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Xu L, Cao P, Wang J, Zhang P, Hu S, Cheng C, Wang H. IL-22: A key inflammatory mediator as a biomarker and potential therapeutic target for lung cancer. Heliyon 2024; 10:e35901. [PMID: 39263114 PMCID: PMC11387261 DOI: 10.1016/j.heliyon.2024.e35901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/13/2023] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 09/13/2024] Open
Abstract
Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.
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Affiliation(s)
- Ling Xu
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
| | - Peng Cao
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
| | - Jianpeng Wang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Peng Zhang
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
| | - Shuhui Hu
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
| | - Chao Cheng
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
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Feng M, Ye X, Chen B, Zhang J, Lin M, Zhou H, Huang M, Chen Y, Zhu Y, Xiao B, Huang C, Katz RL, Bai C. Detection of circulating genetically abnormal cells using 4-color fluorescence in situ hybridization for the early detection of lung cancer. J Cancer Res Clin Oncol 2021; 147:2397-2405. [PMID: 33547948 PMCID: PMC8236478 DOI: 10.1007/s00432-021-03517-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/26/2020] [Accepted: 01/10/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE Available biomarkers lack sensitivity for an early lung cancer. Circulating genetically abnormal cells (CACs) occur early in tumorigenesis. To determine the diagnostic value of CACs in blood detected by 4-color fluorescence in situ hybridization (FISH) for lung cancer. METHODS This was a prospective study of patients with pulmonary nodules ≤ 30 mm detected between 10/2019 and 01/2020 at four tertiary hospitals in China. All patients underwent a pathological examination of lung nodules found by imaging and were grouped as malignant and benign. CACs were detected by 4-color FISH. Patients were divided into the training and validation cohorts. Receiver operating characteristics analysis was used to analyze the diagnosis value of CACs. RESULTS A total of 205 participants were enrolled. Using a cut-off value of ≥ 3, blood CACs achieved areas under the curve (AUCs) of 0.887, 0.823, and 0.823 for lung cancer in the training and validation cohorts, and all patients, respectively. CACs had high diagnostic values across all tumor sizes and imaging lesion types. CACs were decreased after surgery (median, 4 vs. 1, P < 0.001) in the validation set. The CAC status between blood and tissues was highly consistent (kappa = 0.909, P < 0.001). The AUC of CAC (0.823) was higher than that of CEA (0.478), SCC (0.516), NSE (0.506), ProGRP (0.519), and CYFRA21-1 (0.535) (all P < 0.001). CONCLUSION CACs might have a high value for the early diagnosis of lung cancer. These findings might need to be validated in future studies. Evidence suggested homology in genetic aberrations between the CACs and the tumor cells.
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Affiliation(s)
- Mingxiang Feng
- Division of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Ye
- Zhuhai Sanmed Biotech. Ltd, Zhuhai, China
- Joint Research Center of Liquid Biopsy in Guangdong, Hongkong and Macao, Zhuhai, China
- Department of Thoracic surgery, Respiratory Center of Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, An Affiliated Hospital of North Sichuan Medical College, Suining, Sichuan, China
| | - Baishen Chen
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Juncheng Zhang
- Zhuhai Sanmed Biotech. Ltd, Zhuhai, China
- Joint Research Center of Liquid Biopsy in Guangdong, Hongkong and Macao, Zhuhai, China
| | - Miao Lin
- Division of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haining Zhou
- Department of Thoracic surgery, Respiratory Center of Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, An Affiliated Hospital of North Sichuan Medical College, Suining, Sichuan, China
| | - Meng Huang
- Zhuhai Sanmed Biotech. Ltd, Zhuhai, China
- Joint Research Center of Liquid Biopsy in Guangdong, Hongkong and Macao, Zhuhai, China
| | - Yanci Chen
- Zhuhai Sanmed Biotech. Ltd, Zhuhai, China
- Joint Research Center of Liquid Biopsy in Guangdong, Hongkong and Macao, Zhuhai, China
| | - Yunhe Zhu
- Department of Thoracic surgery, Respiratory Center of Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, An Affiliated Hospital of North Sichuan Medical College, Suining, Sichuan, China
| | - Botao Xiao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Chuoji Huang
- Zhuhai Sanmed Biotech. Ltd, Zhuhai, China.
- Joint Research Center of Liquid Biopsy in Guangdong, Hongkong and Macao, Zhuhai, China.
| | - Ruth L Katz
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chunxue Bai
- Division of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
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circRNA circFAT1(e2) Elevates the Development of Non-Small-Cell Lung Cancer by Regulating miR-30e-5p and USP22. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6653387. [PMID: 33884267 PMCID: PMC8041530 DOI: 10.1155/2021/6653387] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 12/29/2020] [Revised: 02/04/2021] [Accepted: 03/06/2021] [Indexed: 01/22/2023]
Abstract
Background As a newly discovered regulatory RNA, circular RNA (circRNA) has become a hot spot in many tumor pieces of research. In recent years, it has been discovered that circRNAs have multiple biological effects in different stages of cancer. However, the expression pattern and mechanism of circFAT1(e2) in non-small-cell lung cancer (NSCLC) are still unclear. Methods The expressions of circFAT1(e2) in NSCLC tissues and cell lines were studied. Functionally, CCK-8 and transwell experiments were performed in A549 and H1299. In addition, we also performed a dual-luciferase report analysis to clarify the mechanism of action of circFAT1(e2). Results circFAT1(e2) was significantly upregulated in NSCLC tissues and cell lines. circFAT1(e2) gene knockdown could significantly inhibit the proliferation, migration, and invasion of NSCLC cells. Loss of function testing found that circFAT1(e2) functioned as an oncogene in NSCLC cells. In addition, circFAT1(e2) acted as a ceRNA to spongy miR-30e-5p, which led to the increase in USP22 and promoted cell growth. Conclusions The circFAT1(e2)-miR-30e-5p-USP22 axis is a crucial part of the progression of NSCLC. This study suggests that circFAT1(e2) may be an important potential of prognostic prediction and treatment targets for NSCLC patients.
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Ye M, Zheng X, Ye X, Zhang J, Huang C, Liu Z, Huang M, Fan X, Chen Y, Xiao B, Sun J, Bai C. Circulating Genetically Abnormal Cells Add Non-Invasive Diagnosis Value to Discriminate Lung Cancer in Patients With Pulmonary Nodules ≤10 mm. Front Oncol 2021; 11:638223. [PMID: 33777797 PMCID: PMC7991838 DOI: 10.3389/fonc.2021.638223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/05/2020] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Background Lung cancer screening using low-dose computed tomography (LDCT) often leads to unnecessary biopsy because of the low specificity among patients with pulmonary nodules ≤10 mm. Circulating genetically abnormal cells (CACs) can be used to discriminate lung cancer from benign lung disease. To examine the diagnostic value of CACs in detecting lung cancer for patients with malignant pulmonary nodules ≤10 mm. Methods In this prospective study, patients with pulmonary nodules ≤10 mm who were detected at four hospitals in China from January 2019 to January 2020 were included. CACs were detected using fluorescence in-situ hybridization. All patients were confirmed as lung cancer or benign disease by further histopathological examination. Multivariable logistic regression models were established to detect the presence of lung cancer using CACs and other associated characteristics. Receiver operating characteristic analysis was used to evaluate the performance of CACs for lung cancer diagnosis. Results Overall, 125 patients were included and analyzed. When the cutoff value of CACs was >2, the sensitivity and specificity for lung cancer were 70.5 and 86.4%. Male (OR = 0.330, P = 0.005), maximum solid nodule (OR = 2.362, P = 0.089), maximum nodule located in upper lobe (OR = 3.867, P = 0.001), and CACs >2 (OR = 18.525, P < 0.001) met the P < 0.10 criterion for inclusion in the multivariable models. The multivariable logistic regression model that included the dichotomized CACs (>2 vs. ≤2) and other clinical factors (AUC = 0.907, 95% CI = 0.842–0.951) was superior to the models that only considered dichotomized CACs or other clinical factors and similar to the model with numerical CACs and other clinical factors (AUC = 0.913, 95% CI = 0.850–0.956). Conclusion CACs presented a significant diagnostic value in detecting lung cancer for patients with pulmonary nodules ≤10 mm.
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Affiliation(s)
- Maosong Ye
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoxuan Zheng
- Department of Respiratory Endoscopy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Ye
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China.,School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Juncheng Zhang
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China
| | - Chuoji Huang
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China
| | - Zilong Liu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meng Huang
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China
| | - Xianjun Fan
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China
| | - Yanci Chen
- Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong, and Macao, Zhuhai, China.,Zhuhai Sanmed Biotech Ltd., Zhuhai, China
| | - Botao Xiao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Jiayuan Sun
- Department of Respiratory Endoscopy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chunxue Bai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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Kim MJ, Chen G, Sica GL, Deng X. Epigenetic modulation of FBW7/Mcl-1 pathway for lung cancer therapy. Cancer Biol Ther 2021; 22:55-65. [PMID: 33336620 PMCID: PMC7833779 DOI: 10.1080/15384047.2020.1856756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/01/2020] [Revised: 08/24/2020] [Accepted: 11/23/2020] [Indexed: 01/09/2023] Open
Abstract
Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a tumor suppressor that functions as an Mcl-1 E3 ligase to degrade Mcl-1 by ubiquitination. Here we discovered that treatment of various human lung cancer cells with DAC resulted in activation of FBW7 expression, decreased levels of Mcl-1 protein, and growth inhibition. DAC-activated FBW7 expression promoted Mcl-1 ubiquitination and degradation leading to a significant reduction in the half-life of Mcl-1 protein. Mechanistically, treatment of lung cancer cells or lung cancer xenografts with DAC induced the conversion of the FBW7 gene from a methylated form to an unmethylated form, which was associated with the increased expression of FBW7 and decreased expression of Mcl-1 in vitro and in vivo. DAC suppressed lung cancer growth in a dose-dependent manner in vivo. Combined treatment with DAC and a Bcl2 inhibitor, venetoclax, exhibited strong synergistic potency against lung cancer without normal tissue toxicity. These findings uncover a novel mechanism by which DAC suppresses tumor growth by targeting the FBW7/Mcl-1 signaling pathway. Combination of DAC with Bcl2 inhibitor venetoclax provides more effective epigenetic therapy for lung cancer.
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Affiliation(s)
- Mi Jeong Kim
- Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
- Department of Food and Nutrition, Changwon National University, Gyeongsangnam-do, Korea
| | - Guo Chen
- Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
| | - Gabriel L. Sica
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
| | - Xingming Deng
- Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
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Yuan F, Zhang S, Xie W, Yang S, Lin T, Chen X. Effect and mechanism of miR-146a on malignant biological behaviors of lung adenocarcinoma cell line. Oncol Lett 2020; 19:3643-3652. [PMID: 32382320 PMCID: PMC7202298 DOI: 10.3892/ol.2020.11474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/18/2018] [Accepted: 06/28/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to assess the expression of microRNA-146a (miR-146a) in human lung adenocarcinoma cells, its effect on cellular behaviors, and the underlying molecular mechanisms. Reverse transcription-quantitative PCR (RT-qPCR) was used to measure miR-146a expression in the human normal lung epithelial cell line, BEAS-2B, and human lung adenocarcinoma cell lines, A549, PC-9 and H1299, to determine whether miR-146a acts as an oncogene or anti-oncogene. miR-146a mimics were transfected into target cells to observe the proliferation, apoptosis, invasion and migration of human lung adenocarcinoma cells. The target genes of miR-146a were predicted using bioinformatics analysis, and binding sites were validated by dual-luciferase reporter assay. Target gene expression at the mRNA and protein levels was measured by RT-qPCR and western blot analysis, respectively. The expression levels of miR-146a in human lung adenocarcinoma cell lines were lower than its expression in BEAS-2B (P<0.01). A549 cell line is a EGFR wild-type lung adenocarcinoma cell line, which is also the most widely studied in NSCLC, and therefore this was chosen as the target cell line for further investigation. Overexpression of miR-146a in A549 cells can inhibit cell proliferation (P<0.05), promote apoptosis (P<0.05), and reduce the cells' migratory ability (P<0.01). Bioinformatics prediction indicated that interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6) are the target genes of miR-146a. Dual-luciferase reporter assay showed that miR-146a could specifically bind to 3′-untranslated regions of IRAK1 and TRAF6. The protein and mRNA levels of IRAK1 and TRAF6 were significantly downregulated after miR-146a overexpression in A549 cells (P<0.01). The results of this study demonstrated that the expression of miR-146a in human lung adenocarcinoma cells was significantly lower than in normal lung epithelial cells, indicating that miR-146a acts as an anti-oncogene. miR-146a suppresses the proliferation and migration of human lung adenocarcinoma cells by downregulating the expression of IRAK1 and TRAF6.
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Affiliation(s)
- Fang Yuan
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China.,Department of Respiratory, The First Hospital of Jiujiang City, Jiujiang, Jiangxi 332000, P.R. China
| | - Suyun Zhang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Wenying Xie
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Sheng Yang
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Tingyan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Xiangqi Chen
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
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Rupika Sunidhi C, Jeyaprakash MR, Rajeshkumar R. Sonic Hedgehog gene as a potential target for the early prophylactic detection of cancer. Med Hypotheses 2020; 137:109534. [PMID: 32001417 DOI: 10.1016/j.mehy.2019.109534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/06/2019] [Revised: 12/11/2019] [Accepted: 12/17/2019] [Indexed: 01/22/2023]
Abstract
In the search for newer and advanced methods for the detection of cancer, quicker and non-invasive techniques are imperative. One such potential approach for detection is the detection of oncogenes in the suspected tumour tissues. This search has led to the identification of the oncogene SHh, which is a key influencer in the tumourigenic pathways. Therefore, a cancer detection method, which would target the identification of the oncogene SHh would therefore be a step forward in the advancement of cancer research.
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Affiliation(s)
- C Rupika Sunidhi
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Udhagamandalam, Tamil Nadu, India
| | - M R Jeyaprakash
- Department of Pharmaceutical Analysis, JSS College of Pharmacy, Udhagamandalam, Tamil Nadu, India.
| | - Raman Rajeshkumar
- Department of Biotechnology, JSS College of Pharmacy, Udhagamandalam, Tamil Nadu, India
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Zhang Z, Dong C, Yu G, Cheng W, Liang Y, Pan Y, Li H, Ji H. Smart and dual-targeted BSA nanomedicine with controllable release by high autolysosome levels. Colloids Surf B Biointerfaces 2019; 182:110325. [PMID: 31301582 DOI: 10.1016/j.colsurfb.2019.06.055] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/05/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 12/30/2022]
Abstract
Targeting modifications and smart responsiveness of nanomedicines can enable anticancer drugs to be selectively delivered to and controllably released in tumour cells or tissues, which can reduce the treatment's toxicity and side effects. Good biocompatibility is crucial for the clinical application of any nanomedicine. In this study, a double-targeting molecule, an RGD peptide- and 4-(2-aminoethyl) morpholine-modified, doxorubicin (DOX)-loaded bovine serum albumin (BSA) nanomedicine, that can be controllably released by the high levels of autophagic lysosomes in tumour cells was developed. The size of the spherical BSA nanoparticles is approximately 60 nm. In vitro experiments indicated that the RGD peptide- and 4-(2-aminoethyl) morpholine-modified, DOX-loaded BSA nanomedicine has a better therapeutic effect than free DOX. In vivo experiments suggested that the BSA nanomedicine can successfully suppress the progression of PC9 xenograft tumours. This phenomenon may be attributable to the endocytosis of a relatively large amount of nanomedicine and the effective release of the loaded chemotherapeutic agent, as induced by high levels of autolysosomes. Collectively, the results of this study provide a smart approach for increasing therapeutic efficacy using a double-targeting molecule-modified BSA nanomedicine.
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Affiliation(s)
- Zhanxia Zhang
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China.
| | - Changsheng Dong
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China
| | - Guanzhen Yu
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China
| | - Wei Cheng
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China
| | - Yupei Liang
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China
| | - Yongfu Pan
- Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China
| | - Hegen Li
- National Clinical Research Base of Traditional Chinese Medicine, Tumor Department, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 Wanping South Road, Shanghai, 200032, China.
| | - Hongbin Ji
- Key Laboratory of Systems Biology, 320 Yueyang Road, Shanghai, 200031, China; CAS Center for Excellence in Molecular Cell Science, 320 Yueyang Road, Shanghai, 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, 320 Yueyang Road, Shanghai, 200031, China
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MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion. Oncotarget 2018; 9:12226-12239. [PMID: 29552305 PMCID: PMC5844741 DOI: 10.18632/oncotarget.24203] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2017] [Accepted: 12/04/2017] [Indexed: 12/20/2022] Open
Abstract
Air pollution is one of the leading causes of lung cancer. Air pollution-related lung cancer is a deteriorating public health problem, particularly in developing countries. The MUC16 gene is one of the most frequently mutated genes in air pollution-related lung cancer. In the present study, MUC16 mRNA expression was increased in ∼50% of air pollution-related lung cancer samples obtained from patients residing in air-polluted regions (Xuanwei and Fuyuan, Yunnan, China), and MUC16 mRNA levels were correlated with the degree of air pollution. Furthermore, sequencing of the captured MUC16 gene identified 561 mutation sites within the MUC16 gene in the air pollution-related lung cancer tissues. Interestingly, some mutations at specific sites and one region were associated with MUC16 mRNA up-regulation. Therefore, we further investigated the impacts of gene mutation on MUC16 expressions and cell behaviors in cultured cells by inducing certain mutations within the MUC16 gene using CRISPER/Cas9 genome editing technology. Certain mutations within the MUC16 gene induced MUC16 overexpression at both the mRNA and the protein level in the cultured cells. Additionally, MUC16 overexpression induced by gene mutations had functional effects on the behavior of lung cancer cells, including increasing their resistance to cisplatin, promoting their growth, and enhancing their migration and invasion capabilities. Based on the data, we suggest that MUC16 mutations potentially associated with air pollution may participate in the development and progression of air pollution-related lung cancer. In addition to ovarian cancer, MUC16 may be a candidate biomarker for lung cancer.
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Zhao S, Jiang T, Zhang L, Yang H, Liu X, Jia Y, Zhou C. Clinicopathological and prognostic significance of regulatory T cells in patients with non-small cell lung cancer: A systematic review with meta-analysis. Oncotarget 2017; 7:36065-36073. [PMID: 27153545 PMCID: PMC5094983 DOI: 10.18632/oncotarget.9130] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/03/2016] [Accepted: 04/11/2016] [Indexed: 12/13/2022] Open
Abstract
The prognostic and clinicopathological value of regulatory T cells (Tregs) infiltration in patients with non-small cell lung cancer (NSCLC) remains undetermined. A comprehensive literature search of electronic databases (up to December 2015) was conducted. Relationship between Tregs infiltration and clinicopathological features, recurrence-free survival (RFS) and overall survival (OS) was investigated by synthesizing the qualified data. A total of 1303 NSCLC patients from 11 studies were included. The pooled hazard ratio (HR) for survival showed that high Tregs infiltration had no effect on RFS (HR = 2.03, 95% CI: 0.61–3.44, P = 0.708) and OS (HR = 1.20, 95% CI: 0.58–1.62, P = 0.981). High FoxP3+ Tregs infiltration was significantly associated with poor OS in NSCLC (HR = 3.88, 95% CI: 2.45–5.40, P = 0.000). Test methods, ethnicity and types of specimens had no effect on predicting prognosis of Tregs infiltration. While high Tregs infiltration was significantly correlated with smoking status [odds ratios (ORs) = 1.54, 95% CI: 1.15–2.08; P = 0.004], none of other clinicopathological characteristics such as gender, histological type, lymph node metastasis status, tumor size, vascular invasion, lymphatic invasion and pleural invasion were associated with Tregs infiltration. The present study demonstrated that high FoxP3+ Tregs infiltration was significantly associated with poor prognosis in NSCLC and smoking status.
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Affiliation(s)
- Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Tao Jiang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Limin Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Hui Yang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Xiaozhen Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Yijun Jia
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, China
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Abstract
Gene therapy was originally conceived to treat monogenic diseases. The replacement of a defective gene with a functional gene can theoretically cure the disease. In cancer, multiple genetic defects are present and the molecular profile changes during the course of the disease, making the replacement of all defective genes impossible. To overcome these difficulties, various gene therapy strategies have been adopted, including immune stimulation, transfer of suicide genes, inhibition of driver oncogenes, replacement of tumor-suppressor genes that could mediate apoptosis or anti-angiogenesis, and transfer of genes that enhance conventional treatments such as radiotherapy and chemotherapy. Some of these strategies have been tested successfully in non-small-cell lung cancer patients and the results of laboratory studies and clinical trials are reviewed herein.
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Affiliation(s)
- Humberto Lara-Guerra
- Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Jack A Roth
- Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Kanwal M, Ding XJ, Cao Y. Familial risk for lung cancer. Oncol Lett 2017; 13:535-542. [PMID: 28356926 PMCID: PMC5351216 DOI: 10.3892/ol.2016.5518] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2015] [Accepted: 08/26/2016] [Indexed: 01/07/2023] Open
Abstract
Lung cancer, which has a low survival rate, is a leading cause of cancer-associated mortality worldwide. Smoking and air pollution are the major causes of lung cancer; however, numerous studies have demonstrated that genetic factors also contribute to the development of lung cancer. A family history of lung cancer increases the risk for the disease in both smokers and never-smokers. This review focuses on familial lung cancer, in particular on the familial aggregation of lung cancer. The development of familial lung cancer involves shared environmental and genetic factors among family members. Familial lung cancer represents a good model for investigating the association between environmental and genetic factors, as well as for identifying susceptibility genes for lung cancer. In addition, studies on familial lung cancer may help to elucidate the etiology and mechanism of lung cancer, and may identify novel biomarkers for early detection and diagnosis, targeted therapy and improved prevention strategies. This review presents the aetiology and molecular biology of lung cancer and then systematically introduces and discusses several aspects of familial lung cancer, including the characteristics of familial lung cancer, population-based studies on familial lung cancer and the genetics of familial lung cancer.
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Affiliation(s)
- Madiha Kanwal
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P.R. China
- Kunming College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Xiao-Ji Ding
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P.R. China
| | - Yi Cao
- Laboratory of Molecular and Experimental Pathology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, P.R. China
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Niwa O, Barcellos-Hoff MH, Globus RK, Harrison JD, Hendry JH, Jacob P, Martin MT, Seed TM, Shay JW, Story MD, Suzuki K, Yamashita S. ICRP Publication 131: Stem Cell Biology with Respect to Carcinogenesis Aspects of Radiological Protection. Ann ICRP 2016; 44:7-357. [PMID: 26637346 DOI: 10.1177/0146645315595585] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
This report provides a review of stem cells/progenitor cells and their responses to ionising radiation in relation to issues relevant to stochastic effects of radiation that form a major part of the International Commission on Radiological Protection's system of radiological protection. Current information on stem cell characteristics, maintenance and renewal, evolution with age, location in stem cell 'niches', and radiosensitivity to acute and protracted exposures is presented in a series of substantial reviews as annexes concerning haematopoietic tissue, mammary gland, thyroid, digestive tract, lung, skin, and bone. This foundation of knowledge of stem cells is used in the main text of the report to provide a biological insight into issues such as the linear-no-threshold (LNT) model, cancer risk among tissues, dose-rate effects, and changes in the risk of radiation carcinogenesis by age at exposure and attained age. Knowledge of the biology and associated radiation biology of stem cells and progenitor cells is more developed in tissues that renew fairly rapidly, such as haematopoietic tissue, intestinal mucosa, and epidermis, although all the tissues considered here possess stem cell populations. Important features of stem cell maintenance, renewal, and response are the microenvironmental signals operating in the niche residence, for which a well-defined spatial location has been identified in some tissues. The identity of the target cell for carcinogenesis continues to point to the more primitive stem cell population that is mostly quiescent, and hence able to accumulate the protracted sequence of mutations necessary to result in malignancy. In addition, there is some potential for daughter progenitor cells to be target cells in particular cases, such as in haematopoietic tissue and in skin. Several biological processes could contribute to protecting stem cells from mutation accumulation: (a) accurate DNA repair; (b) rapidly induced death of injured stem cells; (c) retention of the DNA parental template strand during divisions in some tissue systems, so that mutations are passed to the daughter differentiating cells and not retained in the parental cell; and (d) stem cell competition, whereby undamaged stem cells outcompete damaged stem cells for residence in the niche. DNA repair mainly occurs within a few days of irradiation, while stem cell competition requires weeks or many months depending on the tissue type. The aforementioned processes may contribute to the differences in carcinogenic radiation risk values between tissues, and may help to explain why a rapidly replicating tissue such as small intestine is less prone to such risk. The processes also provide a mechanistic insight relevant to the LNT model, and the relative and absolute risk models. The radiobiological knowledge also provides a scientific insight into discussions of the dose and dose-rate effectiveness factor currently used in radiological protection guidelines. In addition, the biological information contributes potential reasons for the age-dependent sensitivity to radiation carcinogenesis, including the effects of in-utero exposure.
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Lu L, Yang LN, Wang XX, Song CL, Qin H, Wu YJ. Synergistic cytotoxicity of ampelopsin sodium and carboplatin in human non-small cell lung cancer cell line SPC-A1 by G1 cell cycle arrested. Chin J Integr Med 2016; 23:125-131. [DOI: 10.1007/s11655-016-2591-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/19/2012] [Indexed: 12/19/2022]
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15
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Mittal V, El Rayes T, Narula N, McGraw TE, Altorki NK, Barcellos-Hoff MH. The Microenvironment of Lung Cancer and Therapeutic Implications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 890:75-110. [PMID: 26703800 DOI: 10.1007/978-3-319-24932-2_5] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.
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MESH Headings
- Antibodies, Monoclonal/therapeutic use
- Antineoplastic Agents/therapeutic use
- Carcinogenesis/drug effects
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Cell Communication/drug effects
- Drug Resistance, Neoplasm/genetics
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Diseases, Obstructive/complications
- Lung Diseases, Obstructive/drug therapy
- Lung Diseases, Obstructive/genetics
- Lung Diseases, Obstructive/metabolism
- Lung Neoplasms/complications
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mesenchymal Stem Cells/drug effects
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/prevention & control
- Pulmonary Emphysema/complications
- Pulmonary Emphysema/drug therapy
- Pulmonary Emphysema/genetics
- Pulmonary Emphysema/metabolism
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
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Affiliation(s)
- Vivek Mittal
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
| | - Tina El Rayes
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Weill Cornell Graduate School of Medical Sciences, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Navneet Narula
- Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Timothy E McGraw
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Nasser K Altorki
- Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
- Neuberger Berman Lung Cancer Research Center, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, New York University School of Medicine, 566 First Avenue, New York, NY, 10016, USA.
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16
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The Effect of C-X-C Motif Chemokine 13 on Hepatocellular Carcinoma Associates with Wnt Signaling. BIOMED RESEARCH INTERNATIONAL 2015; 2015:345413. [PMID: 26161394 PMCID: PMC4486493 DOI: 10.1155/2015/345413] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 10/01/2014] [Accepted: 01/04/2015] [Indexed: 12/18/2022]
Abstract
Objects. To investigate the effect of CXCL13 (C-X-C motif chemokine 13) on hepatocellular carcinoma and clarify the potential mechanisms. Methods. 32 patients with hepatocellular carcinoma and 12 healthy controls were recruited for analyzing the expression of CXCL13 by RT-PCR (reverse transcription-polymerase chain reaction). ELISA (enzyme-linked immune-sorbent assay) was used to test the concentration of serum CXCL13. The interaction between CXCL13 and Wnt signaling was analyzed by western blot. In vitro PBMCs cultured with HepG2 supernatant, the levels of IL-12, IL4, IL-6, and IL-17, and four IgG subclasses were detected by ELISA. Results. The rate of high expression CXCL13 was 63.4% in advanced HCC patients, and the serum CXCL13 was also at a high level in stage IV HCC patients. Meanwhile CXCL13 level was positively correlated with serum ALT (Alanine Transaminase) and AST (Aspartate Aminotransferase). CXCL13 and Wnt/β-catenin signaling shared a positive feedback loop. Furthermore, CXCL13 could obviously promote the expressions of IL-12 and IL-17, and induce IgG4 secreted by B cells. Conclusions. The effect of CXCL13 on promoting liver cancer is related to the activation of Wnt/β-catenin pathway and the facilitation of IL-12, IL-17 and IgG4. CXCL13 plays an important role in the progression of HCC, and it may act as a potential target for the diagnosis and treatment of HCC.
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Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR) Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy. PLoS One 2015; 10:e0123967. [PMID: 26053020 PMCID: PMC4460038 DOI: 10.1371/journal.pone.0123967] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2014] [Accepted: 01/29/2015] [Indexed: 11/19/2022] Open
Abstract
Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.
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18
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Durrans A, Gao D, Gupta R, Fischer KR, Choi H, El Rayes T, Ryu S, Nasar A, Spinelli CF, Andrews W, Elemento O, Nolan D, Stiles B, Rafii S, Narula N, Davuluri R, Altorki NK, Mittal V. Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC. PLoS One 2015; 10:e0129123. [PMID: 26046767 PMCID: PMC4457876 DOI: 10.1371/journal.pone.0129123] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/08/2014] [Accepted: 05/05/2015] [Indexed: 02/02/2023] Open
Abstract
Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor “activated/reprogrammed” stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value.
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Affiliation(s)
- Anna Durrans
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Dingcheng Gao
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Ravi Gupta
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, United States of America
| | - Kari R. Fischer
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Hyejin Choi
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Tina El Rayes
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Seongho Ryu
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Abu Nasar
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Cathy F. Spinelli
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Weston Andrews
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Olivier Elemento
- Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Daniel Nolan
- HHMI, Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Brendon Stiles
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Shahin Rafii
- HHMI, Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Navneet Narula
- Department of Pathology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
| | - Ramana Davuluri
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, United States of America
| | - Nasser K. Altorki
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- * E-mail: (NKA); (VM)
| | - Vivek Mittal
- Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America
- * E-mail: (NKA); (VM)
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Kim EJ, Juhnn YS. Cyclic AMP signaling reduces sirtuin 6 expression in non-small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf-MEK-ERK (Raf/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase) pathway. J Biol Chem 2015; 290:9604-13. [PMID: 25713071 DOI: 10.1074/jbc.m114.633198] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/15/2014] [Indexed: 12/18/2022] Open
Abstract
The cAMP signaling system regulates various cellular functions, including metabolism, gene expression, and death. Sirtuin 6 (SIRT6) removes acetyl groups from histones and regulates genomic stability and cell viability. We hypothesized that cAMP modulates SIRT6 activity to regulate apoptosis. Therefore, we examined the effects of cAMP signaling on SIRT6 expression and radiation-induced apoptosis in lung cancer cells. cAMP signaling in H1299 and A549 human non-small cell lung cancer cells was activated via the expression of constitutively active Gαs plus treatment with prostaglandin E2 (PGE2), isoproterenol, or forskolin. The expression of sirtuins and signaling molecules were analyzed by Western blotting. Activation of cAMP signaling reduced SIRT6 protein expression in lung cancer cells. cAMP signaling increased the ubiquitination of SIRT6 protein and promoted its degradation. Treatment with MG132 and inhibiting PKA with H89 or with a dominant-negative PKA abolished the cAMP-mediated reduction in SIRT6 levels. Treatment with PGE2 inhibited c-Raf activation by increasing inhibitory phosphorylation at Ser-259 in a PKA-dependent manner, thereby inhibiting downstream MEK-ERK signaling. Inhibiting ERK with inhibitors or with dominant-negative ERKs reduced SIRT6 expression, whereas activation of ERK by constitutively active MEK abolished the SIRT6-depleting effects of PGE2. cAMP signaling also augmented radiation-induced apoptosis in lung cancer cells. This effect was abolished by exogenous expression of SIRT6. It is concluded that cAMP signaling reduces SIRT6 expression by promoting its ubiquitin-proteasome-dependent degradation, a process mediated by the PKA-dependent inhibition of the Raf-MEK-ERK pathway. Reduced SIRT6 expression mediates the augmentation of radiation-induced apoptosis by cAMP signaling in lung cancer cells.
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Affiliation(s)
- Eui-Jun Kim
- From the Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
| | - Yong-Sung Juhnn
- From the Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
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20
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Zou Y, Qin X, Xiong H, Zhu F, Chen T, Wu H. Apoptosis of human non-small-cell lung cancer A549 cells triggered by evodiamine through MTDH-dependent signaling pathway. Tumour Biol 2015; 36:5187-93. [PMID: 25652471 DOI: 10.1007/s13277-015-3174-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2015] [Accepted: 01/26/2015] [Indexed: 01/28/2023] Open
Abstract
Metadherin (MTDH), a novel oncoprotein, has been implicated in the carcinogenesis in various aspects of tumor malignancy. Overexpression of the MTDH promotes the survival and proliferation of lung cancer cells. Agent that can suppress MTDH activation would have potential to be developed for cancer therapeutics. In this study, we investigated the antitumor effect of evodiamine in human non-small-cell lung carcinoma (NSCLC) A549 cell line and the inhibitory effect of evodiamine on MTDH pathway. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and annexin V/propidium iodide (PI) staining assays demonstrated that evodiamine or MTDH short hairpin RNA (shRNA) significantly inhibited proliferation of A549 cells via induction of apoptosis. Besides, evodiamine or MTDH shRNA-induced activation of the caspase-3 in A549 cells under same conditions. In addition, Western blotting analysis showed that treatment of A549 cells with evodiamine or MTDH shRNA resulted in an increase of proapoptotic protein Bax expression but decreased the expression levels of antiapoptotic protein Bcl-2 and MTDH, which altogether account for apoptotic cell death. Taken together, our results suggest that the evodiamine suppress the proliferation of lung cancer cells, at least, in part, via inhibition of MTDH expression and activation of apoptosis.
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Affiliation(s)
- Yanmei Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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21
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Shi C, Ahmad Khan S, Wang K, Schneider M. Improved delivery of the natural anticancer drug tetrandrine. Int J Pharm 2015; 479:41-51. [DOI: 10.1016/j.ijpharm.2014.12.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/01/2014] [Revised: 12/10/2014] [Accepted: 12/11/2014] [Indexed: 12/18/2022]
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22
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Shi X, Liang W, Yang W, Xia R, Song Y. Decorin is responsible for progression of non-small-cell lung cancer by promoting cell proliferation and metastasis. Tumour Biol 2014; 36:3345-54. [PMID: 25524578 DOI: 10.1007/s13277-014-2968-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2014] [Accepted: 12/09/2014] [Indexed: 12/30/2022] Open
Abstract
Decorin, a member of the small leucine-rich proteoglycans family, exists and plays multifunctional roles in stromal and epithelial cells. Emerging evidences showed that decorin is dysregulated expression in a wide variety of human tumors and affects a broad biology process of cancer cells, including growth, metastasis, and angiogenesis. Recent studies demonstrated that decorin could affect A549 proliferation though decreasing TGF-β1, cycling D1 expression and increasing P53 and P21 expression. However, limited data are available on the effect of decorin on metastasis of non-small-cell lung cancer (NSCLC) cell lines and how decorin impacts metastasis is still unknown. In this study, we identified decorin mRNA expression through Oncomine database and verified the expression of decorin mRNA and protein in 50 patients who underwent primary surgical resection of a NSCLC in the Department of Thoracic Surgery, Jinling Hospital, Nanjing University School of Medicine, China, between September 2013 and March 2014 by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot. Also, the correlationship between decorin and the NSCLC patients' clinical characteristics or survival ( www.kmplot.com ) was analyzed. Via ectopic expression analyses and Western blot, the roles of decorin in proliferation, metastasis, and the underline mechanism for decorin expression were further explored. We found that decorin was downregulated in NSCLC tissues compared with the adjacent normal lung tissues or normal tissues. Additionally, the expression of decorin was correlated with tumor size, lymph node metastasis, tumor stage, and prognosis. We also showed that overexpression of decorin could inhibit NSCLC cell lines proliferation and metastasis. Through Western blot analysis, we identified that E-cadherin and vascular endothelial growth factor (VEGF) are two key factors responsible for the growth arrest and metastasis inhibition induced by decorin in NSCLC. Our results indicated that decorin plays crucial roles in NSCLC against carcinogenesis and progression. Decorin might be a predictive factor and an attractive therapeutic target for NSCLC patients.
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Affiliation(s)
- Xuefei Shi
- Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China,
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Zou Y, Zhang P, Zhu F, Xiong H. WITHDRAWN: Evodiamine triggers apoptosis in human non-small cell lung cancer A549 cells via targeting MTDH-mediated signaling pathway. Pharmacotherapy 2014. [DOI: 10.1016/j.biopha.2014.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/24/2022]
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Liang H, Liu M, Yan X, Zhou Y, Wang W, Wang X, Fu Z, Wang N, Zhang S, Wang Y, Zen K, Zhang CY, Hou D, Li J, Chen X. miR-193a-3p functions as a tumor suppressor in lung cancer by down-regulating ERBB4. J Biol Chem 2014; 290:926-40. [PMID: 25391651 DOI: 10.1074/jbc.m114.621409] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/19/2022] Open
Abstract
ERBB4, one of four ErbB receptor tyrosine kinase family members, plays an important role in the etiology and progression of lung cancer. In this study, we found that the ERBB4 protein levels were consistently up-regulated in lung cancer tissues, whereas the mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in regulating ERBB4 expression. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that can potentially target ERBB4. We identified specific targeting sites for miR-193a-3p in the 3'-UTR of ERBB4. We further identified an inverse correlation between miR-193a-3p levels and ERBB4 protein levels, but not mRNA levels, in lung cancer tissue samples. By overexpressing or knocking down miR-193a-3p in lung cancer cells, we experimentally confirmed that miR-193a-3p directly recognizes the 3'-UTR of the ERBB4 transcript and regulates ERBB4 expression. Furthermore, the biological consequences of the targeting of ERBB4 by miR-193a-3p were examined in vitro via cell proliferation, invasion, and apoptosis assays and in vivo using a mouse xenograft tumor model. We demonstrated that the repression of ERBB4 by miR-193a-3p suppressed proliferation and invasion and promoted apoptosis in lung cancer cells and that miR-193a-3p exerted an anti-tumor effect by negatively regulating ERBB4 in xenograft mice. Taken together, our findings provide the first clues regarding the role of miR-193a-3p as a tumor suppressor in lung cancer through the inhibition of ERBB4 translation.
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Affiliation(s)
- Hongwei Liang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Minghui Liu
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Xin Yan
- the Comprehensive Cancer Center of Drum Tower Hospital affiliated with Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, China, and
| | - Yong Zhou
- the Department of Thoracic and Cardiovascular surgery, Drum Tower Hospital affiliated with Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Wengong Wang
- the Department of Thoracic and Cardiovascular surgery, Drum Tower Hospital affiliated with Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Xueliang Wang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Zheng Fu
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Nan Wang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Suyang Zhang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Yanbo Wang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Ke Zen
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Chen-Yu Zhang
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Dongxia Hou
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China,
| | - Jing Li
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China,
| | - Xi Chen
- From the Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China,
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Wang N, Liang H, Zhou Y, Wang C, Zhang S, Pan Y, Wang Y, Yan X, Zhang J, Zhang CY, Zen K, Li D, Chen X. miR-203 suppresses the proliferation and migration and promotes the apoptosis of lung cancer cells by targeting SRC. PLoS One 2014; 9:e105570. [PMID: 25140799 PMCID: PMC4139332 DOI: 10.1371/journal.pone.0105570] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/07/2014] [Accepted: 07/21/2014] [Indexed: 12/19/2022] Open
Abstract
SRC, also known as proto-oncogene c-Src, is a non-receptor tyrosine kinase that plays an important role in cancer progression by promoting survival, angiogenesis, proliferation, and invasion pathways. In this study, we found that SRC protein levels were consistently upregulated in lung cancer tissues, but that SRC mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in SRC regulation. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for miRNAs that potentially target SRC. We identified specific targeting sites for miR-203 in the 3′-untranslated region (3′-UTR) of SRC. We then experimentally validated miR-203 as a direct regulator of SRC using cell transfection and luciferase assays and showed that miR-203 inhibited SRC expression and consequently triggered suppression of the SRC/Ras/ERK pathway. Finally, we demonstrated that the repression of SRC by miR-203 suppressed the proliferation and migration and promoted the apoptosis of lung cancer cells. In summary, this study provides the first clues regarding the role of miR-203 as a tumor suppressor in lung cancer cells through the inhibition of SRC translation.
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Affiliation(s)
- Nan Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Hongwei Liang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yong Zhou
- Department of Thoracic and Cardiovascular surgery, Affiliated Gulou Hospital, Medical college of Nanjing University, Nanjing, Jiangsu, China
| | - Chen Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Suyang Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yi Pan
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yanbo Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Yan
- The Comprehensive Cancer Center of Drum Tower Hospital affiliated to Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, China
| | - Junfeng Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Chen-Yu Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Ke Zen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Donghai Li
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
- * E-mail: (XC); or (DL)
| | - Xi Chen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
- * E-mail: (XC); or (DL)
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Davidson MR, Gazdar AF, Clarke BE. The pivotal role of pathology in the management of lung cancer. J Thorac Dis 2014; 5 Suppl 5:S463-78. [PMID: 24163740 DOI: 10.3978/j.issn.2072-1439.2013.08.43] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/31/2013] [Accepted: 08/19/2013] [Indexed: 12/14/2022]
Abstract
The last decade has seen significant advances in our understanding of lung cancer biology and management. Identification of key driver events in lung carcinogenesis has contributed to the development of targeted lung cancer therapies, heralding the era of personalised medicine for lung cancer. As a result, histological subtyping and molecular testing has become of paramount importance, placing increasing demands on often small diagnostic specimens. This has triggered the review and development of the first structured classification of lung cancer in small biopsy/cytology specimens and a new classification of lung adenocarcinoma from the IASLC/ATS/ERS. These have enhanced the clinical relevance of pathological diagnosis, and emphasise the role of the modern surgical pathologist as an integral member of the multidisciplinary team, playing a crucial role in clinical trials and determining appropriate and timely management for patients with lung cancer.
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Affiliation(s)
- Morgan R Davidson
- University of Queensland Thoracic Research Centre, The Prince Charles Hospital, QLD, Australia; ; Department of Anatomical Pathology, Royal Brisbane and Women's Hospital, QLD, Australia
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Benjamin AB, Zhou X, Isaac O, Zhao H, Song Y, Chi X, Sun B, Hao L, Zhang L, Liu L, Guan H, Shao S. PRP19 upregulation inhibits cell proliferation in lung adenocarcinomas by p21-mediated induction of cell cycle arrest. Biomed Pharmacother 2014; 68:463-70. [DOI: 10.1016/j.biopha.2014.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/14/2014] [Accepted: 03/04/2014] [Indexed: 11/25/2022] Open
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Cao M, Hou D, Liang H, Gong F, Wang Y, Yan X, Jiang X, Wang C, Zhang J, Zen K, Zhang CY, Chen X. miR-150 promotes the proliferation and migration of lung cancer cells by targeting SRC kinase signalling inhibitor 1. Eur J Cancer 2014; 50:1013-24. [PMID: 24456795 DOI: 10.1016/j.ejca.2013.12.024] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2013] [Revised: 10/30/2013] [Accepted: 12/27/2013] [Indexed: 11/15/2022]
Abstract
microRNAs (miRNAs) are a class of endogenously expressed, small non-coding RNAs that play an important role in the regulation of gene expression at the post-transcriptional level. Dysregulation of miRNAs is associated with a variety of diseases, including lung cancer. In the present study, miR-150 was found to be significantly upregulated in lung cancer clinical specimens by quantitative real-time polymerase chain reaction (RT-PCR). Using bioinformatics analysis, v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) kinase signalling inhibitor 1 (SRCIN1), an important regulator of SRC activity, was predicted to be a potential target of miR-150. Furthermore, an inverse correlation between miR-150 and SRCIN1 protein levels, but not mRNA levels, was identified in human lung cancer tissue samples. By overexpressing or knocking down miR-150 in lung adenocarcinoma A549 cells and H1975 cells, it was experimentally validated that miR-150 is a direct regulator of SRCIN1. It was further confirmed that miR-150 directly recognises the 3'-untranslated region (3'-UTR) of SRCIN1 transcript with a luciferase reporter assay. Finally, it was demonstrated that the repression of SRCIN1 by miR-150 consequently triggered the activation of the Src/focal adhesion kinase (FAK) and Src/Ras/extracellular signal-regulated kinase (ERK) pathway, which eventually promoted the proliferation and migration of A549 cells, and this promotion by miR-150 could be reversed by overexpressing SRCIN1. Taken together, our findings provide the first clues regarding the role of miR-150 as an oncogene in lung cancer through the inhibition of SRCIN1 translation.
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Affiliation(s)
- Minghui Cao
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Dongxia Hou
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Hongwei Liang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Fei Gong
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Yilei Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Xin Yan
- Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Tianjin 300060, China
| | - Xiaohong Jiang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Chen Wang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Junfeng Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Ke Zen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China
| | - Chen-Yu Zhang
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
| | - Xi Chen
- Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Synaptic acetylcholinesterase targeted by microRNA-212 functions as a tumor suppressor in non-small cell lung cancer. Int J Biochem Cell Biol 2013; 45:2530-40. [PMID: 23974008 DOI: 10.1016/j.biocel.2013.08.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/31/2013] [Revised: 08/08/2013] [Accepted: 08/12/2013] [Indexed: 11/20/2022]
Abstract
Acetylcholinesterase expression is modulated in various types of tumor, which suggests it is associated with tumor development; however, the mechanism of acetylcholinesterase gene regulation in tumors remains unclear. Here, we report that acetylcholinesterase is aberrantly expressed in non-small cell lung cancer and is an evolutionarily conserved functional target of miR-212. Acetylcholinesterase expression was negatively regulated by miR-212 in vitro and was inversely correlated with miR-212 expression in vivo. In addition, acetylcholinesterase levels were increased, and miR-212 levels decreased, in non-small cell lung cancer cells during cisplatin-induced apoptosis. We further determined that acetylcholinesterase acted as a pro-apoptotic gene in non-small cell lung cells; and attenuated the growth of xenografts in nude mice when upregulated. In contrast, elevated miR-212 levels preserved the protective effect of acetylcholinesterase silencing by RNA interference against cisplatin-induced apoptosis, whereas restoration of miR-212-resistant synaptic acetylcholinesterase expression inhibited the miR-212 anti-apoptotic function. The results demonstrated that miR-212 exerted an anti-apoptotic effect through direct repression of synaptic acetylcholinesterase expression in non-small cell lung cancer cells. Taken together, our study revealed that synaptic acetylcholinesterase may be a tumor suppressor and is modulated by miR-212 in non-small cell lung cancer.
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Shimojo M, Shudo Y, Ikeda M, Kobashi T, Ito S. The small cell lung cancer-specific isoform of RE1-silencing transcription factor (REST) is regulated by neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100). Mol Cancer Res 2013; 11:1258-68. [PMID: 23928058 DOI: 10.1158/1541-7786.mcr-13-0269] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Small cell lung cancer (SCLC) is a highly malignant form of cancer, which originates from primitive neuroendocrine cells in the lung. SCLC cells express several autocrine neurotransmitters/neuropeptides and their respective receptors. Expression of these neuronal markers is frequently regulated by RE1-silencing transcription factor (REST). In SCLC cells, an SCLC-specific isoform of REST (sREST) is highly expressed, whereas REST expression is undetectable, suggesting that the expression of sREST correlates with the pathogenesis of SCLC. Expression of sREST, which is derived through alternative splicing of REST, is abnormally regulated in SCLC cells, but the mechanism is unknown. Most recently, nSR100 (SRRM4) was described as an activator of REST alternative splicing. We now show that nSR100 is highly expressed in SCLC cells correlating with high sREST and low REST expression. Adhesion to the extracellular matrix (ECM) is thought to enhance tumorigenicity and confer resistance to apoptosis. Interestingly, nSR100 expression is enhanced in cells grown with ECM. Overexpression of REST caused repression of sREST and nSR100, the latter containing RE1 element controlled by REST. Culturing the SCLC cell line NCI-N417 cells with ECM also upregulated RE1-containing gene, the voltage-gated calcium channel subunit. Inhibition of the PI3K/Akt/mTOR pathway by LY294002 induced nSR100 expression, whereas the specific MEK/ERK inhibitor U0126 inhibited nSR100 expression. Repressing nSR100 by siRNA effectively repressed sREST, and conversely increased REST in NCI-N417 cells. Taken together, this report clarifies the ECM-dependent signaling pathway that impacts nSR100 expression and its regulation of alternative splicing in SCLC. IMPLICATIONS The splicing factor nSR100 may be novel SCLC-specific biomarker, as well as a therapeutic target.
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Affiliation(s)
- Masahito Shimojo
- Department of Medical Chemistry, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan.
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Shan Z, Shakoori A, Bodaghi S, Goldsmith P, Jin J, Wiest JS. TUSC1, a putative tumor suppressor gene, reduces tumor cell growth in vitro and tumor growth in vivo. PLoS One 2013; 8:e66114. [PMID: 23776618 PMCID: PMC3679066 DOI: 10.1371/journal.pone.0066114] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2013] [Accepted: 04/05/2013] [Indexed: 12/31/2022] Open
Abstract
We previously reported the identification of TUSC1 (Tumor Suppressor Candidate 1), as a novel intronless gene isolated from a region of homozygous deletion at D9S126 on chromosome 9p in human lung cancer. In this study, we examine the differential expression of TUSC1 in human lung cancer cell lines by western blot and in a primary human lung cancer tissue microarray by immunohistochemical analysis. We also tested the functional activities and mechanisms of TUSC1 as a tumor suppressor gene through growth suppression in vitro and in vivo. The results showed no expression of TUSC1 in TUSC1 homozygously deleted cells and diminished expression in some tumor cell lines without TUSC1 deletion. Interestingly, the results from a primary human lung cancer tissue microarray suggested that higher expression of TUSC1 was correlated with increased survival times for lung cancer patients. Our data demonstrated that growth curves of tumor cell lines transfected with TUSC1 grew slower in vitro than those transfected with the empty vector. More importantly, xenograph tumors in nude mice grew significantly slower in vivo in cells stably transfected with TUSC1 than those transfected with empty vector. In addition, results from confocal microscopy and immunohistochemical analyses show distribution of TUSC1 in the cytoplasm and nucleus in tumor cell lines and in normal and tumor cells in the lung cancer tissue microarray. Taken together, our results support TUSC1 has tumor suppressor activity as a candidate tumor suppressor gene located on chromosome 9p.
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Affiliation(s)
- Zhihong Shan
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Abbas Shakoori
- Advanced Genome Technology Center, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America
| | - Sohrab Bodaghi
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Paul Goldsmith
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Jen Jin
- Advanced Genome Technology Center, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America
| | - Jonathan S. Wiest
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
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Qiu X, Wang Z, Li Y, Miao Y, Ren Y, Luan Y. Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446. Cancer Lett 2012; 323:161-70. [DOI: 10.1016/j.canlet.2012.04.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2011] [Revised: 03/06/2012] [Accepted: 04/08/2012] [Indexed: 01/06/2023]
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NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer. PLoS One 2012; 7:e45305. [PMID: 23028920 PMCID: PMC3444449 DOI: 10.1371/journal.pone.0045305] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/20/2012] [Accepted: 08/21/2012] [Indexed: 12/26/2022] Open
Abstract
Background Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. Methodology/Principal Findings Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (rs). Occupational exposure was associated with an up-regulation of NOTCH1 (radon rs = 0.18, 95% CI 0.02–0.33; arsenic: rs = 0.23, 95% CI 0.07–0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. Conclusions/Significance These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.
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Jadus MR, Natividad J, Mai A, Ouyang Y, Lambrecht N, Szabo S, Ge L, Hoa N, Dacosta-Iyer MG. Lung cancer: a classic example of tumor escape and progression while providing opportunities for immunological intervention. Clin Dev Immunol 2012; 2012:160724. [PMID: 22899945 PMCID: PMC3414063 DOI: 10.1155/2012/160724] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2012] [Revised: 04/29/2012] [Accepted: 04/30/2012] [Indexed: 12/31/2022]
Abstract
Lung cancers remain one of the most common and deadly cancers in the world today (12.5% of newly diagnosed cancers) despite current advances in chemo- and radiation therapies. Often, by the time these tumors are diagnosed, they have already metastasized. These tumors demonstrate the classic hallmarks of cancer in that they have advanced defensive strategies allowing them to escape various standard oncological treatments. Immunotherapy is making inroads towards effectively treating other fatal cancers, such as melanoma, glioblastoma multiforme, and castrate-resistant prostate cancers. This paper will cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. We also review the history of immunotherapy directed towards lung cancers.
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Affiliation(s)
- Martin R Jadus
- Research Service, VA Long Beach Healthcare System, 5901 E. 7th Street, Long Beach, CA 90822, USA.
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Dey S, Maiti AK, Hegde ML, Hegde PM, Boldogh I, Sarkar PS, Abdel-Rahman SZ, Sarker AH, Hang B, Xie J, Tomkinson AE, Zhou M, Shen B, Wang G, Wu C, Yu D, Lin D, Cardenas V, Hazra TK. Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2. DNA Repair (Amst) 2012; 11:570-8. [PMID: 22497777 DOI: 10.1016/j.dnarep.2012.03.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/26/2011] [Revised: 03/19/2012] [Accepted: 03/20/2012] [Indexed: 01/29/2023]
Abstract
Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Polβ, Lig IIIα and XRCC1) or using NEIL2-FLAG immunocomplexes, an ~5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Polβ. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development.
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Affiliation(s)
- Sanjib Dey
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
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Hubaux R, Becker-Santos DD, Enfield KSS, Lam S, Lam WL, Martinez VD. MicroRNAs As Biomarkers For Clinical Features Of Lung Cancer. METABOLOMICS : OPEN ACCESS 2012; 2:1000108. [PMID: 25221729 PMCID: PMC4159950 DOI: 10.4172/2153-0769.1000108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/19/2022]
Abstract
Each year about 1.4 million people die from lung cancer worldwide. Despite efforts in prevention, diagnosis and treatment, survival rate remains poor for this disease. This unfortunate situation is largely due to the fact that a high proportion of cases are diagnosed at advanced stages, highlighting the great need for identifying new biomarkers in order to improve early diagnosis and treatment. Recent studies on microRNAs have not only shed light on their involvement in tumor development and progression, but also suggested their potential utility as biomarkers for subtype diagnostics, staging and prediction of treatment response. This review article summarizes the impact of microRNAs on lung cancer biology, and highlights their role in the detection and classification of lung cancer as well as direct targets for drug development.
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Affiliation(s)
- Roland Hubaux
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
| | - Daiana D. Becker-Santos
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
| | - Katey S. S. Enfield
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
| | - Stephen Lam
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
| | - Wan L. Lam
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
| | - Victor D. Martinez
- Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, V5Z 1L3 Vancouver, B.C., Canada
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TFPI-2 methylation predicts poor prognosis in non-small cell lung cancer. Lung Cancer 2011; 76:106-11. [PMID: 21983100 DOI: 10.1016/j.lungcan.2011.09.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/30/2011] [Revised: 08/03/2011] [Accepted: 09/06/2011] [Indexed: 12/25/2022]
Abstract
BACKGROUND Methylation of human tissue factor pathway inhibitor-2 (TFPI-2) gene has been detected in several types of cancer, including non-small cell lung cancer (NSCLC). However, an association between the methylation status of TFPI-2 gene and prognosis has not yet been investigated. METHODS Methylation of TFPI-2 gene was examined in a consecutive series of 133 non-metastatic NSCLC patients using methylation-specific PCR (MSP). Univariate and multivariate analyses were conducted to investigate the association between clinical variables and overall survival time. RESULTS Methylation of TFPI-2 gene was detected in 36 of 133 patients (27.1%). Of these 36 patients, seventeen individuals (47.2%) carried stage III tumors. The 5-year disease free survival rate among patients carrying methylated TFPI-2 tumors was significantly lower as compared to those with unmethylated TFPI-2 tumors (35.5% versus 6.1%, P<0.0001). Moreover, methylation of TFPI-2 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (P=0.013), as was age >62 years old (P<0.0001) and TNM stage of disease (P<0.0001). CONCLUSIONS The results of the present study suggest that methylation of TFPI-2 gene is an independent factor for an unfavorable prognosis in patients with NSCLC.
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Baldi A, De Luca A, Esposito V, Campioni M, Spugnini EP, Citro G. Tumor suppressors and cell-cycle proteins in lung cancer. PATHOLOGY RESEARCH INTERNATIONAL 2011; 2011:605042. [PMID: 22007345 PMCID: PMC3189597 DOI: 10.4061/2011/605042] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 12/31/2010] [Accepted: 08/08/2011] [Indexed: 11/20/2022]
Abstract
The cell cycle is the cascade of events that allows a growing cell to duplicate all its components and split into two daughter cells. Cell cycle progression is mediated by the activation of a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). CDKs are also regulated by related proteins called cdk inhibitors grouped into two families: the INK4 inhibitors (p16, p15, p19, and p18) and the Cip/Kip inhibitors (p21, p27, and p53). Several studies report the importance of cell-cycle proteins in the pathogenesis and the prognosis of lung cancer. This paper will review the most recent data from the literature about the regulation of cell cycle. Finally, based essentially on the data generated in our laboratory, the expression, the diagnostic, and prognostic significance of cell-cycle molecules in lung cancer will be examined.
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Affiliation(s)
- Alfonso Baldi
- Section of Pathology, Department of Biochemistry, Second University of Naples, 80138 Naples, Italy
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Kim CE, Tchou-Wong KM, Rom WN. Sputum-based molecular biomarkers for the early detection of lung cancer: limitations and promise. Cancers (Basel) 2011; 3:2975-89. [PMID: 24212941 PMCID: PMC3759181 DOI: 10.3390/cancers3032975] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/03/2011] [Revised: 07/11/2011] [Accepted: 07/12/2011] [Indexed: 12/31/2022] Open
Abstract
Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputum-based molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers.
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Affiliation(s)
- Connie E. Kim
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016, USA; E-Mails: (C.E.K.); (K.-M.T.-W.)
| | - Kam-Meng Tchou-Wong
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016, USA; E-Mails: (C.E.K.); (K.-M.T.-W.)
- Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
| | - William N. Rom
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016, USA; E-Mails: (C.E.K.); (K.-M.T.-W.)
- Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 212-263-6479; Fax: 212-263-8442
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Buonomo T, Carraresi L, Rossini M, Martinelli R. Involvement of aryl hydrocarbon receptor signaling in the development of small cell lung cancer induced by HPV E6/E7 oncoproteins. J Transl Med 2011; 9:2. [PMID: 21205295 PMCID: PMC3022727 DOI: 10.1186/1479-5876-9-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/22/2010] [Accepted: 01/04/2011] [Indexed: 12/30/2022] Open
Abstract
Background Lung cancers consist of four major types that and for clinical-pathological reasons are often divided into two broad categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). All major histological types of lung cancer are associated with smoking, although the association is stronger for SCLC and squamous cell carcinoma than adenocarcinoma. To date, epidemiological studies have identified several environmental, genetic, hormonal and viral factors associated with lung cancer risk. It has been estimated that 15-25% of human cancers may have a viral etiology. The human papillomavirus (HPV) is a proven cause of most human cervical cancers, and might have a role in other malignancies including vulva, skin, oesophagus, head and neck cancer. HPV has also been speculated to have a role in the pathogenesis of lung cancer. To validate the hypothesis of HPV involvement in small cell lung cancer pathogenesis we performed a gene expression profile of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins. Methods Gene expression profile of SCLC has been performed using Agilent whole mouse genome (4 × 44k) representing ~ 41000 genes and mouse transcripts. Samples were obtained from two HPV16-E6/E7 transgenic mouse models and from littermate's normal lung. Data analyses were performed using GeneSpring 10 and the functional classification of deregulated genes was performed using Ingenuity Pathway Analysis (Ingenuity® Systems, http://www.ingenuity.com). Results Analysis of deregulated genes induced by the expression of E6/E7 oncoproteins supports the hypothesis of a linkage between HPV infection and SCLC development. As a matter of fact, comparison of deregulated genes in our system and those in human SCLC showed that many of them are located in the Aryl Hydrocarbon Receptor Signal transduction pathway. Conclusions In this study, the global gene expression of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins led us to identification of several genes involved in SCLC tumor development. Furthermore, our study reveled that the Aryl Hydrocarbon Receptor Signaling is the primarily affected pathway by the E6/E7 oncoproteins expression and that this pathway is also deregulated in human SCLC. Our results provide the basis for the development of new therapeutic approaches against human SCLC.
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Affiliation(s)
- Tonia Buonomo
- CEINGE Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Napoli, Italy
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Körner A, Mudduluru G, Manegold C, Allgayer H. Enzastaurin inhibits invasion and metastasis in lung cancer by diverse molecules. Br J Cancer 2010; 103:802-11. [PMID: 20736951 PMCID: PMC2966618 DOI: 10.1038/sj.bjc.6605818] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Revised: 06/22/2010] [Accepted: 06/28/2010] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Enzastaurin (Enz) is a serine/threonine kinase inhibitor blocking protein kinase C (PKC)beta/AKT pathway. However, an ability of this compound to inhibit cancer invasion and metastasis is not yet clearly elucidated. METHODS The ability of Enz to inhibit invasion and metastasis, and to target molecules was investigated in non-small cell lung cancer (NSCLC) by RT-PCR validated microarray, Matrigel, and in vivo chorionallantoic membrane (CAM) assays. RESULTS Enzastaurin significantly reduced migration, invasion, and in vivo metastasis to lungs and liver (CAM assay) of diverse NSCLC cell lines. Genes promoting cancer progression (u-PAR, VEGFC, and HIF1alpha) and tumour suppression (VHL, RASSF1, and FHIT) of NSCLC were significantly (P<0.05) down- or upregulated after Enz treatment in H460, A549, and H1299 cells, respectively. Luciferase/chromatin immunoprecipitation analysis showed that Enz transcriptionally controls urokinase-type plasminogen activator receptor (u-PAR) expression by promoter inhibition through Sp1, Sp3, and c-Jun(AP-1). Moreover, siRNA knockdown of u-PAR re-sensitised Enz-resistant cells and induced apoptosis, suggesting u-PAR as a marker of Enz resistance. CONCLUSION This study shows that Enz inhibits migration, invasion, and in vivo metastasis by targeting u-PAR, besides further targeting progression-related and tumour-suppressor genes in NSCLC. Together with u-PAR being a novel putative marker of Enz response, these data encourage molecularly tailored clinical studies on Enz in NSCLC therapy.
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Affiliation(s)
- A Körner
- Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors (German Cancer Research Center-DKFZ-Heidelberg), Mannheim Medical Faculty, Ruprecht-Karls-University Heidelberg, Mannheim 68167, Germany
| | - G Mudduluru
- Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors (German Cancer Research Center-DKFZ-Heidelberg), Mannheim Medical Faculty, Ruprecht-Karls-University Heidelberg, Mannheim 68167, Germany
| | - C Manegold
- Interdisciplinary Thoracic Oncology, Department of Surgery, Medical Faculty Mannheim, University Heidelberg, Mannheim 68167, Germany
| | - H Allgayer
- Department of Experimental Surgery Mannheim/Molecular Oncology of Solid Tumors (German Cancer Research Center-DKFZ-Heidelberg), Mannheim Medical Faculty, Ruprecht-Karls-University Heidelberg, Mannheim 68167, Germany
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Yang CJ, Huang YJ, Wang CY, Wang CS, Wang PH, Hung JY, Wang TH, Hsu HK, Huang HW, Kumar SPA, Huang MS, Weng CF. Antiproliferative and antitumorigenic activity of Toona sinensis leaf extracts in lung adenocarcinoma. J Med Food 2010; 13:54-61. [PMID: 20136436 DOI: 10.1089/jmf.2009.1166] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/13/2022] Open
Abstract
Toona sinensis is a traditional Chinese herb, and the extracts of T. sinensis leaf possess a variety of biological functions. This study attempted to test the antiproliferative effect of TSL-1 (a bioactive fraction of T. sinensis) in H441 cells (lung adenocarcinoma). The data showed that the antiproliferative effect of TSL-1 on H441 cells is prominent using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TSL-1-induced apoptosis was confirmed by cell morphology, sub-G(1) peak accumulation, cleavage of poly(ADP)-ribose polymerase, and propidium iodide-annexin V double staining. Furthermore, decreased Bcl-2 accompanied by increased Bax (in western blotting) was found with TSL-1 treatment of H441 cells. TSL-1 treatment-induced G(1) arrest was concurrent with the down-regulation of protein levels of cyclin D1 and cyclin-dependent kinase 4 in H441 cells. Peroral and intraperitoneal administrations of TSL-1 were performed to evaluate the therapeutic efficacy, and peroral administration of TSL-1 was also used to elucidate the therapeutic efficacy in the H441 cell xenograft model in vivo. The data revealed that TSL-1 treatment inhibited H441 tumor growth in both therapeutic and preventive experiments. Taken together, these results demonstrate that TSL-1 possesses the capability of preventing and alleviating lung cancer proliferation in vitro and in vivo with proven nephrological and hepatic safety and has the potential to be developed as an anti-lung cancer drug.
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Affiliation(s)
- Chih-Jen Yang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Department of Internal Medicine, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Alterations in p16 and p53 genes and chromosomal findings in patients with lung cancer: Fluorescence in situ hybridization and cytogenetic studies. Cancer Epidemiol 2010; 34:472-7. [DOI: 10.1016/j.canep.2010.03.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/29/2009] [Revised: 03/07/2010] [Accepted: 03/27/2010] [Indexed: 11/23/2022]
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Dingemans AMC, van den Boogaart V, Vosse BA, van Suylen RJ, Griffioen AW, Thijssen VL. Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer. Mol Cancer 2010; 9:152. [PMID: 20565758 PMCID: PMC2895598 DOI: 10.1186/1476-4598-9-152] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/07/2009] [Accepted: 06/17/2010] [Indexed: 11/10/2022] Open
Abstract
Background Selection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer. Methods A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8. Results The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same. Conclusion Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.
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Affiliation(s)
- Anne-Marie C Dingemans
- Department of Pulmonology, Maastricht University Medical Center, P, Debyeplein 25, Maastricht, The Netherlands.
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Antiproliferative effect of Toona sinensis leaf extract on non-small-cell lung cancer. Transl Res 2010; 155:305-14. [PMID: 20478545 PMCID: PMC7185486 DOI: 10.1016/j.trsl.2010.03.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/14/2009] [Revised: 02/12/2010] [Accepted: 03/16/2010] [Indexed: 11/24/2022]
Abstract
Toona sinensis (TS), which is also known as Cedrela sinensis, belongs to Meliaceae family, the compounds identified from this TS leaves possess a wide range of biologic functions, such as hypoglycemic effects, anti-LDL glycative activity, antioxidant activities, and inhibition of sudden acute respiratory syndrome (SARS) coronavirus replication. However, their effect against cancer cells is not well explored. In this study, to understand the cytotoxic effect and molecular mechanism stimulated by TSL-1 (TS leaf extract fraction) we employed three different non-small-cell lung cancer (NSCLC) cell lines: H441 cells (lung adenocarcinoma), H661 cells (lung large cell carcinoma) and H520 cells (lung squamous cell carcinoma). IC50 value was varied between these three cell lines, the least IC(50) value was observed in TSL-1-treated H661cells. Exposure of NSCLC cells to TSL-1 caused cell-cycle arrest in subG1 phase and caused apoptosis. Moreover, TSL-1 treatment decreased the cell-cycle regulators; cyclin D1 and CDK4 proteins by up regulating p27 expression in a dose-dependent manner. Thus, the TSL-1-induced apoptosis was further confirmed by cell morphology, subG1 peak accumulation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) cleavage, propidium iodide (PI)-Annexin-V double staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The decreased Bcl2 protein level was concurrent with an increased Bax protein level in all 3 cell lines. Additionally, the tumoricidal effect of TSL-1 was measured using a xenograft model, after 5 weeks of TSL-1 treatment by various regimen caused regression of tumor. Taken together both these in vitro and in vivo studies revealed that TSL-1 is a potent inhibitor against NSCLC growth and our provoking result suggest that TSL-1 can be a better nutriceutical as a singlet or along with doublet agents (taxane, vinorelbine, and gemcitabine) for treating NSCLC.
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Key Words
- cdk, cyclin-dependent kinase
- ecl, enhanced chemiluminescence
- facs, fluorescence-activated cell sorting
- fbs, fetal bovine serum
- ic50, half maximal inhibitory concentration
- mtt, tetrazolium dye
- nsclc, non–small-cell lung cancer
- parp, poly(adenosine diphosphate [adp]-ribose) polymerase
- pbs, phosphate-buffered saline
- pi, propidium iodide
- skov3, human ovarian cancer cell
- rt, room temperature
- ts, toona sinensis
- tsl-1, ts leaf extract fraction-1
- tunel, terminal deoxynucleotidyl transferase-mediated dutp nick end-labeling
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Koga T, Takeshita M, Yano T, Maehara Y, Sueishi K. CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non-small cell lung cancer. Int J Cancer 2010; 128:1009-17. [DOI: 10.1002/ijc.25447] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/17/2023]
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Carozzi FM, Bisanzi S, Falini P, Sani C, Venturini G, Lopes Pegna A, Bianchi R, Ronchi C, Picozzi G, Mascalchi M, Carrozzi L, Baliva F, Pistelli F, Tavanti L, Falaschi F, Grazzini M, Innocenti F, Paci E. Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: Perspectives of integrated strategies for early diagnosis. Lung Cancer 2010; 68:216-21. [DOI: 10.1016/j.lungcan.2009.06.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/23/2009] [Revised: 05/22/2009] [Accepted: 06/20/2009] [Indexed: 01/27/2023]
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Hassan MI, Naiyer A, Ahmad F. Fragile histidine triad protein: structure, function, and its association with tumorogenesis. J Cancer Res Clin Oncol 2010; 136:333-50. [PMID: 20033706 DOI: 10.1007/s00432-009-0751-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/17/2009] [Accepted: 12/09/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND The human fragile histidine triad (FHIT) gene is a putative tumor suppressor gene, which is located at chromosome region 3p14.2. It was suggested that the loss of heterozygosity (LOH), homozygous deletions, and abnormal expression of the FHIT gene were involved in several types of human malignancies. MATERIALS AND METHODS To determine the role of FHIT in various cancers, we have performed structural and functional analysis of FHIT in detail. RESULTS AND DISCUSSION The protein FHIT catalyzes the Mg(2+) dependent hydrolysis of P1-5 cent-O-adenosine-P3-5 cent-O-adenosine triphosphate, Ap3A, to AMP, and ADP. The reaction is thought to follow a two-step mechanism. Histidine triad proteins, named for a motif related to the sequence H-cent-H-cent-H-cent-cent- (cent, a hydrophobic amino acid), belong to superfamily of nucleotide hydrolases and transferases. This enzyme acts on the R-phosphate of ribonucleotides, and contain a approximately 30-kDa domain that is typically a homodimer of approximately 15 kDa polypeptides with catalytic site. CONCLUSION Here we have gathered information is known about biological activities of FHIT, the structural and biochemical bases for their functions. Our approach may provide a comparative framework for further investigation of FHIT.
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Affiliation(s)
- Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
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