 DOI: 10.18632/aging.205348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/07/2023] [Indexed: 12/30/2023]
Abstract
We found elevated homeodomain-containing gene C10 (HOXC10) showed dual roles in cancers' prognosis. Some signal pathways associated with tumor were totally positively enriched in HOXC10 for whole cancers. On the contrary, Notch signaling, Wnt-beta catenin signaling, myogenesis, and Hedgehog signaling were almost negatively enriched in HOXC10. Some pathways showed dual roles such as Kras signaling, interferon gram and alpha response, IL6/JAK/STAT3, IL2/STAT5 signaling. HOXC10 was associated with tumor mutation burden and microsatellite instability. HOXC10 also was associated with tumor microenvironment and immune status. HOXC10 was negatively associated with immune score in most cancers except colon adenocarcinoma. The correlations of HOXC10 with immune-related genes presented dual roles in different cancers. Results from our clinical samples indicated that HOXC10 was an independent predictor for distant metastasis-free survival in lung adenocarcinoma (LUAD). Notably, the high levels of HOXC10 were positively correlated with the expression of angiogenic markers, vascular endothelial growth factor and microvessel density, and the number of CTC clusters. Our results demonstrated that aberrant expression happened in most cancers, which also affected the clinical prognosis and involved in progression via multiple signal pathways cancers. HOXC10 overexpression plays an important role in the aggression and metastasis in LUAD, which indicated a potential therapeutic target and an independent factor for the prognosis for LUAD patients.
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Affiliation(s)
- Xiangyuan Tan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Zhanzhan Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Huayan Xie
- Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou 510000, Heyuan, China
| | - Jiarong Chen
- Department of Oncology, Jiangmen Central Hospital, Jiangmen 529030, Guangdong, China
| | - Jian Xiao
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yaofeng Zhi
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen 529030, Guangdong, China
| | - Haixin Mo
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen 529030, Guangdong, China
| | - Yanming Huang
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen 529030, Guangdong, China
| | - Aibin Liu
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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16
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Chen HJ, Huang TX, Jiang YX, Chen X, Wang AF. Multifunctional roles of inflammation and its causative factors in primary liver cancer: A literature review. World J Hepatol 2023; 15:1258-1271. [PMID: 38223416 PMCID: PMC10784815 DOI: 10.4254/wjh.v15.i12.1258] [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] [Received: 08/21/2023] [Revised: 11/06/2023] [Accepted: 11/24/2023] [Indexed: 12/25/2023] Open
Abstract
Primary liver cancer is a severe and complex disease, leading to 800000 global deaths annually. Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma (HCC). Patients with viral hepatitis, alcoholic hepatitis, and steatohepatitis symptoms are at higher risk of developing HCC. However, not all inflammatory factors have a pathogenic function in HCC development. The current study describes the process and mechanism of hepatitis development and its progression to HCC, particularly focusing on viral hepatitis, alcoholic hepatitis, and steatohepatitis. Furthermore, the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.
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Affiliation(s)
- Hong-Jin Chen
- Department of Pharmacology, School of Basic Medical Sciences, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ting-Xiong Huang
- School of Clinical Medical, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yu-Xi Jiang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
| | - Xiong Chen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China
| | - Ai-Fang Wang
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China.
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Fang Z, Jiang J, Zheng X. Interleukin-1 receptor antagonist: An alternative therapy for cancer treatment. Life Sci 2023; 335:122276. [PMID: 37977354 DOI: 10.1016/j.lfs.2023.122276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/03/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
The interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and a naturally occurring antagonist of the IL-1 receptor. It effectively counteracts the IL-1 signaling pathway mediated by IL-1α/β. Over the past few decades, accumulating evidence has suggested that IL-1 signaling plays an essential role in tumor formation, growth, and metastasis. Significantly, anakinra, the first United States Food and Drug Administration (FDA)-approved IL-1Ra drug, has demonstrated promising antitumor effects in animal studies. Numerous clinical trials have subsequently incorporated anakinra into their cancer treatment protocols. In this review, we comprehensively discuss the research progress on the role of IL-1 in tumors and summarize the significant contribution of IL-1Ra (anakinra) to tumor immunity. Additionally, we analyze the potential value of IL-1Ra as a biomarker from a clinical perspective. This review is aimed to highlight the important link between inflammation and cancer and provide potential drug targets for future cancer therapy.
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Affiliation(s)
- Zhang Fang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China.
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China; Institute for Cell Therapy of Soochow University, Changzhou, Jiangsu, China.
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18
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Zheng N, Wei J, Wu D, Xu Y, Guo J. Master kinase PDK1 in tumorigenesis. Biochim Biophys Acta Rev Cancer 2023; 1878:188971. [PMID: 37640147 DOI: 10.1016/j.bbcan.2023.188971] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/13/2023] [Accepted: 08/05/2023] [Indexed: 08/31/2023]
Abstract
3-phosphoinositide-dependent protein kinase 1 (PDK1) is considered as master kinase regulating AGC kinase family members such as AKT, SGK, PLK, S6K and RSK. Although autophosphorylation regulates PDK1 activity, accumulating evidence suggests that PDK1 is manipulated by many other mechanisms, including S6K-mediated phosphorylation, and the E3 ligase SPOP-mediated ubiquitination and degradation. Dysregulation of these upstream regulators or downstream signals involves in cancer development, as PDK1 regulating cell growth, metastasis, invasion, apoptosis and survival time. Meanwhile, overexpression of PDK1 is also exposed in a plethora of cancers, whereas inhibition of PDK1 reduces cell size and inhibits tumor growth and progression. More importantly, PDK1 also modulates the tumor microenvironments and markedly influences tumor immunotherapies. In summary, we comprehensively summarize the downstream signals, upstream regulators, mouse models, inhibitors, tumor microenvironment and clinical treatments for PDK1, and highlight PDK1 as a potential cancer therapeutic target.
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Affiliation(s)
- Nana Zheng
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Jiaqi Wei
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China.
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China.
| | - Jianping Guo
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
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He X, Wang H, Wang R, Li Y, Li S, Cao X, Xu J. HOXC10 promotes esophageal squamous cell carcinoma progression by targeting FOXA3 and indicates poor survival outcome. Heliyon 2023; 9:e21056. [PMID: 37876483 PMCID: PMC10590975 DOI: 10.1016/j.heliyon.2023.e21056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/07/2023] [Accepted: 10/13/2023] [Indexed: 10/26/2023] Open
Abstract
Background Esophageal cancer is one of the most unknown and deadliest cancers in the world. Although recent studies have identified some mutations linked to the development of squamous cell carcinoma of the esophagus (ESCC), the specific role of HomeoboxC10 (HOXC10) in the pathogenesis still requires further investigation. Methods Agilent mRNA single-channel gene expression was employed to identify genome-wide gene signatures in ESCC. These signatures were also verified using qRT-PCR, immunohistochemical staining as well as Western blot. The biological functions of HOXC10 were further investigated through cellular studies conducted on ESCC cells. Survival analysis was conducted utilizing the Kaplan-Meier method. The GEPIA database and the STRING website were utilized to predict the potential targets that bind to HOXC10. Co-immunoprecipitation assays were performed to investigate the binding interaction between HOXC10 and Forkhead Box A3 (FOXA3). Animal models were established to analyze the effects of HOXC10 silencing on tumorigenesis in vivo. Results The expression levels of HOXC10 mRNA were found to be upregulated in ESCC. Survival analysis revealed a significant association between abnormally elevated levels of HOXC10 mRNA and an unfavorable prognosis in patients with ESCC. In vitro studies revealed that the knockdown of HOXC10 expression resulted in the inhibition of the proliferation, invasion, and migrating ability of ESCC cells through the upregulation of FOXA3. Furthermore, tumor-bearing mouse models studies demonstrated that HOXC10 through knockdown techniques significantly suppressed ESCC tumor growth. HOXC10 was found to enhance the activation of the MAPK signaling pathway by regulating FOXA3 in ESCC cells. Conclusion These results support a key role for HOXC10 in the tumorigenesis of ESCC by upregulating FOXA3 via the MAPK pathway and highlight its potential as a promising diagnostic and prognostic marker for ESCC.
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Affiliation(s)
- Xiaoting He
- Oncology Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Huiyu Wang
- Oncology Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Runjie Wang
- Oncology Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Yuting Li
- Oncology Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China
| | - Suqing Li
- General Surgery Department, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210012, China
| | - Xiufeng Cao
- General Surgery Department, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210012, China
| | - Junying Xu
- Oncology Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China
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20
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Li M, Guo Q, Shi Q, Rao Y, Dong Y, Chen F, Qi X. M 6A-mediated upregulation of HOXC10 promotes human hepatocellular carcinoma development through PTEN/AKT/mTOR signaling pathway. Discov Oncol 2023; 14:175. [PMID: 37733108 PMCID: PMC10514025 DOI: 10.1007/s12672-023-00786-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023] Open
Abstract
Human Hox genes (Homeobox) play a crucial role in embryonic development and cancer. The HOXC10 gene, a member of the HOX family, has been reported abnormally expressed in several cancers. However, the association between HOXC10 and hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, tissue microarray cohort data showed that high levels of HOXC10 expression predicted a poor survival in HCC patients. Meanwhile, HOXC10 was significantly upregulated in the Huh7 cell line compared with the well differentiated cell line HepG2 and human normal liver cells. Functionally, silencing HOXC10 in Huh7 cells inhibited cell proliferation, increased apoptosis, and inhibited invasion and migration of HCC cells. HOXC10 overexpression in HepG2 cells increased cell proliferation, decreased apoptosis, and increased invasion and migration of HCC cells. In the HepG2 xenograft models, HOXC10 increased the tumor volume and weight compared with control. Mechanistically, the m6A modification of HOXC10 by METTL3 enhanced its expression by enhancing its mRNA stability. Both the in vitro and in vivo results showed that overexpressed HOXC10 activated the PTEN/AKT/mTOR pathway. In summary, the findings highlight the importance of HOXC10 in the regulation of HCC progression. HOXC10 is potentially a future therapeutic target for HCC treatment.
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Affiliation(s)
- Miao Li
- Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, China
| | - Qianwen Guo
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, 155 Nanjing Bei Street, Shenyang, 110001, China
| | - Qian Shi
- Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, China
| | - Yanzhi Rao
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, 155 Nanjing Bei Street, Shenyang, 110001, China
| | - Yixin Dong
- Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang, 110122, China
| | - Fangjie Chen
- Department of Medical Genetics, School of Life Sciences, China Medical University, No.77 Puhe Road, Shenyang, 110122, China.
| | - Xun Qi
- Key Laboratory of Diagnostic Imaging and Interventional Radiology of Liaoning Province, Department of Radiology, The First Hospital of China Medical University, 155 Nanjing Bei Street, Shenyang, 110001, China.
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21
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Krizanac M, Mass Sanchez PB, Schröder SK, Weiskirchen R, Asimakopoulos A. Lipid-Independent Regulation of PLIN5 via IL-6 through the JAK/STAT3 Axis in Hep3B Cells. Int J Mol Sci 2023; 24:ijms24087219. [PMID: 37108378 PMCID: PMC10138877 DOI: 10.3390/ijms24087219] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/04/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Perilipin 5 (PLIN5) is a lipid droplet coat protein that is highly expressed in oxidative tissues such as those of muscles, the heart and the liver. PLIN5 expression is regulated by a family of peroxisome proliferator-activated receptors (PPARs) and modulated by the cellular lipid status. So far, research has focused on the role of PLIN5 in the context of non-alcoholic fatty liver disease (NAFLD) and specifically in lipid droplet formation and lipolysis, where PLIN5 serves as a regulator of lipid metabolism. In addition, there are only limited studies connecting PLIN5 to hepatocellular carcinoma (HCC), where PLIN5 expression is proven to be upregulated in hepatic tissue. Considering that HCC development is highly driven by cytokines present throughout NAFLD development and in the tumor microenvironment, we here explore the possible regulation of PLIN5 by cytokines known to be involved in HCC and NAFLD progression. We demonstrate that PLIN5 expression is strongly induced by interleukin-6 (IL-6) in a dose- and time-dependent manner in Hep3B cells. Moreover, IL-6-dependent PLIN5 upregulation is mediated by the JAK/STAT3 signaling pathway, which can be blocked by transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α). Furthermore, IL-6-mediated PLIN5 upregulation changes when IL-6 trans-signaling is stimulated through the addition of soluble IL-6R. In sum, this study sheds light on lipid-independent regulation of PLIN5 expression in the liver, making PLIN5 a crucial target for NAFLD-induced HCC.
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Affiliation(s)
- Marinela Krizanac
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
| | - Paola Berenice Mass Sanchez
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
| | - Sarah K Schröder
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
| | - Anastasia Asimakopoulos
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
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22
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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Hou X, Zhang Z, Ma Y, Jin R, Yi B, Yang D, Ma L. Mechanism of hydroxysafflor yellow A on acute liver injury based on transcriptomics. Front Pharmacol 2022; 13:966759. [PMID: 36120318 PMCID: PMC9478418 DOI: 10.3389/fphar.2022.966759] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: To investigate how Hydroxysafflor yellow A (HSYA) effects acute liver injury (ALI) and what transcriptional regulatory mechanisms it may employ.Methods: Rats were randomly divided into five groups (n = 10): Control, Model, HSYA-L, HSYA-M, and HSYA-H. In the control and model groups, rats were intraperitoneally injected with equivalent normal saline, while in the HSYA groups, they were also injected with different amounts of HSYA (10, 20, and 40 mg/kg/day) once daily for eight consecutive days. One hour following the last injection, the control group was injected into the abdominal cavity with 0.1 ml/100 g of peanut oil, and the other four groups got the same amount of a peanut oil solution containing 50% CCl4. Liver indexes were detected in rats after dissection, and hematoxylin and eosin (HE) dyeing was utilized to determine HSYA’s impact on the liver of model rats. In addition, with RNA-Sequencing (RNA-Seq) technology and quantitative real-time PCR (qRT-PCR), differentially expressed genes (DEGs) were discovered and validated. Furthermore, we detected the contents of anti-superoxide anion (anti-O2−) and hydrogen peroxide (H2O2), and verified three inflammatory genes (Icam1, Bcl2a1, and Ptgs2) in the NF-kB pathway by qRT-PCR.Results: Relative to the control and HSYA groups, in the model group, we found 1111 DEGs that were up-/down-regulated, six of these genes were verified by qRT-PCR, including Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, and Creld2, indicated that these genes were obviously involved in the regulation of HSYA in ALI model. Membrane rafts, membrane microdomains, inflammatory response, regulation of cytokine production, monooxygenase activity, and iron ion binding were significantly enriched in GO analysis. KEGG analysis revealed that DEGs were primarily enriched for PPAR, retinol metabolism, NF-kB signaling pathways, etc. Last but not least, compared with the control group, the anti-O2− content was substantially decreased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were considerably elevated in the model group. Compared with the model group, the anti-O2− content was substantially increased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were substantially decreased in the HSYA group (p < 0.05).Conclusion: HSYA could improve liver function, inhibit oxidative stress and inflammation, and improve the degree of liver tissue damage. The RNA-Seq results further verified that HSYA has the typical characteristics of numerous targets and multiple pathway. Protecting the liver from damage by regulating the expression of Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, Creld2, and the PPAR, retinol metabolism, NF-kappa B signaling pathways.
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24
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Li W, Li Y, Li P, Ma F, Liu M, Kong S, Xue H. miR-200a-3p- and miR-181-5p-Mediated HOXB5 Upregulation Promotes HCC Progression by Transcriptional Activation of EGFR. Front Oncol 2022; 12:822760. [PMID: 35847904 PMCID: PMC9277860 DOI: 10.3389/fonc.2022.822760] [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: 12/20/2021] [Accepted: 05/02/2022] [Indexed: 12/29/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) remains a worldwide burden. However, the mechanisms behind the malignant biological behavior of HCC remain unclear. The homeobox (HOX) family could act as either promoters or suppressors in different kinds of malignancies. Our study discovered the role of HOXB5 in regulating HCC progression. Methods The HOXB5 expression was assessed by RT-PCR analysis in human HCC samples and cell lines. HOXB5 transcriptional regulation of the EGFR was verified by the luciferase reporter assay and chromatin immunoprecipitation experiment. The oncogenic role of HOXB5 in HCC progression was analyzed by CCK8, colony-forming, and transwell assays. Results Upregulation of HOXB5 was found in human HCC, and was strongly correlated with HCC tumor size, tumor-nodule metastasis, TNM stage, and relatively unfavorable OS and DFS. Ectopic expression of HOXB5 promoted the capacity of cell growth and clonogenicity, while the inhibition of HOXB5 decreased the proliferation and clonogenicity potential in vitro by CCK8 and colony-forming assays. In addition, HOXB5 also promoted cell migration by transwell experiment. Mechanism studies elucidated that HOXB5 triggers HCC progression via direct transcriptional activation of EGFR. The upregulation of HOXB5 is regulated by miR-200a-3p and miR-181-5p. Transfection of miR-200a-3p and miR-181-5p mimics blocked the cell proliferation and migration regulated by HOXB5, while overexpression of the 3′-UTR mutant HOXB5 abolished the suppressive effect of miR-200a-3p and miR-181-5p, but not the wild-type HOXB5. Conclusion HOXB5 is a promising prognostic factor in human HCC. Targeting miR-200a-3p and the miR-181-5p/HOXB5/EGFR signaling pathway may provide new options for the treatment strategies of HCC.
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Affiliation(s)
- Weizhi Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yingchao Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peijie Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fuquan Ma
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengying Liu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuzhen Kong
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Xue
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Wu K, Liu Z, Dong C, Gu S, Li L, Wang W, Zhou Y. MiR-4739 inhibits the malignant behavior of esophageal squamous cell carcinoma cells via the homeobox C10/vascular endothelial growth factor A/phosphatidylinositol 3-kinase/AKT pathway. Bioengineered 2022; 13:14066-14079. [PMID: 35730500 PMCID: PMC9342426 DOI: 10.1080/21655979.2022.2068783] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Esophageal cancer is a lethal disease, and emerging evidence has shown that microRNAs are involved in its development, progression, and clinical outcome. MicroRNAs are potential biomarkers for esophageal squamous cell carcinoma (ESCC), and may be useful in advanced RNA therapy for ESCC. This study was conducted to evaluate the molecular mechanism of miR-4739 in ESCC. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to measure RNA and protein levels. Transwell assay, Cell Counting Kit-8 assay, cytometry analysis, and human umbilical vein endothelial cell tube formation assay were conducted to determine the molecular function of miR-4739 in ESCC. Potential targets of miR-4739 were predicted using bioinformatics tools and confirmed in ESCC cells using a luciferase reporter and RNA pulldown assay. Finally, we performed immunohistochemistry to evaluate the effects of administering agomir-4739 to a mouse model of ESCC. MiR-4739 expression was downregulated in ESCC tissues and cells. MiR-4739 overexpression inhibited cell proliferation, migration, and invasion, and promoted apoptosis of ESCC cells. Furthermore, vascular endothelial growth factor A expression was downregulated by miR-4739 mimics in ESCC cells. MiR-4739 negatively regulated homeobox C10 expression. Additionally, agomir-4739 inhibited tumor growth and angiogenesis in vivo. We demonstrated that miR-4739 overexpression exerted an inhibitory effect on ESCC cells by preventing the expression of homeobox C10 via the vascular endothelial growth factor A/phosphatidylinositol 3-kinase/AKT pathway, indicating the potential of this microRNA as a treatment target in ESCC.
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Affiliation(s)
- Kaiqin Wu
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Zhenchuan Liu
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Chenglai Dong
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Shaorui Gu
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Lei Li
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Wenli Wang
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
| | - Yongxin Zhou
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, Jiangsu, China
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Comprehensive Analysis of HOX Family Members as Novel Diagnostic and Prognostic Markers for Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:5758601. [PMID: 35251173 PMCID: PMC8890896 DOI: 10.1155/2022/5758601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/26/2022] [Accepted: 01/29/2022] [Indexed: 11/17/2022]
Abstract
Background. The homeobox (HOX) gene family has been found to be involved in human cancers. However, its involvement in hepatocellular carcinoma (HCC) has not been well documented. Here, we comprehensively evaluated the role of HOXs in HCC. Methods. RNA sequencing profile of TCGA-LIHC and LIRI-JP were obtained from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), respectively. Data of TCGA-LIHC methylation were downloaded from UCSC Xena. Genetic alteration data for the TCGA samples was obtained from cBioPortal and GSCA. The diagnostic efficiency was assessed using ROC curves. The prognostic significance was evaluated by the Kaplan–Meier method and Cox regression analysis. Subsequent functional analysis was performed through the clusterProfiler package. ssGSEA, ESTIMATE, and TIDE algorithms were employed to explore the relationship between HOXs and the HCC microenvironment. Finally, pRRophetic package and NCI-60 cancerous cell lines were applied to estimate anticancer drug sensitivity. Results. The mRNA levels of HOXs in HCC tissues were higher than those of noncancerous tissues and were correlated with poor overall survival (OS). HOXA6, C6, D9, D10, and D13 could serve as independent risk factors for OS. Further functional analysis revealed that these five HOXs regulate the cell proliferation, cell cycle, immune response, and microenvironment composition of HCC. In addition, the aberrant expression and methylation of HOXs is of great value in the diagnosis of HCC. Conclusion. HOXs play crucial roles in HCC and could serve as potential markers for HCC diagnosis and prognosis.
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Dang Y, Yu J, Zhao S, Cao X, Wang Q. HOXA7 promotes the metastasis of KRAS mutant colorectal cancer by regulating myeloid-derived suppressor cells. Cancer Cell Int 2022; 22:88. [PMID: 35183163 PMCID: PMC8858502 DOI: 10.1186/s12935-022-02519-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
KRAS mutation accounts for 30–50% of human colorectal cancer (CRC) cases. Due to the scarcity of effective treatment options, KRAS mutant CRC is difficult to treat in the clinic. Metastasis is still the major cause of the high mortality associated with KRAS mutant CRC, but the exact mechanism remains unclear. Here, we report a unique function of Homeobox 7 (HOXA7) in driving KRAS mutant CRC metastasis and explore therapeutic strategies for subpopulations of patients with this disease.
Methods
The expression of HOXA7 in a human CRC cohort was measured by immunohistochemistry. The function of HOXA7 in KRAS mutant CRC metastasis was analyzed with the cecum orthotopic model.
Results
Elevated HOXA7 expression was positively correlated with lymph node metastasis, distant metastasis, poor tumor differentiation, high TNM stage, and poor prognosis in CRC patients. Furthermore, HOXA7 was an independent prognostic marker in KRAS mutant CRC patients (P < 0.001) but not in KRAS wild-type CRC patients (P = 0.575). Overexpression of HOXA7 improved the ability of KRAS mutant CT26 cells to metastasize and simultaneously promoted the infiltration of myeloid-derived suppressor cells (MDSCs). When MDSC infiltration was blocked by a CXCR2 inhibitor, the metastasis rate of CT26 cells was markedly suppressed. The combination of the CXCR2 inhibitor SB265610 and programmed death-ligand 1 antibody (anti-PD-L1) could largely inhibit the metastasis of KRAS mutant CRC.
Conclusions
HOXA7 overexpression upregulated CXCL1 expression, which promoted MDSC infiltration. Interruption of this loop might provide a promising treatment strategy for HOXA7-mediated KRAS mutant CRC metastasis.
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28
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Zhang H, Zhao H, Wang H, Yin Z, Huang K, Yu M. High PLA2 level is correlated with glioblastoma progression via regulating DNA replication. J Cell Mol Med 2022; 26:1466-1472. [PMID: 35166019 PMCID: PMC8899163 DOI: 10.1111/jcmm.17140] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/21/2021] [Accepted: 12/01/2021] [Indexed: 12/05/2022] Open
Abstract
Phospholipases A2 (PLA2) are a superfamily of enzymes, playing a critical role in the development of various human cancers. However, the mechanism of PLA2 as an oncogene in glioblastoma remains largely unknown. In this study, we explored the effects of PLA2 on glioblastoma and investigated the underlying mechanism. The results showed that PLA2 was highly expressed in glioblastoma. Patients with a high PLA2 level have low overall survival than those with low PLA2 expression. PLA2 overexpression promoted glioblastoma cell proliferation and viability and inhibited cell apoptosis by inducing cell cycle transition from G1 to S stage. Knockdown of PLA2 inhibited tumor growth in the xenograft mice model. In addition, PLA2 knockdown decreased the protein level of MCM2 and MCM5. These findings identify PLA2 as an oncogene in glioblastoma progression and provide a promising strategy to treat glioblastoma in the future.
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Affiliation(s)
- Haiyun Zhang
- Department of Laboratory Medicine, The Sixth People's Hospital of Nantong, Jiangsu, China
| | - Hanwei Zhao
- Department of Critical Care Medicine, 902 Hospital of PLA, Bengbu, China
| | - Hongliang Wang
- Department of Laboratory Medicine, The Sixth People's Hospital of Nantong, Jiangsu, China
| | - Zhongbo Yin
- Department of Laboratory Medicine, The Sixth People's Hospital of Nantong, Jiangsu, China
| | - Kai Huang
- Department of Orthopaedics, Changshu No. 2 People's Hospital (The 5th Clinical Medical College of Yangzhou University), Changshu, China
| | - Minhong Yu
- Department of Laboratory Medicine, The Sixth People's Hospital of Nantong, Jiangsu, China.,Medical Laboratory Department, Daqing people's Hospital of Heilongjiang Province, Daqing, China
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Shenoy US, Adiga D, Kabekkodu SP, Hunter KD, Radhakrishnan R. Molecular implications of HOX genes targeting multiple signaling pathways in cancer. Cell Biol Toxicol 2022; 38:1-30. [PMID: 34617205 PMCID: PMC8789642 DOI: 10.1007/s10565-021-09657-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/10/2021] [Indexed: 11/17/2022]
Abstract
Homeobox (HOX) genes encode highly conserved homeotic transcription factors that play a crucial role in organogenesis and tissue homeostasis. Their deregulation impacts the function of several regulatory molecules contributing to tumor initiation and progression. A functional bridge exists between altered gene expression of individual HOX genes and tumorigenesis. This review focuses on how deregulation in the HOX-associated signaling pathways contributes to the metastatic progression in cancer. We discuss their functional significance, clinical implications and ascertain their role as a diagnostic and prognostic biomarker in the various cancer types. Besides, the mechanism of understanding the theoretical underpinning that affects HOX-mediated therapy resistance in cancers has been outlined. The knowledge gained shall pave the way for newer insights into the treatment of cancer.
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Affiliation(s)
- U Sangeetha Shenoy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Keith D Hunter
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, S10 2TA, UK
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India.
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Morgan R, Hunter K, Pandha HS. Downstream of the HOX genes: explaining conflicting tumour suppressor and oncogenic functions in cancer. Int J Cancer 2022; 150:1919-1932. [PMID: 35080776 PMCID: PMC9304284 DOI: 10.1002/ijc.33949] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/24/2021] [Accepted: 01/07/2022] [Indexed: 11/07/2022]
Abstract
The HOX genes are a highly conserved group of transcription factors that have key roles in early development, but which are also highly expressed in most cancers. Many studies have found strong associative relationships between the expression of individual HOX genes in tumours and clinical parameters including survival. For the majority of HOX genes, high tumour expression levels seem to be associated with a worse outcome for patients, and in some cases this has been shown to result from the activation of pro-oncogenic genes and pathways. However, there are also many studies that indicate a tumour suppressor role for some HOX genes, sometimes with conclusions that contradict earlier work. In this review, we have attempted to clarify the role of HOX genes in cancer by focusing on their downstream targets as identified in studies that provide experimental evidence for their activation or repression. On this basis, the majority of HOX genes would appear to have a pro-oncogenic function, with the notable exception of HOXD10, which acts exclusively as a tumour suppressor. HOX proteins regulate a wide range of target genes involved in metastasis, cell death, proliferation, and angiogenesis, and activate key cell signalling pathways. Furthermore, for some functionally related targets, this regulation is achieved by a relatively small subgroup of HOX genes.
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Affiliation(s)
- Richard Morgan
- School of Biomedical SciencesUniversity of West LondonLondonUK
| | - Keith Hunter
- Unit of Oral and Maxillofacial Pathology, School of Clinical DentistryUniversity of SheffieldSheffieldUK
| | - Hardev S. Pandha
- Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
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Cao D, Ge S, Li M. MiR-451a Promotes Cell Growth, Migration and EMT in Osteosarcoma by Regulating YTHDC1-mediated m6A Methylation to Activate the AKT/mTOR Signaling Pathway. J Bone Oncol 2022; 33:100412. [PMID: 35198364 PMCID: PMC8842083 DOI: 10.1016/j.jbo.2022.100412] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 01/06/2022] [Accepted: 01/14/2022] [Indexed: 11/25/2022] Open
Abstract
It’s first proved that miR-451a can promote the malignant progression of osteosarcoma cells through AKT/mTOR pathway. It’s first proved that YTHDC1 modifies the m6A methylation of PDPK1. It’s first proved that YTHDC1 can promote the malignant progression of osteosarcoma cells. Background Osteosarcoma is the most prevalent primary malignant bone tumor containing mesenchymal cells with poor prognosis. Being a hot spot of anti-tumor therapy researches, AKT/mammalian target of rapamycin (mTOR) signaling pathway could affect various cellular processes including transcription, protein synthesis, apoptosis, autophagy and growth. Materials and methods The levels of RNA and protein were detected by quantitative real-time polymerase chain reaction (q-PCR) and western blot analyses respectively. Functional assays were carried out to analyze the malignant phenotypes of osteosarcoma cells. RNA-binding protein immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP), RNA pulldown, luciferase reporter and in vitro kinase assays were conducted to uncover the specific mechanism of microRNA-451a (miR-451a) in osteosarcoma cells. Results Functionally, miR-451a represses the malignant progression of osteosarcoma. Mechanically, miR-451a could curb the AKT/mTOR pathway via 3-phosphoinositide dependent protein kinase 1 (PDPK1)-mediated phosphorylation modification. After the certification that YTH domain containing 1 (YTHDC1) regulates the m6A phosphorylation modification of PDPK1 mRNA, we further proved that miR-451a-mediated YTHDC1 stabilizes PDPK1 mRNA via m6A-dependent regulation. Conclusion This study demonstrated that miR-451a regulates YTHDC1-mediated m6A methylation to activate the AKT/mTOR pathway, stimulating the malignancy of osteosarcoma.
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Ibrahim YF, Refaie MM, Kamel MY, Ahmed SM, Moussa RA, Bayoumi AM, Ibrahim MA. Molecular mechanisms underlying the effect of diacerein on trichloroacetic acid-induced hepatic pre-neoplastic lesions in rats. Hum Exp Toxicol 2021; 40:S788-S803. [PMID: 34794354 DOI: 10.1177/09603271211056331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
CONCLUSION IL-1β mediates angiogenesis indirectly, as it has been shown to induce hypoxia-inducible factor-1α (HIF-1α) which upregulates VEGF.
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Affiliation(s)
- Yasmine F Ibrahim
- Department of Pharmacology, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Marwa Mm Refaie
- Department of Pharmacology, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Maha Y Kamel
- Department of Pharmacology, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Sara M Ahmed
- Department of Pharmacology, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Rabab A Moussa
- Department of Pathology, Faculty of Medicine, 68877Minia University, Minia, Egypt
| | - Asmaa Ma Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, 68877Minia University, Minia, Egypt.,Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mohamed A Ibrahim
- Department of Pharmacology, Faculty of Medicine, 68877Minia University, Minia, Egypt
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Feng Y, Zhang T, Wang Y, Xie M, Ji X, Luo X, Huang W, Xia L. Homeobox Genes in Cancers: From Carcinogenesis to Recent Therapeutic Intervention. Front Oncol 2021; 11:770428. [PMID: 34722321 PMCID: PMC8551923 DOI: 10.3389/fonc.2021.770428] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
The homeobox (HOX) genes encoding an evolutionarily highly conserved family of homeodomain-containing transcriptional factors are essential for embryogenesis and tumorigenesis. HOX genes are involved in cell identity determination during early embryonic development and postnatal processes. The deregulation of HOX genes is closely associated with numerous human malignancies, highlighting the indispensable involvement in mortal cancer development. Since most HOX genes behave as oncogenes or tumor suppressors in human cancer, a better comprehension of their upstream regulators and downstream targets contributes to elucidating the function of HOX genes in cancer development. In addition, targeting HOX genes may imply therapeutic potential. Recently, novel therapies such as monoclonal antibodies targeting tyrosine receptor kinases, small molecular chemical inhibitors, and small interfering RNA strategies, are difficult to implement for targeting transcriptional factors on account of the dual function and pleiotropic nature of HOX genes-related molecular networks. This paper summarizes the current state of knowledge on the roles of HOX genes in human cancer and emphasizes the emerging importance of HOX genes as potential therapeutic targets to overcome the limitations of present cancer therapy.
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Affiliation(s)
- Yangyang Feng
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tongyue Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yijun Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Xie
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyu Ji
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyuan Luo
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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RNA-sequence reveals differentially expressed genes affecting the crested trait of Wumeng crested chicken. Poult Sci 2021; 100:101357. [PMID: 34329989 PMCID: PMC8335650 DOI: 10.1016/j.psj.2021.101357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Wumeng crested chicken has a cluster of slender feathers on its head, and the underlying skull region exhibits an obvious tumor-like protrusion. This is the typical skull structure of crested chickens. The associated regulatory genes are located on autosomes and are incompletely dominant. This trait is related to brain herniation, but the genetic mechanisms of its formation and development are unclear. In this study, RNA sequencing (RNA-Seq) analysis was conducted on 6 skull tissue samples from 3 Wumeng crested chickens with prominent skull protrusions and 3 without a prominent skull protrusion phenotype. A total of 46,376,934 to 43,729,046 clean reads were obtained, the percentage of uniquely mapped reads compared with the reference genome was between 89.73%-91.00%, and 39,795,458-41,836,502 unique reads were obtained. Among different genomic regions, the highest frequency of sequencing reads occurred in exon regions (85.44-88.28%). Additionally, a total of 423 new transcripts and 26,999 alternative splicings (AS) events were discovered in this sequencing analysis. This study identified 1,089 differentially expressed genes (DEGs), among which 485 were upregulated and 604 were downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the DEGs were enriched in terms related to signal transduction, cell development, cell differentiation, the lysosome, serine, and threonine metabolism, and the interaction of cytokines with cytokine receptors. Based on the comprehensive analysis of DEGs combined with reported quantitative trait loci (QTLs), the expression of BMP2, EPHA3, EPHB1, HOXC6, SCN2B, BMP7, and HOXC10 was verified by real-time quantitative polymerase chain reaction (qRT-PCR). The qRT-PCR results were consistent with the RNA-Seq results, indicating that these 7 genes may be candidates genes regulating the crested trait.
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Abstract
The HOXC10 gene, a member of the HOX genes family, plays crucial roles in mammalian physiological processes, such as limb morphological development, limb regeneration, and lumbar motor neuron differentiation. HOXC10 is also associated with angiogenesis, fat metabolism, and sex regulation. Additional evidence suggests that HOXC10 dysregulation is closely associated with various tumors. HOXC10 is an important transcription factor that can activate several oncogenic pathways by regulating various target molecules such as ERK, AKT, p65, and epithelial mesenchymal transition-related genes. HOXC10 also induces drug resistance in cancers by promoting the DNA repair pathway. In this review, we summarize HOXC10 gene structure and expression as well as the role of HOXC10 in different human cancer processes. This review will provide insight into the status of HOXC10 research and help identify novel targets for cancer therapy.
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Affiliation(s)
- Jinyong Fang
- Department of Science and Education, Jinhua Guangfu Oncology Hospital, Jinhua, China
| | - Jianjun Wang
- Department of Gastroenterological Surgery, Jinhua Guangfu Oncology Hospital, Jinhua, China
| | - Liangliang Yu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Wenxia Xu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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He Q, Huang W, Liu D, Zhang T, Wang Y, Ji X, Xie M, Sun M, Tian D, Liu M, Xia L. Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation. Am J Cancer Res 2021; 11:5759-5777. [PMID: 33897880 PMCID: PMC8058721 DOI: 10.7150/thno.57659] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 03/17/2021] [Indexed: 02/07/2023] Open
Abstract
Background: Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed. Here, we elucidated the role of Homeobox B5 (HOXB5), a member of the HOX transcriptional factor family, in promoting HCC metastasis. Method: The expression of HOXB5 and its functional targets fibroblast growth factor receptor 4 (FGFR4) and C-X-C motif chemokine ligand 1 (CXCL1) were detected by immunohistochemistry. Luciferase reporter and chromatin immunoprecipitation assays were performed to measure the transcriptional regulation of target genes by HOXB5. The effects of FGFR4 and CXCL1 on HOXB5-mediated metastasis were analyzed by an orthotopic metastasis model. Results: Elevated expression of HOXB5 had a positive correlation with poor tumour differentiation, higher TNM stage, and indicated unfavorable prognosis. Overexpression of HOXB5 promoted HCC metastasis through transactivating FGFR4 and CXCL1 expression, whereas knockdown of FGFR4 and CXCL1 decreased HOXB5-enhanced HCC metastasis. Moreover, HOXB5 overexpression in HCC cells promoted myeloid derived suppressor cells (MDSCs) infiltration through CXCL1/CXCR2 axis. Either depletion of MDSCs by anti-Gr1 or blocking CXCL1-CXCR2 axis by CXCR2 inhibitor impaired HOXB5-mediated HCC metastasis. In addition, fibroblast growth factor 19 (FGF19) contributed to the HOXB5 upregulation through PI3K/AKT/HIF1α pathway. Overexpression of FGF15 (an analog of FGF19 in mouse) promoted HCC metastasis, whereas knockdown of HOXB5 significantly inhibited FGF15-enhanced HCC metastasis in immunocompetent mice. HOXB5 expression was positively associated with CXCL1 expression and intratumoral MDSCs accumulation in human HCC tissues. Patients who co-expressed HOXB5/CXCL1 or HOXB5/CD11b exhibited the worst prognosis. Furthermore, the combination of FGFR4 inhibitor BLU-554 and CXCR2 inhibitor SB265610 dramatically decreased HOXB5-mediated HCC metastasis. Conclusion: HOXB5 was a potential prognostic biomarker in HCC patients and targeting this loop may provide a promising treatment strategy for the inhibition of HOXB5-mediated HCC metastasis.
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Gong J, Li R, Chen Y, Zhuo Z, Chen S, Cao J, Zhang Q, Chong Y, Hu B. HCC subtypes based on the activity changes of immunologic and hallmark gene sets in tumor and nontumor tissues. Brief Bioinform 2021; 22:6123970. [PMID: 33515024 DOI: 10.1093/bib/bbaa427] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/19/2022] Open
Abstract
The prognostic role of adjacent nontumor tissue in hepatocellular carcinoma (HCC) patients is still not clear. The activity changes of immunologic and hallmark gene sets in adjacent nontumor tissues may substantially impact on prognosis by affecting proliferation of liver cells and colonization of circulating tumor cells after HCC treatment measures such as hepatectomy. We aimed to identify HCC subtypes and prognostic gene sets based on the activity changes of gene sets in tumor and nontumor tissues, to improve patient outcomes. We comprehensively revealed the activity changes of immunologic and hallmark gene sets in HCC and nontumor samples by gene set variation analysis (GSVA), and identified three clinically relevant subtypes of HCC by nonnegative matrix factorization method (NMF). Patients with subtype 1 had good overall survival, whereas those with subtype 2 and subtype 3 had poor prognosis. Patients with subtype 1 in the validation group also tended to live longer. We also identified three prognostic gene sets in tumor and four prognostic gene sets in nontumor by least absolute shrinkage and selection operator method (LASSO). Interestingly, functional enrichment analysis revealed that in nontumor tissues, genes from four gene sets correlated with immune reaction, cell adhesion, whereas in tumor tissue, genes from three gene sets closely correlated with cell cycle. Our results offer new insights on accurately evaluating prognosis-the important role of gene sets in both tumor and adjacent nontumor tissues, suggesting that when selecting for HCC treatment modality, changes in tumor and nontumor tissues should also be considered, especially after hepatectomy.
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Affiliation(s)
- Jiao Gong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Rong Li
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou 510630, China
| | - Yaqiong Chen
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Shuru Chen
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Jing Cao
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Qi Zhang
- Cell-Gene Therapy Translational Medicine Research Center, Key Laboratory of Liver Disease of Guangdong Province, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
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Abstract
Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins.
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Xu H, Huang J, Hua S, Liang L, He X, Zhan M, Lu L, Chu J. Interactome analysis of gene expression profiles identifies CDC6 as a potential therapeutic target modified by miR-215-5p in hepatocellular carcinoma. Int J Med Sci 2020; 17:2926-2940. [PMID: 33173413 PMCID: PMC7646103 DOI: 10.7150/ijms.51145] [Citation(s) in RCA: 5] [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: 07/27/2020] [Accepted: 10/07/2020] [Indexed: 01/11/2023] Open
Abstract
Background: Illustrating the pathogenesis of hepatocellular carcinoma (HCC) pathogenesis as well as identifying specific biomarkers are of great significance. Methods: The original CEL files were obtain from Gene Expression Omnibus, then affymetrix package was used to preprocess the CEL files, the function of DEGs were investigated by multiple bioinformatics approach. Finally, typical HCC cell lines and tissue samples were using to validate the role of CDC6 in vitro. Bioinformatics software was used to predict potential microRNA of CDC6. Luciferase assay was used to verify the interactions between CDC6 and microRNA. Results: A total of 445 DEGs were identified in HCC tissues based on two GEO datasets. GSEA results showed that the significant enriched gene sets were only associated with cell cycle signaling pathway. In the co-expression analysis, there were 370 hub genes from the blue modules were screened. We integrated DEGs, hub genes, TCGA cohort and GSEA analyses to further obtain 10 upregulated genes for validation. These genes were overexpressed in HCC tissues and negatively associated with overall and disease-free survival in HCC patients and related to immune cell infiltration in HCC microenvironments. Finally, Cell Division Cycle 6 (CDC6) was highlighted as one of the most probable genes among the 10 candidates participating in cancer process. The expression of CDC6 either in public datasets and HCC tissues sample were commonly high than the non-cancerous counterpart. Furthermore, we recognized that miR-215-5p, could directly bind to the 3'UTR of CDC6. In addition, CDC6 promoted proliferation via regulation of G1 phase checkpoint and was negative regulated by miR-215-5p to involve in the proliferation of HCC. Conclusion: Our study suggested that CDC6 served as a potential therapeutic target for HCC.
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Affiliation(s)
- Hongfa Xu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Jianwen Huang
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Shengni Hua
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Linjun Liang
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Xu He
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Meixiao Zhan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Ligong Lu
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
| | - Jing Chu
- Department of Urology, Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, China
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Pai P, Sukumar S. HOX genes and the NF-κB pathway: A convergence of developmental biology, inflammation and cancer biology. Biochim Biophys Acta Rev Cancer 2020; 1874:188450. [PMID: 33049277 DOI: 10.1016/j.bbcan.2020.188450] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/11/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023]
Abstract
The roles of HOX transcription factors as oncogenes and tumor suppressor genes, and the NF-KB pathway in chronic inflammation, both leading to cancer are well-established. HOX transcription factors are members of an evolutionarily conserved family of proteins required for anteroposterior body axis patterning during embryonic development, and are often dysregulated in cancer. The NF-KB pathway aids inflammation and immunity but it is also important during embryonic development. It is frequently activated in both solid and hematological malignancies. NF-KB and HOX proteins can influence each other through mutual transcriptional regulation, protein-protein interactions, and regulation of upstream and downstream interactors. These interactions have important implications both in homeostasis and in disease. In this review, we summarize the role of HOX proteins in regulating inflammation in homeostasis and disease- with a particular emphasis on cancer. We also describe the relationship between HOX genes and the NF-KB pathway, and discuss potential therapeutic strategies.
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Affiliation(s)
- Priya Pai
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
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