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For:
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Xie D, Sham JST, Zeng WF, Lin HL, Che LH, Wu HX, Wen JM, Fang Y, Hu L, Guan XY. Heterogeneous expression and association of beta-catenin, p16 and c-myc in multistage colorectal tumorigenesis and progression detected by tissue microarray. Int J Cancer 2004;107:896-902. [PMID: 14601048 DOI: 10.1002/ijc.11514] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] |
Graphical abstract
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Chandramohan K, Balan DJ, Devi KP, Nabavi SF, Reshadat S, Khayatkashani M, Mahmoodifar S, Filosa R, Amirkhalili N, Pishvaei S, Aval OS, Nabavi SM. Short interfering RNA in colorectal cancer: is it wise to shoot the messenger? Eur J Pharmacol 2023; 949:175699. [PMID: 37011722 DOI: 10.1016/j.ejphar.2023.175699] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the leading cause of gastrointestinal cancer death. 90% of people diagnosed with colorectal cancer are over the age of 50; nevertheless, the illness is more aggressive among those detected at a younger age. Chemotherapy-based treatment has several adverse effects on both normal and malignant cells. The primary signaling pathways implicated in the advancement of CRC include hedgehog (Hh), janus kinase and signal transducer and activator of transcription (JAK/STAT), Wingless-related integration site (Wnt)/β-catenin, transforming growth factor-β (TNF-β), epidermal growth factor receptor (EGFR)/Mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and Notch. Loss of heterozygosity in tumor suppressor genes like adenomatous polyposis coli, as well as mutation or deletion of genes like p53 and Kirsten rat sarcoma viral oncogene (KRAS), are all responsible for the occurrence of CRC. Novel therapeutic targets linked to these signal-transduction cascades have been identified as a consequence of advances in small interfering RNA (siRNA) treatments. This study focuses on many innovative siRNA therapies and methodologies for delivering siRNA therapeutics to the malignant site safely and effectively for the treatment of CRC. Treatment of CRC using siRNA-associated nanoparticles (NPs) may inhibit the activity of oncogenes and MDR-related genes by targeting a range of signaling mechanisms. This study summarizes several siRNAs targeting signaling molecules, as well as the therapeutic approaches that might be employed to treat CRC in the future.
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He WP, Yang GP, Yang ZX, Shen HW, You ZS, Yang GF. Maelstrom promotes tumor metastasis through regulation of FGFR4 and epithelial-mesenchymal transition in epithelial ovarian cancer. J Ovarian Res 2022; 15:55. [PMID: 35513870 PMCID: PMC9074322 DOI: 10.1186/s13048-022-00992-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/27/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Increasing evidence has indicated that Maelstrom (MAEL) plays an oncogenic role in various human carcinomas. However, the exact function and mechanisms by which MAEL acts in epithelial ovarian cancer (EOC) remain unclear. RESULTS This study demonstrated that MAEL was frequently overexpressed in EOC tissues and cell lines. Overexpression of MAEL was positively correlated with the histological grade of tumors, FIGO stage, and pT/pN/pM status (p < 0.05), and it also acted as an independent predictor of poor patient survival (p < 0.001). Ectopic overexpression of MAEL substantially promoted invasiveness/metastasis and induced epithelial-mesenchymal transition (EMT), whereas silencing MAEL by short hairpin RNA effectively inhibited its oncogenic function and attenuated EMT. Further study demonstrated that fibroblast growth factor receptor 4 (FGFR4) was a critical downstream target of MAEL in EOC, and the expression levels of FGFR4 were significantly associated with MAEL. (P < 0.05). CONCLUSION Our findings suggest that overexpression of MAEL plays a crucial oncogenic role in the development and progression of EOC through the upregulation of FGFR4 and subsequent induction of EMT, and also provide new insights on its potential as a therapeutic target for EOC.
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Affiliation(s)
- Wei-Peng He
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China
| | - Gui-Ping Yang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China
| | - Zun-Xian Yang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China
| | - Hong-Wei Shen
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China
| | - Ze-Shan You
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China
| | - Guo-Fen Yang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, Guangzhou, 510080, China.
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ITLN1 inhibits tumor neovascularization and myeloid derived suppressor cells accumulation in colorectal carcinoma. Oncogene 2021; 40:5925-5937. [PMID: 34363021 DOI: 10.1038/s41388-021-01965-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
Low levels of ITLN1 have been correlated with obesity-related colorectal carcinogenesis, however, the specific functions and underlying mechanisms remain unclear. Thus, we sought to explore the inhibitory role of ITLN1 in the tumor-permissive microenvironment that exists during the first occurrence and subsequent development of colorectal carcinoma (CRC). Results indicated that ITLN1 was frequently lost in CRC tissues and ITLN1 to be an independent prognostic predictor of CRC. Orthotopic and subcutaneous tumor xenograft approaches were then used to further confirm the protective role of ITLN1 during tumor progression. Increased ITLN1 expression in CRC cells significantly inhibited local pre-existing vessels sprouting, EPC recruitment and the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumor tissues without affecting the behavior of CRC cells in vitro. Comparatively, ITLN1-derived MDSCs had a lower suppressive effect on T cell proliferation, NOS2 expression, and ROS production. In addition, ITLN1 overexpression markedly suppressed bone marrow (BM)-derived hematopoietic progenitor cells (HPC) differentiation into MDSCs as well as NOS2 activity on MDSCs. Using H-2b+YFP + chimerism through bone marrow transplantation, increased ITLN1 in HCT116 significantly reduced the BM-derived EPCs and MDSCs in vivo mobilization. Mechanistically, results indicated ITLN1 inhibited tumor-derived IL-17D and CXCL2 (MIP2) through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-ĸB/CXCL2 signaling cascades dependent on PI3K/AKT/GSK3ß. This effect was reversed by the PI3K selective inhibitor LY294002. Collectively, ITLN1 synergistically suppressed IL-17D and CXCL2-mediated tumor vascularization, bone marrow derived EPC recruitment, as well as MDSCs generation and trafficking. Thus, ITLN1 potentially serves as a critical prognostic and therapeutic target for CRC.
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Sin RWY, Foo DCC, Iyer DN, Fan MSY, Li X, Lo OSH, Law WL, Ng L. A Pilot Study Investigating the Expression Levels of Pluripotency-Associated Genes in Rectal Swab Samples for Colorectal Polyp and Cancer Diagnosis and Prognosis. Stem Cells Int 2021; 2021:4139528. [PMID: 34335790 PMCID: PMC8324395 DOI: 10.1155/2021/4139528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 12/11/2020] [Accepted: 06/09/2021] [Indexed: 02/06/2023] Open
Abstract
Change in gene expression is inevitable in cancer development. With more studies demonstrating the contributions of cancer stem cells (CSCs) in colorectal cancer (CRC) development, this study is aimed at investigating whether rectal swab specimen serves as a tool for detection of dysregulation of CSC or stem cell (SC) markers and at evaluating its potential as a new promising screening method for high-risk patients. Expression levels of 15 pluripotency-associated genes were assessed by quantitative PCR in 53 rectal swab specimens referred for endoscopic screening. Dysregulated genes and joint panels based on such genes were examined for their diagnostic potentials for both polyp and CRC. Out of 15 genes, Oct4, CD26, c-MYC, and CXCR4 showed significantly differential expression among normal, polyp, and CRC patients. A panel of Oct4 and CD26 showed an AUC value of 0.80 (p = 0.003) in identifying CRC patients from polyp/normal subjects, with sensitivity and specificity of 84.6% and 69.2%. A panel of c-MYC and CXCR4 achieved CRC/polyp identification with an AUC value of 0.79 (p = 0.002), with a sensitivity of 82.8% and specificity of 80.0%. The sensitivity for polyp and CRC was 80.0% and 85.7%, respectively. Further analysis showed that higher c-MYC and CXCR4 level was detected in normal subjects who developed polyps after 5-6 years, in comparison with subjects with no lesion developed, and the AUC of the c-MYC and CXCR4 panel increased to 0.88 (p < 0.001), with sensitivity and specificity of 84.4% and 92.3%, respectively, when these patients were included in the polyp group. This study suggests that the Oct4 and CD26 panel is a promising biomarker for distinguishing CRC from normal and polyp patients, whereas the c-MYC and CXCR4 panel may identify polyp and CRC from normal individuals.
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Affiliation(s)
- Ryan Wai-Yan Sin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Dominic Chi-Chung Foo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Deepak Narayanan Iyer
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - May Sau-Yee Fan
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xue Li
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oswens Siu-Hung Lo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai-Lun Law
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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5
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Chen W, Liang JL, Zhou K, Zeng QL, Ye JW, Huang MJ. Effect of CIP2A and its mechanism of action in the malignant biological behavior of colorectal cancer. Cell Commun Signal 2020; 18:67. [PMID: 32321509 PMCID: PMC7178757 DOI: 10.1186/s12964-020-00545-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 03/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background Increasing evidence has revealed a close correlation between cancerous inhibitor of protein phosphatase 2A (CIP2A) and cancer progression. CIP2A has been shown to participate in diverse biological processes, such as development, tumorigenic transformation and chemoresistance. However, the functions of CIP2A in colorectal cancer (CRC) and its underlying mechanisms of action are not yet completely understood. The purpose of this study was to explore its clinical significance, function and relevant pathways in CRC. Methods Quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC), western blotting and enzyme-linked immunosorbent assay (ELISA) were used to identify the expression of CIP2A in CRC tissues, sera and CRC cell lines. The association between the expressions of CIP2A and patient survival was analyzed using the Kaplan-Meier curves. Additionally, the functional role of CIP2A in the cell lines was identified through small interfering RNA (siRNA)-mediated depletion of the protein followed by analyses of proliferation and xenograft growth in vivo using short hairpin (sh) RNAs. Effects of the C-myc inhibitor 10,058-F4 on the expressions of C-myc, and CIP2A in CRC cell lines and its potential mechanisms of action were investigated. Finally, the potential molecular pathways associated with CIP2A were screened using the phosphokinase array and identified through western blotting. Results CIP2A mRNA and protein levels were upregulated in CRC tissues compared to those of the corresponding normal tissues. It can be used as an independent prognostic indicator to determine overall survival (OS) and disease-free survival (DFS). Depletion of CIP2A substantially suppressed the growth of CRC cells and colony formation in vitro, and inhibited the growth of xenograft tumors in vivo. Additionally, the levels of CIP2A in the sera of patients with CRC were higher than those of the control subjects. Multivariate analyses revealed that the levels of CIP2A in the sera were not independent prognostic indicators in patients with CRC. Moreover, 10,058-F4 could effectively inhibit the growth of CRC cells in vitro, which could be correlated with an inhibition in the expressions of C-myc, CIP2A and its downstream regulatory anti-apoptotic proteins. Furthermore, the Human Phosphokinase Antibody Array was used to gain insights into the CIP2A-dependent intermediary signaling pathways. The results revealed that several signaling pathways were affected and the protein levels of p-p53 (S392), p-STAT5a (Y694), Cyclin D1, p-ERK1/2 and p-AKT (T308) had decreased in CIP2A-shRNA group based on the results of the western blot analysis. Conclusions CIP2A could promote the development of CRC cells and predict poor prognosis in patients with CRC, suggesting that it may serve as a potential prognostic marker and therapeutic target against CRC.
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Video Abstract
- Wei Chen
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
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- Jing-Lin Liang
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
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- Kai Zhou
- Jiangxi Provincial People's Hospital, Nanchang, 330006, Jiangxi, China
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- Qing-Li Zeng
- Jiangxi Provincial People's Hospital, Nanchang, 330006, Jiangxi, China.,The 334 Hospital Affiliated of Nanchang University, Nanchang, 330024, Jiangxi, China
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- Jun-Wen Ye
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
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- Mei-Jin Huang
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. .,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China. .,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.
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He WP, Guo YY, Yang GP, Lai HL, Sun TT, Zhang ZW, Ouyang LL, Zheng Y, Tian LM, Li XH, You ZS, Xie D, Yang GF. CHD1L promotes EOC cell invasiveness and metastasis via the regulation of METAP2.
Int J Med Sci 2020;
17:2387-2395. [PMID:
32922205 PMCID:
PMC7484650 DOI:
10.7150/ijms.48615]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 08/16/2020] [Indexed: 11/06/2022] Open
Abstract
Chromodomain helicase DNA binding protein 1-like (CHD1L) gene has been proposed to play an oncogenic role in human hepatocellular carcinoma. Previously we reported that CHD1L overexpression is significantly associated with the metastasis proceeding of epithelial ovarian cancer (EOC), and may predict a poor prognosis in EOC patients. However, the potential oncogenic mechanisms by which CHD1L acts in EOC remain unclear. To elucidate the oncogenic function of CHD1L, we carried out a series of in vitro assays, with effects of CHD1L ectogenic overexpression and silencing being determined in EOC cell lines (HO8910, A2780 and ES2). Real-time PCR and Western blotting analyses were used to identify potential downstream targets of CHD1L in the process of EOC invasion and metastasis. In ovarian carcinoma HO8910 cell lines, ectopic overexpression of CHD1L substantially induced the invasive and metastasis ability of the cancer cells in vitro. In contrast, knockdown of CHD1L using shRNA inhibited cell invasion in vitro in ovarian carcinoma A2780 and ES2 cell lines. We also demonstrated that methionyl aminopeptidase 2 (METAP2) was a downstream target of CHD1L in EOC, and we found a significant, positive correlation between the expression of CHD1L and METAP2 in EOC tissues (P<0.05). Our findings indicate that CHD1L plays a potential role in the inducement of EOC cancer cell invasion and/or metastasis via the regulation of METAP2 expression and suggests that CHD1L inhibition may provide a potential target for therapeutic intervention in human EOC.
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Affiliation(s)
- Wei-Peng He
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Yun-Yun Guo
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Gui-Ping Yang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Hui-Ling Lai
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Ting-Ting Sun
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Zu-Wei Zhang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Ling-Long Ouyang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Yu Zheng
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Li-Ming Tian
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Xiao-Hui Li
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Ze-Shan You
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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- Dan Xie
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, 510060 Guangzhou, China
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- Guo-Fen Yang
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Road II, 510080 Guangzhou, China
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KIFC1 is activated by TCF-4 and promotes hepatocellular carcinoma pathogenesis by regulating HMGA1 transcriptional activity.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019;
38:329. [PMID:
31340839 PMCID:
PMC6657086 DOI:
10.1186/s13046-019-1331-8]
[Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 07/18/2019] [Indexed: 12/21/2022]
Abstract
Background
Kinesins play important roles in the development and progression of many human cancers. The functions and underlying mechanisms of kinesin family member C1 (KIFC1), a member of the kinesin-14 family, in the pathogenesis of hepatocellular carcinoma (HCC) have not been fully elucidated.
Methods
In this study, 168 HCC samples were first analyzed to examine the association between KIFC1 expression and patient clinicopathological features and prognosis. The role of KIFC1 in HCC cell proliferation and metastasis was investigated both in vivo and in vitro. The upstream regulation and downstream targets of KIFC1 were studied by qRT-PCR, western blotting, coimmunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.
Results
KIFC1 was highly expressed in HCC tissues and positively associated with advanced stages and poor prognosis. KIFC1 knockdown suppressed HCC cell proliferation and invasion both in vitro and in vivo. Furthermore, KIFC1 knockdown decreased invadopodia formation and reduced epithelial-mesenchymal transition (EMT). HMGA1, an architectural transcriptional factor, was identified to interact with KIFC1. HMGA1 could bind to the promoters of Stat3, MMP2 and EMT-related genes and promote gene transcription. KIFC1 enhanced HMGA1 transcriptional activity and facilitated HCC proliferation and invasion. Moreover, KIFC1 was activated by TCF-4, and KIFC1 inhibition enhanced HCC cell sensitivity to paclitaxel.
Conclusions
Our findings suggest that KIFC1, activated by TCF-4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity and that KIFC1 is a potential therapeutic target to enhance the paclitaxel sensitivity of HCC.
Electronic supplementary material
The online version of this article (10.1186/s13046-019-1331-8) contains supplementary material, which is available to authorized users.
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Tang H, Jiang L, Zhu C, Liu R, Wu Y, Yan Q, Liu M, Jia Y, Chen J, Qin Y, Lee VHF, Luo S, Wang Q, Guan XY. Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma.
Oncogene 2019;
38:3119-3133. [DOI:
10.1038/s41388-018-0648-7]
[Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 11/05/2018] [Accepted: 12/05/2018] [Indexed: 12/19/2022]
9
Hua W, Zhao Y, Jin X, Yu D, He J, Xie D, Duan P. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition.
Gynecol Oncol 2018;
151:356-365. [PMID:
30249526 DOI:
10.1016/j.ygyno.2018.09.015]
[Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/06/2018] [Accepted: 09/16/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE
As the most prevalent internal modification in mammalian messenger RNA, N6‑methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer.
METHODS
METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo.
RESULTS
METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL.
CONCLUSION
Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer.
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Affiliation(s)
- Wenfeng Hua
- Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
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- Yuan Zhao
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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- Xiaohan Jin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
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- Danyang Yu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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- Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
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- Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
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- Ping Duan
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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10
Yu Y, Ke L, Lv X, Ling YH, Lu J, Liang H, Qiu W, Huang X, Liu G, Li W, Guo X, Xia W, Xiang Y. The prognostic significance of carcinoma-associated fibroblasts and tumor-associated macrophages in nasopharyngeal carcinoma.
Cancer Manag Res 2018;
10:1935-1946. [PMID:
30022852 PMCID:
PMC6042505 DOI:
10.2147/cmar.s167071]
[Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose
Tumor stroma cells play an important role in the carcinogenesis and progression of cancer. The aim of the present investigation was to explore the predictive role of carcinoma-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in nasopharyngeal carcinoma (NPC).
Patients and methods
The densities of CAFs and TAMs were measured by immunohistochemistry staining for α-smooth muscle actin (α-SMA), CD68, and CD163 in two sets of tissue microarrays including 260 pretreatment NPC tissues, that is, a training test comprising of 152 patients and a validation set comprising of 108 patients. Chi-square tests were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan–Meier method and compared with log-rank tests. Cox proportional hazards models were used to identify significant independent variables.
Results
Patients older than 50 years showed a lower expression of CD68, and there was a positive relationship between the densities of CAFs and CD163+ TAMs (p=0.001). In the multivariate analysis of the training test, both α-SMA and CD163 were independent prognostic factors for overall survival and progression-free survival (all p<0.05). Based on the expression levels of α-SMA and CD163, patients were categorized into three groups: high-risk, intermediate-risk, and low-risk groups according to both high, either high, and both low, respectively. Survival analysis and Cox multivariate analysis showed that the risk groups based on α-SMA and CD163 expression were independent predictors for the survival of patients with NPC in the training test, which was also confirmed by the validation test.
Conclusion
A patient’s risk group based on the level of CD163+ TAMs and CAFs was an independent predictor of survival, which may facilitate patient counseling and individualized treatment.
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Affiliation(s)
- Yahui Yu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Radiation Oncology, Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
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- Liangru Ke
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Diagnostic Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
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- Xing Lv
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Yi Hong Ling
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
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- Jiabin Lu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
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- Hu Liang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Wenze Qiu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Xinjun Huang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Guoying Liu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Wangzhong Li
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Xiang Guo
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Weixiong Xia
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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- Yanqun Xiang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People's Republic of China, ; .,Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China, ;
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11
Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.
Oncotarget 2018;
8:42300-42313. [PMID:
28404945 PMCID:
PMC5522068 DOI:
10.18632/oncotarget.15857]
[Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 01/13/2017] [Indexed: 11/25/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.
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12
Barbier J, Chen X, Sanchez G, Cai M, Helsmoortel M, Higuchi T, Giraud P, Contreras X, Yuan G, Feng Z, Nait-Saidi R, Deas O, Bluy L, Judde JG, Rouquier S, Ritchie W, Sakamoto S, Xie D, Kiernan R. An NF90/NF110-mediated feedback amplification loop regulates dicer expression and controls ovarian carcinoma progression.
Cell Res 2018;
28:556-571. [PMID:
29563539 DOI:
10.1038/s41422-018-0016-8]
[Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 01/26/2018] [Accepted: 01/28/2018] [Indexed: 01/16/2023] Open
Abstract
Reduced expression of DICER, a key enzyme in the miRNA pathway, is frequently associated with aggressive, invasive disease, and poor survival in various malignancies. Regulation of DICER expression is, however, poorly understood. Here, we show that NF90/NF110 facilitates DICER expression by controlling the processing of a miRNA, miR-3173, which is embedded in DICER pre-mRNA. As miR-3173 in turn targets NF90, a feedback amplification loop controlling DICER expression is established. In a nude mouse model, NF90 overexpression reduced proliferation of ovarian cancer cells and significantly reduced tumor size and metastasis, whereas overexpression of miR-3173 dramatically increased metastasis in an NF90- and DICER-dependent manner. Clinically, low NF90 expression and high miR-3173-3p expression were found to be independent prognostic markers of poor survival in a cohort of ovarian carcinoma patients. These findings suggest that, by facilitating DICER expression, NF90 can act as a suppressor of ovarian carcinoma.
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Affiliation(s)
- Jérôme Barbier
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Xin Chen
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Gabriel Sanchez
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Muyan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Marion Helsmoortel
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Takuma Higuchi
- Laboratory of Molecular Biology, Science Research Center, Kochi Medical School, Kochi University, Kochi, 783-8505, Japan
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- Pierre Giraud
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Xavier Contreras
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Gangjun Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Zihao Feng
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510060, China
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- Rima Nait-Saidi
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Olivier Deas
- XenTech SAS, 4 rue Pierre Fontaine, Evry, 91000, France
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- Lisa Bluy
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- Sylvie Rouquier
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France
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- William Ritchie
- Institut de Génétique Humaine, CNRS, University of Montpellier, Machine Learning and Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, 34396, France
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- Shuji Sakamoto
- Laboratory of Molecular Biology, Science Research Center, Kochi Medical School, Kochi University, Kochi, 783-8505, Japan
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- Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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- Rosemary Kiernan
- Institut de Génétique Humaine, CNRS, University of Montpellier, Gene Regulation Laboratory, 141 rue de la cardonille, Montpellier, France.
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13
Zhou N, Gu Q. Prognostic and clinicopathological value of p16 protein aberrant expression in colorectal cancer: A PRISMA-compliant Meta-analysis.
Medicine (Baltimore) 2018;
97:e0195. [PMID:
29561443 PMCID:
PMC5895319 DOI:
10.1097/md.0000000000010195]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE
Several studies have examined the potential role of p16 protein expression as a diagnostic and prognostic biomarker in various cancers. However, it remains unclear whether p16 protein expression is a prognostic and diagnostic factor for colorectal cancer. Therefore, this meta-analysis is conducted to evaluate the associations of p16 protein expression with overall survival (OS) and clinicopathological characteristics of colorectal cancer.
METHODS
According to PRISMA guideline, relevant literatures were identified by searching Medicine, Web of Science, WanFang, and CNKI databases. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from included studies to assess the association between p16 protein expression and OS of patients with colorectal cancer. Other relevant data were extracted to evaluate the correlations of p16 protein expression with risk and clinicopathological characteristics of colorectal cancer. Stata 12.0 software was applied to calculate the strength of association between p16 protein expression and colorectal cancer.
RESULTS
Forty-one studies were included to evaluate the association between p16 protein expression and colorectal cancer. Nine studies involving 1731 patients with colorectal cancer found that there was no association between p16 protein expression and OS of colorectal cancer in the overall analysis (HR = 0.78, 95% CI: 0.55-1.10). However, p16 protein overexpression was significantly associated with a better prognosis in patients with colorectal cancer when cut-off value of p16 protein expression was <10% (HR = 0.23, 95% CI: 0.08-0.66). The results of subgroup analysis based on ethnicity indicated that p16 protein overexpression was a risk factor for the occurrence of colorectal cancer in Caucasians (odds ratio = 28.95, 95% CI: 6.08-137.89), but not in Asians. Furthermore, p16 protein overexpression was significantly associated with the Dukes stage, lymph node metastasis, tumor location, and Tumor Lymph Node Metastasis-stage of colorectal cancer.
CONCLUSIONS
p16 protein overexpression might be a useful biomarker to predict the clinicopathological progress and prognosis of colorectal cancer.
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14
CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction.
Oncotarget 2017;
7:15525-38. [PMID:
26771842 PMCID:
PMC4941258 DOI:
10.18632/oncotarget.6900]
[Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 12/01/2015] [Indexed: 01/21/2023] Open
Abstract
Purpose
Oncology immunity was reported to play a key role in cancer development and progression, so we investigated the prediction role of several immune markers in esophageal squamous cell carcinoma (ESCC) patients after operation in this study.
Patients and Methods
66 primary ESCC tumor tissues and four sets of tissue microarrays including 705 primary ESCC tumor tissues from four centers were collected and analyzed. Expressions of several immune markers in ESCC tumor tissue were detected with immunohistochemistry staining. Their distribution densities were analyzed with InForm™ 2.0.1 software. All statistic analyses were performed with SPSS16.0 and Stata version 10.0.
Results
Survival analyses assessed by Kaplan-Meier plots and log-rank tests demonstrated that densities of CD68 and interleukin 13 (IL-13) in tumor stroma were positively correlated with the overall survival of ESCC patients after operation (p < 0.01 for CD68, p < 0.001 for IL-13). Further, a model based on tumor stroma densities of CD68 and IL-13 was constructed and it could significantly classify patients with poor or good prognosis. This model could further identify high-risk group and low-risk group at the same Tumor lymph Nodes Metastases (TNM) stage. Lastly, a more accuracy model based on TNM stage, densities of CD68 and IL-13 was constructed to predict the prognosis of ESCC patient after operation.
Conclusion
Combining the TNM staging system and densities of CD68 and IL-13 could substantially improve the prognosis prediction accuracy of ESCC patient after operation, which might be an excellent tool for selecting patients for individualized therapy in future.
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15
Tang H, Wu Y, Qin Y, Wang H, Jia Y, Yang S, Luo S, Wang Q. Predictive significance of HMGCS2 for prognosis in resected Chinese esophageal squamous cell carcinoma patients.
Onco Targets Ther 2017;
10:2553-2560. [PMID:
28546759 PMCID:
PMC5438074 DOI:
10.2147/ott.s132543]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Despite a series of attempts during the last decades, the prognosis of esophageal squamous cell carcinoma (ESCC) remains poor. Different responses of individual tumors encouraged us to look for valuable prognostic markers. As a key regulator controlling the anabolic ketogenic pathway, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) has been reported to play a crucial role in colorectal cancer and prostate cancer. However, its importance to ESCC has not been verified. Therefore, a large cohort retrospective study was planned, to investigate the relationship between HMGCS2 expression and ESCC prognosis. By adopting real-time polymerase chain reaction (PCR) and immunohistochemical (IHC) staining, HMGCS2 expression was examined in tissues of 300 ESCC patients with complete resection. Besides, the association between HMGCS2 protein expression and survival time was evaluated through chi-square test and Kaplan–Meier analysis. With the use of Cox-proportional hazards model, the prognostic impact of clinicopathologic variables and biomarker expression was evaluated. Compared with their non-tumor counterparts, HMGCS2 downregulation occurred in 65.5% and 37.6% of primary ESCCs on the mRNA and protein levels (P<0.001), respectively. On the protein level, HMGCS2 expression was associated with tumor cell differentiation (P=0.003), pT status (P=0.006), and TNM stage (P=0.010). In the down-HMGCS2 expression group, the 5-year overall survival (OS) and relapse-free survival (RFS) are poorer than those in the normal expression group (19 months vs 24 months, P=0.002; 13 months vs 17 months, P=0.007, respectively). According to the TNM stage, stratified analysis revealed that its discernibility on RFS was only pronounced in patients with advanced clinical stage (P=0.001). In addition, multivariate Cox regression analysis showed that HMGCS2 expression was an independent risk factor for RFS (P=0.032) instead of OS (P=0.099). The findings of this study provided the evidence that HMGSC2 represented a potential novel prognostic biomarker for ESCC patients.
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Affiliation(s)
- Hong Tang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Yufeng Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Yanru Qin
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
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- Hongyan Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Yongxu Jia
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China
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- Shujun Yang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Suxia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Qiming Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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16
Kuang P, Chen Z, Wang J, Liu Z, Wang J, Gao J, Shen L. Characterization of Aurora A and Its Impact on the Effect of Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer.
Transl Oncol 2017;
10:367-377. [PMID:
28431392 PMCID:
PMC5397579 DOI:
10.1016/j.tranon.2017.02.010]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 02/17/2017] [Accepted: 02/23/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE: Aurora A, as a member of serine/threonine kinase family and a common characteristic of epithelial cancers, plays a critical role in cell mitosis. However, the clinical significance of Aurora A in non–small cell lung cancer (NSCLC) remains undetermined. METHODS: The expression of Aurora A in NSCLC and paired normal adjacent lung tissues was determined by immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was employed to determine a cutoff score for Aurora A expression in a training set (n = 135). For validation, the ROC-derived cutoff score was subjected to analysis of the association of Aurora A expression with patient outcome and clinicopathological characteristics in a testing set (n = 128) and overall patients (n = 263). The correlation of Aurora A with cisplatin resistance and epithelial-mesenchymal transition (EMT) was examined in vitro in NSCLC cells by overexpression or knockdown of Aurora A. RESULTS: Aurora A expression was significantly upregulated in tumor tissues compared with paired normal tissues (P < .01). The expression of Aurora A was closely associated with clinical stage, lymph node metastasis, and recurrence and was an independent prognostic parameter in multivariate analysis. High level of Aurora A expression predicted poorer overall survival and disease-free survival in NSCLC patients treated with cisplatin-based adjuvant chemotherapy. In vitro data showed that overexpression or knockdown of Aurora A resulted in increased or decreased cellular resistance to cisplatin. Furthermore, inhibition of Aurora A reversed the EMT process. CONCLUSIONS: Aurora A was identified as an inferior prognostic and cisplatin-resistant biomarker in NSCLC patients, which provided potential evidences for therapeutic target and reversing drug resistance.
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Affiliation(s)
- Peng Kuang
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- Zuhua Chen
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- JiaYuan Wang
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- Zhentao Liu
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- Jingyuan Wang
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- Jing Gao
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
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- Lin Shen
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute.
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17
Tang H, Wu Y, Qin Y, Wang H, Wang L, Guan X, Luo S, Wang Q. Reduction of AZGP1 predicts poor prognosis in esophageal squamous cell carcinoma patients in Northern China.
Onco Targets Ther 2017;
10:85-94. [PMID:
28053542 PMCID:
PMC5189973 DOI:
10.2147/ott.s113932]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND
As a key regulator in lipid mobilization, AZGP1 has been reported to play a significant role in various cancers. This study was carried out to investigate the role of AZGP1 in the development of esophageal squamous cell carcinoma (ESCC) patients in Northern China.
MATERIALS AND METHODS
Through the application of quantitative real-time polymerase chain reaction and immunohistochemical staining, AZGP1 expression in ESCC tissues from Northern China was examined.
RESULTS
Decreased expression of AZGP1 was observed in ~60% ESCC patients. AZGP1 downregulation was significantly associated with lymph node metastasis (P=0.035), advanced clinical stage (P=0.018), poor prognosis for 5-year disease-specific survival (DSS; P<0.001), local recurrence-free survival (LRFS; P=0.016), and metastasis-free survival (MeFS; P=0.014). In addition, Cox multivariate analysis revealed that AZGP1 downregulation remained to be an independent prognosticator for shorter DSS (P=0.001), LRFS (P=0.011), and MeFS (P=0.004).
CONCLUSION
AZGP1 might be a candidate tumor suppressor and a potential novel prognostic biomarker for ESCC patients in Northern China.
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Affiliation(s)
- Hong Tang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Yufeng Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Yanru Qin
- Department of Clinical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan
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- Haiying Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
| |
- Lili Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Xinyuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China
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- Suxia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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- Qiming Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital
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18
Wong CC, Qian Y, Li X, Xu J, Kang W, Tong JH, To KF, Jin Y, Li W, Chen H, Go MYY, Wu JL, Cheng KW, Ng SSM, Sung JJY, Cai Z, Yu J. SLC25A22 Promotes Proliferation and Survival of Colorectal Cancer Cells With KRAS Mutations and Xenograft Tumor Progression in Mice via Intracellular Synthesis of Aspartate.
Gastroenterology 2016;
151:945-960.e6. [PMID:
27451147 DOI:
10.1053/j.gastro.2016.07.011]
[Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 06/14/2016] [Accepted: 07/06/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS
Many colorectal cancer (CRC) cells contain mutations in KRAS. Analyses of CRC cells with mutations in APC or CTNNB1 and KRAS identified SLC25A22, which encodes mitochondrial glutamate transporter, as a synthetic lethal gene. We investigated the functions of SLC25A22 in CRC cells with mutations in KRAS.
METHODS
We measured levels of SLC25A22 messenger RNA and protein in paired tumor and nontumor colon tissues collected from 130 patients in Hong Kong and 17 patients in China and compared protein levels with patient survival times. Expression of SLC25A22 was knocked down in KRAS mutant CRC cell lines (DLD1, HCT116, LOVO, SW480, SW620, and SW1116) and CRC cell lines without mutations in KRAS (CACO-2, COLO205, HT29, and SW48); cells were analyzed for colony formation, proliferation, glutaminolysis and aspartate synthesis, and apoptosis in Matrigel and polymerase chain reaction array analyses. DLD1 and HCT116 cells with SLC25A22 knockdown were grown as xenograft tumors in nude mice; tumor growth and metastasis were measured. SLC25A22 was expressed ectopically in HCT116 cells, which were analyzed in vitro and grown as xenograft tumors in nude mice.
RESULTS
Levels of SLC25A22 messenger RNA and protein were increased in colorectal tumor tissues compared with matched nontumor colon tissues; increased protein levels were associated with shorter survival times of patients (P = .01). Knockdown of SLC25A22 in KRAS mutant CRC cells reduced their proliferation, migration, and invasion in vitro, and tumor formation and metastasis in mice, compared with cells without SLC25A22 knockdown. Knockdown of SLC25A22 reduced aspartate biosynthesis, leading to apoptosis, decreased cell proliferation in KRAS mutant CRC cells. Incubation of KRAS mutant CRC cells with knockdown of SLC25A22 with aspartate increased proliferation and reduced apoptosis, which required GOT1, indicating that oxaloacetate is required for cell survival. Decreased levels of oxaloacetate in cells with knockdown of SLC25A22 reduced regeneration of oxidized nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate. Reduced oxidized nicotinamide adenine dinucleotide inhibited glycolysis and decreased levels of adenosine triphosphate, which inactivated mitogen-activated protein kinase kinase and extracellular signal-regulated kinase signaling via activation of AMP-activated protein kinase. An increased ratio of oxidized nicotinamide adenine dinucleotide phosphate to reduced nicotinamide adenine dinucleotide phosphate induced oxidative stress and glutathione oxidation, which suppressed cell proliferation. Asparagine synthetase mediated synthesis of asparagine from aspartate to promote cell migration.
CONCLUSIONS
SLC25A22 promotes proliferation and migration of CRC cells with mutations KRAS, and formation and metastasis of CRC xenograft tumors in mice. Patients with colorectal tumors that express increased levels of SLC25A22 have shorter survival times than patients whose tumors have lower levels. SLC25A22 induces intracellular synthesis of aspartate, activation of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase signaling and reduces oxidative stress.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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- Yun Qian
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China
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- Xiaona Li
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
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- Jiaying Xu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
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- Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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- Joanna H Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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- Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| |
- Ye Jin
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| |
- Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| |
- Huarong Chen
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| |
- Minnie Y Y Go
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| |
- Jian-Lin Wu
- State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| |
- Ka Wing Cheng
- College of Engineering, Peking University, Peking, China
| |
- Simon S M Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| |
- Joseph J Y Sung
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| |
- Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China
| |
- Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
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19
Tang H, Wu Y, Liu M, Qin Y, Wang H, Wang L, Li S, Zhu H, He Z, Luo J, Wang H, Wang Q, Luo S. SEMA3B improves the survival of patients with esophageal squamous cell carcinoma by upregulating p53 and p21.
Oncol Rep 2016;
36:900-8. [PMID:
27349960 DOI:
10.3892/or.2016.4901]
[Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/18/2016] [Indexed: 12/16/2022] Open
Abstract
As one of the most common malignancies, esophageal squamous cell carcinoma (ESCC) is ranked as the sixth leading cause of cancer-related death worldwide. In our previous study, by employing cDNA microarray analysis, semaphorin 3B (SEMA3B) was found to be significantly downregulated in ESCC. In the present study, SEMA3B downregulation at the mRNA level was found in 34 of 60 primary ESCCs (56.7%) and in 6 of 9 ESCC cell lines (66.7%) by transcription-polymerase chain reaction (RT-PCR). Moreover, immunohistochemical (IHC) staining of SEMA3B in a tissue microarray further indicated that downregulated expression of SEMA3B protein was found in 125 of 222 (56.3%) ESCC cases and downregulation of SEMA3B protein was significantly correlated with lymph node metastasis (P=0.000), advanced clinicopathological stage (P=0.001) and poor disease-specific survival (P=0.017) of ESCC patients. In addition, functional studies demonstrated that the SEMA3B gene could suppress the tumorigenic ability of ESCC cells and cell motility. Furthermore, it was found that by upregulating p53 and p21 expression and inhibiting Akt (Ser473) phosphorylation, SEMA3B could induce cell cycle arrest at G1/S phase. Taken together, our results suggest that SEMA3B may be an important tumor-suppressor gene in the malignant progression of ESCC, as well as a valuable prognostic marker for ESCC patients.
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Affiliation(s)
- Hong Tang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Yufeng Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Ming Liu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, SAR, L10-56, P.R. China
| |
- Yanru Qin
- Department of Clinical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| |
- Haiying Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Lili Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Shaomei Li
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Hui Zhu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Zheng He
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Junpeng Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Hongyan Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| |
- Qiming Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
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- Suxia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
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20
Li CP, Cai MY, Jiang LJ, Mai SJ, Chen JW, Wang FW, Liao YJ, Chen WH, Jin XH, Pei XQ, Guan XY, Zeng MS, Xie D. CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma.
Carcinogenesis 2016;
37:557-566. [DOI:
10.1093/carcin/bgw036]
[Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
21
Xu L, Li X, Cai M, Chen J, Li X, Wu WKK, Kang W, Tong J, To KF, Guan XY, Sung JJY, Chan FKL, Yu J. Increased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer.
Gut 2016;
65:635-46. [PMID:
25947013 PMCID:
PMC4819609 DOI:
10.1136/gutjnl-2014-308257]
[Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 01/12/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVE
Using whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC.
DESIGN
SLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC.
RESULTS
Amplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan-Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC.
CONCLUSIONS
SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC.
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Affiliation(s)
- Lixia Xu
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong,Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
- Xiaoxing Li
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| |
- Muyan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| |
- Jinna Chen
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, Hong Kong
| |
- Xiangchun Li
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| |
- William K K Wu
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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- Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| |
- Joanna Tong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| |
- Ka-Fai To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| |
- Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, Hong Kong
| |
- Joseph J Y Sung
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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- Francis K L Chan
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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- Jun Yu
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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22
Zhang LY, Wu JL, Qiu HB, Dong SS, Zhu YH, Lee VHF, Qin YR, Li Y, Chen J, Liu HB, Bi J, Ma S, Guan XY, Fu L. PSCA acts as a tumor suppressor by facilitating the nuclear translocation of RB1CC1 in esophageal squamous cell carcinoma.
Carcinogenesis 2016;
37:320-332. [PMID:
26785734 DOI:
10.1093/carcin/bgw010]
[Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/14/2016] [Indexed: 12/12/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. By high-throughput transcriptome sequencing (RNA-Seq) profiling of three pairs of primary ESCCs and their corresponding non-tumorous tissues, we identified that prostate stem cell antigen (PSCA), a gene that encodes a glycosylphosphatidylinositol-anchored protein, is significantly downregulated in ESCC. Here, we reported decreased expression of PSCA in 188/218 (86.2%) of primary ESCC cases and was negatively regulated by its transcription factor sex-determining region Y-box5 that was significantly associated with the poor differentiation (P = 0.003), increased lymph node metastasis (P < 0.0001), advanced stage (P = 0.007), and disease-specific survival (P < 0.0001), but not associated with the recently reported transcrible rs2294008 (C > T) polymorphism in ESCC. Functional studies showed that PSCA could arrest cell cycle progression and promote cell differentiation independent of the start codon polymorphism. Further mechanistic studies revealed that retinoblastoma 1-inducible coiled-coil 1 (RB1CC1), a key signaling node to regulate cellular proliferation and differentiation, interacted specifically with PSCA in ESCC cells. Binding of PSCA and RB1CC1 in cytoplasm resulted in stabilization and translocation of RB1CC1 into nucleus, thereby activating key factors involved in cell cycle arrest and differentiation. Collectively, our data provide a novel molecular mechanism for the tumor suppressor role of PSCA and may help design effective therapy targeting PSCA-RB1CC1 pathway to control esophageal cancer growth and differentiation.
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Affiliation(s)
- Li-Yi Zhang
- Department of Clinical Oncology, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077, China.,State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China
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- Jian-Lin Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau 999078 , China
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- Hai-Bo Qiu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China.,Department of Gastric and Pancreatic Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China
| |
- Sui-Sui Dong
- Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China
| |
- Ying-Hui Zhu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China
| |
- Victor Ho-Fun Lee
- Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China
| |
- Yan-Ru Qin
- Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University , Zhengzhou 450000 , China
| |
- Yan Li
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China
| |
- Juan Chen
- Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China
| |
- Hai-Bo Liu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China
| |
- Jiong Bi
- Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou 510000 , China and
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- Stephanie Ma
- Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China
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- Xin-Yuan Guan
- Department of Clinical Oncology, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077, China.,State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China
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- Li Fu
- Shenzhen Key Laboratory of Translational Medicine of Tumor and Cancer Research Centre, School of Medicine, Shenzhen University , Shenzhen 518000 , China
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23
IFITM1 promotes the metastasis of human colorectal cancer via CAV-1.
Cancer Lett 2015;
368:135-143. [DOI:
10.1016/j.canlet.2015.07.034]
[Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 07/30/2015] [Accepted: 07/31/2015] [Indexed: 11/21/2022]
24
Song Y, Li J, Zhu Y, Dai Y, Zeng T, Liu L, Li J, Wang H, Qin Y, Zeng M, Guan XY, Li Y. MicroRNA-9 promotes tumor metastasis via repressing E-cadherin in esophageal squamous cell carcinoma.
Oncotarget 2015;
5:11669-80. [PMID:
25375090 PMCID:
PMC4294333 DOI:
10.18632/oncotarget.2581]
[Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 10/09/2014] [Indexed: 01/23/2023] Open
Abstract
MicroRNAs (miRNAs) play a critical role in development and progression of cancers. Deregulation of MicroRNA-9 (miR-9) has been documented in many types of cancers but their role in the development of esophageal squamous cell carcinoma (ESCC) has not been studied. This study aimed to investigate the effect of miR-9 in esophageal cancer metastasis. The up-regulation of miR-9 was frequently detected in primary ESCC tumor tissue, which was significantly associated with clinical progression (P = 0.022), lymph node metastasis (P = 0.007) and poor overall survival (P < 0.001). Functional study demonstrated that miR-9 promoted cell migration and tumor metastasis, which were effectively inhibited when expression of miR-9 was silenced. Moreover, we demonstrated that miR-9 interacted with the 3'-untranslated region of E-cadherin and down-regulated its expression, which induced β-catenin nuclear translocation and subsequently up-regulated c-myc and CD44 expression. In addition, miR-9 induced epithelial-mesenchymal transition (EMT) in ESCC, a key event in tumor metastasis. Taken together, our study demonstrates that miR-9 plays an important role in ESCC metastasis by activating β-catenin pathway and inducing EMT via targeting E-cadherin. Our study also suggests miR-9 can be served as a new independent prognostic marker and/or as a novel potential therapeutic target for ESCC.
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Affiliation(s)
- Ye Song
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Jiangchao Li
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, 510060, China
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- Yinghui Zhu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Yongdong Dai
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Tingting Zeng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| |
- Lulu Liu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Jianbiao Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Hongbo Wang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| |
- Yanru Qin
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, 510060, China
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- Musheng Zeng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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- Xin-Yuan Guan
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
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- Yan Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
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25
Li YL, Liu L, Xiao Y, Zeng T, Zeng C. 14-3-3σ is an independent prognostic biomarker for gastric cancer and is associated with apoptosis and proliferation in gastric cancer.
Oncol Lett 2014;
9:290-294. [PMID:
25435977 PMCID:
PMC4246703 DOI:
10.3892/ol.2014.2676]
[Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 09/26/2014] [Indexed: 11/13/2022] Open
Abstract
14-3-3 proteins participate in various cellular processes, including apoptosis, proliferation and malignant transformation. 14-3-3σ, a member of the 14-3-3 protein family, is important in several types of cancer; however, little is known about the clinical significance and biological roles of 14-3-3σ in gastric cancer. The present study analyzed the expression pattern of 14-3-3σ in gastric cancer and investigated its correlation with the prognosis of gastric cancer patients. Furthermore, the association of 14-3-3σ with Ki-67, Bcl-2 and Bax was evaluated. 14-3-3σ was expressed at higher level in gastric cancer tissue compared with healthy gastric tissue, and 14-3-3σ expression was significantly correlated with tumor size and tumor node metastasis stage (P<0.05). To the best of our knowledge, the present study data are the first to suggest that 14-3-3σ expression has been significantly associated with poor prognosis in gastric cancer. Additionally, 14-3-3σ overexpression was positively correlated with Ki-67 and Bcl-2 expression levels. Thus, 14-3-3σ is a potential prognostic marker for gastric cancer patients, and may be involved in regulating the apoptosis and proliferation of gastric cancer cells.
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Affiliation(s)
- Yi-Liang Li
- Department of Neurology, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan 417000, P.R. China
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- Lihua Liu
- Department of Respiratory Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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- Yang Xiao
- Department of Orthopaedics, The Central Hospital of Loudi Affiliated to the University of South China, Loudi, Hunan 417000, P.R. China
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- Tao Zeng
- School of Laboratory Medicine, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
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- Chao Zeng
- Department of Pathology, Guangdong Medical College, Dongguan, Guangdong 523808, P.R. China
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26
Gui T, Bai H, Zeng J, Zhong Z, Cao D, Cui Q, Chen J, Yang J, Shen K. Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins.
Onco Targets Ther 2014;
7:1705-16. [PMID:
25285018 PMCID:
PMC4181627 DOI:
10.2147/ott.s67570]
[Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
PURPOSE
To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins.
METHODS
Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling.
RESULTS
PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3.
CONCLUSION
Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer.
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Affiliation(s)
- Ting Gui
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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- Huimin Bai
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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- Jianfang Zeng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Zhaoji Zhong
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Dongyan Cao
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Quancai Cui
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Jiaxin Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| |
- Keng Shen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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27
Wang FW, Cai MY, Mai SJ, Chen JW, Bai HY, Li Y, Liao YJ, Li CP, Tian XP, Kung HF, Guan XY, Xie D. Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.
Oncotarget 2014;
5:6716-33. [PMID:
25071013 PMCID:
PMC4196158 DOI:
10.18632/oncotarget.2236]
[Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 07/15/2014] [Indexed: 12/21/2022] Open
Abstract
UNLABELLED
Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways.
CONCLUSION
This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Down-Regulation
- Female
- Humans
- Liver Neoplasms/blood supply
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- MAP Kinase Signaling System
- Male
- Matrix Metalloproteinase 2/biosynthesis
- Mice
- Mice, Nude
- Middle Aged
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/therapy
- Peptide Initiation Factors/genetics
- Peptide Initiation Factors/metabolism
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Xenograft Model Antitumor Assays
- p38 Mitogen-Activated Protein Kinases/metabolism
- Eukaryotic Translation Initiation Factor 5A
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Affiliation(s)
- Feng-Wei Wang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Mu-Yan Cai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
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- Shi-Juan Mai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Jie-Wei Chen
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
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- Hai-Yan Bai
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Yan Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Yi-Ji Liao
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Chang-Peng Li
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Xiao-Peng Tian
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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- Hsiang-Fu Kung
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China
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- Xin-Yuan Guan
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
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- Dan Xie
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China
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28
Zhai JM, Sun SJ, Wang W, Zeng C. Expression of Annexin A3 in Gastric Cancer and its Correlation with Proliferation and Apoptosis.
Asian Pac J Cancer Prev 2014;
15:3001-4. [DOI:
10.7314/apjcp.2014.15.7.3001]
[Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
29
α4 contributes to bladder urothelial carcinoma cell invasion and/or metastasis via regulation of E-cadherin and is a predictor of outcome in bladder urothelial carcinoma patients.
Eur J Cancer 2014;
50:840-51. [DOI:
10.1016/j.ejca.2013.11.038]
[Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 11/25/2013] [Accepted: 11/30/2013] [Indexed: 02/02/2023]
30
Zhu YH, Liu H, Zhang LY, Zeng T, Song Y, Qin YR, Li L, Liu L, Li J, Zhang B, Guan XY. Downregulation of LGI1 promotes tumor metastasis in esophageal squamous cell carcinoma.
Carcinogenesis 2014;
35:1154-61. [PMID:
24510112 DOI:
10.1093/carcin/bgu040]
[Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Here, we report the characterization of a candidate tumor suppressor gene leucine-rich glioma inactivated 1 (LGI1) in human esophageal squamous cell carcinoma (ESCC). Downregulation of LGI1 has been detected in approximately 50% of primary ESCCs, which was significantly associated with advanced clinical stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P = 0.009) and poor disease-specific survival (P < 0.001). Functional studies found that LGI1 could inhibit cell growth, clonogenicity, cell motility and tumor formation in nude mice. Mechanistic investigations suggested that LGI1 acted through extracellular signal-regulated kinase (ERK1/2) signaling to downregulate matrix metalloproteinase (MMP)-3 expression and subsequently suppressed tumor metastasis. Taken together, our study revealed that LGI1 plays an important tumor suppressive role in the development and progression of ESCC, with possible application in clinics as a biomarker and a potential new therapeutic target.
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Affiliation(s)
- Ying-Hui Zhu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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31
Liu JY, Qian D, He LR, Li YH, Liao YJ, Mai SJ, Tian XP, Liu YH, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D. PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway.
Mol Cancer 2013;
12:148. [PMID:
24268029 PMCID:
PMC4176126 DOI:
10.1186/1476-4598-12-148]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 11/19/2013] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND
PIN2/TRF1-interacting telomerase inhibitor1 (PinX1) was recently suggested as a putative tumor suppressor in several types of human cancer, based on its binding to and inhibition of telomerase. Moreover, loss of PinX1 has been detected in many human malignancies. However, the possible involvement of PinX1 and its clinical/prognostic significance in urothelial carcinoma of the bladder (UCB) are unclear.
METHODS
The PinX1 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) in UCB tissues and adjacent normal urothelial bladder epithelial tissues. PinX1 was overexpressed and silenced in UCB cell lines to determine its role in tumorigenesis, development of UCB, and the possible mechanism.
RESULTS
PinX1 expression in UCB was significantly down-regulated at both mRNA and protein level as compared with that in normal urothelial bladder epithelial tissues. PinX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index (Ki-67), and poor survival (P < 0.05). Moreover, overexpression of PinX1 in UCB cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing PinX1 dramatically enhanced cell proliferation. Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway.
CONCLUSIONS
These findings suggest that down-regulation of PinX1 play an important role in the tumorigenesis and development of UCB and that the expression of PinX1 as detected by IHC is an independent molecular marker in patients with UCB.
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Affiliation(s)
- Jian-Ye Liu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No, 651, Dongfeng Road East, Guangzhou 510060, China.
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32
Huang K, Li LA, Meng Y, You Y, Fu X, Song L. High expression of astrocyte elevated gene-1 (AEG-1) is associated with progression of cervical intraepithelial neoplasia and unfavorable prognosis in cervical cancer.
World J Surg Oncol 2013;
11:297. [PMID:
24256614 PMCID:
PMC3866971 DOI:
10.1186/1477-7819-11-297]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 11/09/2013] [Indexed: 01/24/2023] Open
Abstract
Background
Astrocyte elevated gene-1(AEG-1) plays an important role in the development and progression of certain types of human cancers. However, the expression dynamics of AEG-1 in cervical cancer and its clinical/prognostic significance are unclear.
Method
In present study, the methods of tissue microarrays (TMA) and immunohistochemistry (IHC) were utilized to investigate AEG-1 expression in cervical intraepithelial neoplasia (CIN) and cervical cancer. Receiver operating characteristic (ROC) curve analysis, χ2 test, Kaplan-Meier plots, and multivariate Cox regression analysis were used to analyze the data.
Results
The expression level of AEG-1 was increased from CIN I to CIN III. High expression of AEG-1 could be observed in 61.1% (55/90) of cervical cancer. Moreover, high expression of AEG-1 correlated with tumor size and lymph node metastasis (all P <0.05). More importantly, high expression of AEG-1 was closely associated with cervical cancer patient shortened survival time as evidenced by univariate and multivariate analysis (P <0.05).
Conclusions
Our data suggest for the first time that high expression of AEG-1 is associated significantly with progression of cervical cancer. AEG-1 overexpression, as examined by IHC, has the potential to be used as an immunomarker to predict prognosis of cervical cancer patients.
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Affiliation(s)
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- Yuanguang Meng
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
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33
Zhang X, Xu S, Tan Q, Liu L. High expression of heparanase-2 is an independent prognostic parameter for favorable survival in gastric cancer patients.
Cancer Epidemiol 2013;
37:1010-3. [PMID:
24139593 DOI:
10.1016/j.canep.2013.09.012]
[Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Revised: 08/19/2013] [Accepted: 09/20/2013] [Indexed: 12/20/2022]
Abstract
AIM
Heparanase-2 expression has been suggested to up-regulate in several types of human cancers. However, the expression patterns of heparanase-2 in gastric cancer and its effect on prognosis of gastric cancer patients are unclear.
METHODS
In this study, the methods of tissue microarray, immunohistochemistry (IHC), and western blot were used to investigate heparanase-2 expression in gastric cancer and the adjacent non-cancerous tissues. Heparanase-2 expression was analyzed by immunohistochemistry in 95 clinicopathologically characterized gastric cancer cases. In addition Fisher's exact test, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the results.
RESULTS
High expression of cytoplasmic heparanase-2 was observed in 70.5% (67/95) of gastric cancer, when compared with its normal counterpart. Overexpression of heparanase-2 was correlated with tumor size and differentiation (P<0.05). Further analysis showed that a significant correlation between high expression of heparanase-2 and favorable prognosis (P<0.05). In multivariate analysis, high expression of heparanase-2 was evaluated as an independent prognostic factor in gastric cancer (P<0.05).
CONCLUSIONS
Our data suggest for the first time that the high expression of heparanase-2 is associated significantly with tumor growth and differentiation. Importantly, heparanase-2 may be a potential molecular marker for predicting prognosis of gastric cancer.
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Affiliation(s)
- Xiaogang Zhang
- Institute for the Study of Liver Diseases, The Third Hospital of Changzhou, Changzhou 213000, China.
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34
Li K, Zhong C, Wang B, He J, Bi J. Nrf2 expression participates in growth and differentiation of endometrial carcinoma cells in vitro and in vivo.
J Mol Histol 2013;
45:161-7. [PMID:
24048968 DOI:
10.1007/s10735-013-9538-z]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 09/02/2013] [Indexed: 10/26/2022]
Abstract
The expression level of Nrf2 is increased in series of tumors and it plays a vital role in proliferation of cancer cells. However, little is known about the clinical implications and biological functions of Nrf2 in endometrial carcinoma. The aim of this study is to study whether up-regulation of Nrf2 expression can promote growth of endometrial carcinoma cells. Using immunohistochemistry, Nrf2 protein expression was analyzed in endometrial carcinoma patients. A series of assays was performed to elucidate the role of Nrf2 in growth of endometrial carcinoma. Positive rate of Nrf2 was 64.3 % (45/70) in endometrial carcinoma patients, and it was associated with FIGO stage and histological grade (P < 0.05). In addition, ectopic overexpression of Nrf2 promoted the growth of endometrial carcinoma cells in vitro and in vivo. Interestingly, Nrf2 protein translocation from cytoplasm to nucleus may influence differentiation of endometrial carcinoma cells. These results suggest that Nrf2 participates in progression of endometrial carcinoma by influencing the growth and differentiation of endometrial carcinoma cells, and it could be used as a novel and potential therapeutic target for endometrial carcinoma.
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Affiliation(s)
- Kainan Li
- Department of Oncology, General Hospital of Jinan Military Region, Jinan, 250031, People's Republic of China
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35
High expression of H3K27me3 is an independent predictor of worse outcome in patients with urothelial carcinoma of bladder treated with radical cystectomy.
BIOMED RESEARCH INTERNATIONAL 2013;
2013:390482. [PMID:
24093096 PMCID:
PMC3777191 DOI:
10.1155/2013/390482]
[Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 07/31/2013] [Indexed: 11/17/2022]
Abstract
It has been suggested that trimethylation of lysine 27 on histone H3 (H3K27me3) is a crucial epigenetic process in tumorigenesis. However, the expression pattern of H3K27me3 and its clinicopathological/prognostic significance in urothelial carcinoma of bladder (UCB) are unclear. In this study, upregulated expression of H3K27me3 protein was observed in the majority of UCBs by Western blotting. High expression of H3K27me3 was examined by IHC in 59/126 (46.8%) of UCB tissues and in 18/72 (25.0%) of normal urothelial bladder epithelial tissues (P = 0.002). High expression of H3K27me3 was associated with multifocal tumors and lymph node metastases (P < 0.05). Patients with high expression of H3K27me3 had shorter cancer-specific survival (CSS) time than patients with low expression of H3K27me3 (P < 0.001). In different subsets of UCB patients, high expression of H3K27me3 was also a prognostic indicator in patients with grade 2 and grade 3, pT1, pT2, pT3, and pN− disease (P < 0.05). Importantly, expression of H3K27me3 was an independent predictor for CSS (P < 0.001) of UCB patients treated with radical cystectomy (RC). Our data suggests that high expression of H3K27me3 is an independent molecular marker for predicting poor prognosis of UCB patients treated with RC.
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36
Chow JPH, Man WY, Mao M, Chen H, Cheung F, Nicholls J, Tsao SW, Li Lung M, Poon RYC. PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy.
Mol Cancer Ther 2013;
12:2517-28. [PMID:
23979918 DOI:
10.1158/1535-7163.mct-13-0010]
[Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nasopharyngeal carcinoma is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy for advanced nasopharyngeal carcinoma are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target PARP1 for degradation and is epigenetically inactivated in nasopharyngeal carcinoma. We present evidence that PARP1 protein is indeed overexpressed in nasopharyngeal carcinoma cells in comparison with immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary nasopharyngeal carcinoma tissues, with strong correlation with all stages of nasopharyngeal carcinoma development. We found that the PARP inhibitor AZD2281 (olaparib) increased DNA damage, cell-cycle arrest, and apoptosis in nasopharyngeal carcinoma cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA-damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in nasopharyngeal carcinoma development and provide a molecular basis of using PARP inhibitors to potentiate treatment of nasopharyngeal carcinoma with radio- and chemotherapy.
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Affiliation(s)
- Jeremy P H Chow
- Corresponding Author: Randy Y.C. Poon, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
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37
Chen K, Li Y, Dai Y, Li J, Qin Y, Zhu Y, Zeng T, Ban X, Fu L, Guan XY. Characterization of tumor suppressive function of cornulin in esophageal squamous cell carcinoma.
PLoS One 2013;
8:e68838. [PMID:
23894350 PMCID:
PMC3722219 DOI:
10.1371/journal.pone.0068838]
[Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 06/03/2013] [Indexed: 12/16/2022] Open
Abstract
By using cDNA microarray analysis, we identified cornulin (CRNN) gene was frequently downregulated in esophageal squamous cell carcinoma (ESCC). In the present study, we investigated the role of CRNN in ESCC development. The results showed that CRNN was frequently downregulated in primary ESCCs in both mRNA level (26/56, 46.4%) and protein level (137/249, 55%), which was significantly associated with lymph node metastases (P=0.027), advanced clinical stage (P=0.039), and overall survival rate (P<0.001). Multivariate analysis indicated that the CRNN downregulation was an independent prognostic factor for ESCC. Functional studies with both in vitro and in vivo assays demonstrated that CRNN had strong tumor suppressive ability in ESCC cells. The tumor-suppressive mechanism of CRNN was associated with its role in cell cycle arrest at G1/S checkpoint by upregulating expressions of P21WAF1/CIP1 and Rb. Silencing CRNN expression by RNA interference could effectively inhibit its tumor suppressive effect. In conclusion, our findings demonstrate that CRNN is a tumor suppressor gene that plays a critical tumor suppressive role in ESCC.
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Affiliation(s)
- Kai Chen
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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- Yan Li
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- * E-mail: (XG); (YL)
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- Yongdong Dai
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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- Jiangchao Li
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
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- Yanru Qin
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
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- Yinghui Zhu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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- Tingting Zeng
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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- Xiaojiao Ban
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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- Li Fu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
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- Xin-Yuan Guan
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
- * E-mail: (XG); (YL)
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38
Liu JY, Li YH, Lin HX, Liao YJ, Mai SJ, Liu ZW, Zhang ZL, Jiang LJ, Zhang JX, Kung HF, Zeng YX, Zhou FJ, Xie D. Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder.
BMC Cancer 2013;
13:349. [PMID:
23870412 PMCID:
PMC3750259 DOI:
10.1186/1471-2407-13-349]
[Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Accepted: 07/16/2013] [Indexed: 01/29/2023] Open
Abstract
Background
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Methods
In this study, the methods of quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate mRNA/ protein expression of YAP 1 in UCBs. Spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.
Results
Up-regulated expression of YAP 1 mRNA and protein was observed in the majority of UCBs by qRT-PCR and Western blotting, when compared with their paired normal bladder tissues. By IHC, positive expression of YAP 1 was examined in 113/213 (53.1%) of UCBs and in 6/86 (7.0%) of normal bladder specimens tissues. Positive expression of YAP 1 was correlated with poorer differentiation, higher T classification and higher N classification (P < 0.05). In univariate survival analysis, a significant association between positive expression of YAP 1 and shortened patients’ survival was found (P < 0.001). In different subsets of UCB patients, YAP 1 expression was also a prognostic indicator in patients with grade 2 (P = 0.005) or grade 3 (P = 0.046) UCB, and in patients in pT1 (P = 0.013), pT2-4 (P = 0.002), pN- (P < 0.001) or pT2-4/pN- (P = 0.004) stage. Importantly, YAP 1 expression (P = 0.003) together with pT and pN status (P< 0.05) provided significant independent prognostic parameters in multivariate analysis.
Conclusions
Our findings provide evidences that positive expression of YAP 1 in UCB may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with UCB.
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Affiliation(s)
- Jian-Ye Liu
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No 651, Dongfeng Road East, Guangzhou 510060, China
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39
Dai Y, Liu L, Zeng T, Zhu YH, Li J, Chen L, Li Y, Yuan YF, Ma S, Guan XY. Characterization of the oncogenic function of centromere protein F in hepatocellular carcinoma.
Biochem Biophys Res Commun 2013;
436:711-8. [PMID:
23791740 DOI:
10.1016/j.bbrc.2013.06.021]
[Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/07/2013] [Indexed: 11/26/2022]
Abstract
Centromere protein F (CENPF) is an essential nuclear protein associated with the centromere-kinetochore complex and plays a critical role in chromosome segregation during mitosis. Up-regulation of CENPF expression has previously been detected in several solid tumors. In this study, we aim to study the expression and functional role of CENPF in hepatocellular carcinoma (HCC). We found CENPF was frequently overexpressed in HCC as compared with non-tumor tissue. Up-regulated CENPF expression in HCC was positively correlated with serum AFP, venous invasion, advanced differentiation stage and a shorter overall survival. Cox regression analysis found that overexpression of CENPF was an independent prognosis factor in HCC. Functional studies found that silencing CENPF could decrease the ability of the cells to proliferate, form colonies and induce tumor formation in nude mice. Silencing CENPF also resulted in the cell cycle arrest at G2/M checkpoint by down-regulating cell cycle proteins cdc2 and cyclin B1. Our data suggest that CENPF is frequently overexpressed in HCC and plays a critical role in driving HCC tumorigenesis.
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Affiliation(s)
- Yongdong Dai
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
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40
Zhu YH, Fu L, Chen L, Qin YR, Liu H, Xie F, Zeng T, Dong SS, Li J, Li Y, Dai Y, Xie D, Guan XY. Downregulation of the novel tumor suppressor DIRAS1 predicts poor prognosis in esophageal squamous cell carcinoma.
Cancer Res 2013;
73:2298-309. [PMID:
23436800 DOI:
10.1158/0008-5472.can-12-2663]
[Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras-like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal-regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies.
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Affiliation(s)
- Ying-Hui Zhu
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
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41
Xu J, Wu X, Zhou WH, Liu AW, Wu JB, Deng JY, Yue CF, Yang SB, Wang J, Yuan ZY, Liu Q. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer.
PLoS One 2013;
8:e56919. [PMID:
23437271 PMCID:
PMC3577665 DOI:
10.1371/journal.pone.0056919]
[Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 01/16/2013] [Indexed: 12/31/2022] Open
Abstract
Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (P<0.001). In TNBC patients with Aur-A high expression, the risk of distant recurrence peaked at the first 3 years and declined rapidly thereafter, whereas patients with Aur-A low expression showed a relatively constant risk of recurrence during the entire follow-up period. Univariate and multivariate analysis showed that overexpression of Aur-A predicted poor overall survival (P = 0.002) and progression-free survival (P = 0.012) in TNBC. Furthermore, overexpression of Aur-A, associated with high Ki-67, predicted an inferior prognosis compared with low expression of both Aur-A and Ki-67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy.
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Affiliation(s)
- Jie Xu
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
- Department of Oncology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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- Xing Wu
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
- Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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- Wei-hua Zhou
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
- Department of Oncology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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- An-wen Liu
- Department of Oncology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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- Jian-bing Wu
- Department of Oncology, The Second Affiliated Hospital, Nanchang University, Nanchang, China
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- Jin-yun Deng
- Department of the Third Internal Medicine, Jiangxi Province Cancer Hospital, Nanchang, China
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- Cai-feng Yue
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
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- Shao-bing Yang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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- Jing Wang
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
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- Zhong-yu Yuan
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
- * E-mail: (ZY); (ZYY)
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- Quentin Liu
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
- Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- * E-mail: (ZY); (ZYY)
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42
He WP, Zhou J, Cai MY, Xiao XS, Liao YJ, Kung HF, Guan XY, Xie D, Yang GF. CHD1L protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival.
BMC Cancer 2012;
12:437. [PMID:
23020525 PMCID:
PMC3551745 DOI:
10.1186/1471-2407-12-437]
[Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 09/26/2012] [Indexed: 02/02/2023] Open
Abstract
Background
Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure.
Methods
In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients’ survival status.
Results
There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05).
Conclusions
These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma.
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Affiliation(s)
- Wei-Peng He
- Department of Gynecology, the First Affiliated Hospital, Sun Yat-Sen University, No, 78, Zhongshan Road II, 510080 Guangzhou, China
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43
CHD1L protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival.
BMC Cancer 2012. [PMID:
23020525 DOI:
org/10.1186/1471-2407-12-437]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND
Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure.
METHODS
In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients' survival status.
RESULTS
There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05).
CONCLUSIONS
These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma.
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44
Tong M, Chan KW, Bao JYJ, Wong KY, Chen JN, Kwan PS, Tang KH, Fu L, Qin YR, Lok S, Guan XY, Ma S. Rab25 is a tumor suppressor gene with antiangiogenic and anti-invasive activities in esophageal squamous cell carcinoma.
Cancer Res 2012;
72:6024-35. [PMID:
22991305 DOI:
10.1158/0008-5472.can-12-1269]
[Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment.
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Affiliation(s)
- Man Tong
- Department of Pathology, Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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45
Ma S, Bao JYJ, Kwan PS, Chan YP, Tong CM, Fu L, Zhang N, Tong AHY, Qin YR, Tsao SW, Chan KW, Lok S, Guan XY. Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma.
Gastroenterology 2012;
143:675-686.e12. [PMID:
22705009 DOI:
10.1053/j.gastro.2012.06.007]
[Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 05/31/2012] [Accepted: 06/04/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS
Esophageal squamous cell carcinoma (ESCC) is the most commonly observed histologic subtype of esophageal cancer. ESCC is believed to develop via accumulation of numerous genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes. We searched for transcripts that were altered in human ESCC samples compared with nontumor tissues.
METHODS
We performed integrative transcriptome sequencing (RNA-Seq) analysis using ESCC samples from 3 patients and adjacent nontumor tissues to identify transcripts that were altered in ESCC tissue. We performed molecular and functional studies of the transcripts identified and investigated the mechanisms of alteration.
RESULTS
We identified protein tyrosine kinase 6 (PTK6) as a transcript that was significantly down-regulated in ESCC tissues and cell lines compared with nontumor tissues or immortalized normal esophageal cell lines. The promoter of the PTK6 gene was inactivated in ESCC tissues at least in part via hypermethylation and histone deacetylation. Knockdown of PTK6 in KYSE30 ESCC cells using small hairpin RNAs increased their ability to form foci, migrate, and invade extracellular matrix in culture and form tumors in nude mice. Overexpression of PTK6 in these cells reduced their proliferation in culture and tumor formation in mice. PTK6 reduced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, leading to activation of β-catenin.
CONCLUSIONS
PTK6 was identified as a transcript that is down-regulated in human ESCC tissues via epigenetic modification at the PTK6 locus. Its product appears to regulate cell proliferation by reducing phosphorylation of Akt and GSK3β, leading to activation of β-catenin. Reduced levels of PTK6 promote growth of xenograft tumors in mice; it might be developed as a marker of ESCC.
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Affiliation(s)
- Stephanie Ma
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Jessie Y J Bao
- Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Pak Shing Kwan
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Yuen Piu Chan
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Carol M Tong
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Li Fu
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Na Zhang
- Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Amy H Y Tong
- Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Yan-Ru Qin
- Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
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- Sai Wah Tsao
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Kwok Wah Chan
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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- Si Lok
- Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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- Xin-Yuan Guan
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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46
Zhou WH, Tang F, Xu J, Wu X, Yang SB, Feng ZY, Ding YG, Wan XB, Guan Z, Li HG, Lin DJ, Shao CK, Liu Q. Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer.
Autophagy 2012;
8:389-400. [PMID:
22240664 DOI:
10.4161/auto.18641]
[Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Recent studies have suggested that dysregulation of autophagy plays a pivotal role in tumorigenesis. Here, we determined the prognostic value of autophagy-related protein Beclin 1 in gastric cancer. A total of 153 primary gastric cancer patients were subjected to analysis of Beclin 1 expression and survival prognosis. Among them, 68 patients were assigned randomly and used as a training set to generate a cutoff score for Beclin 1 expression by receive operating characteristic (ROC) curve analysis. The ROC-generated cutoff score was subjected to analyze the association of Beclin 1 with clinical characteristics and patient outcome. In a testing set (n = 85) and overall patients (n = 153), both univariate and multivariate analysis found that low expression of Beclin 1 predicted adverse overall survival and progression-free survival for gastric cancer patients. Furthermore, in each stage of gastric cancer patients, Beclin 1 expression was a prognostic indicator in patients with stage II, III and IV. Importantly, a reverse relationship between Beclin 1 and Bcl-xL expression was demonstrated. In patients of elevated Bcl-xL expression, a subset with lower Beclin 1 expression displayed an inferior overall survival and progression-free survival than those with higher Beclin 1 expression. Thus, our data demonstrated that low expression of Beclin 1, associated with high Bcl-xL, played as an independent biomarker, contributing to a more aggressive cancer cell phenotype and poor prognosis for gastric tumor.
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Affiliation(s)
- Wei-Hua Zhou
- Department of Hematology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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47
Liu H, Qin YR, Bi J, Guo A, Fu L, Guan XY. Overexpression of matrix metalloproteinase 10 is associated with poor survival in patients with early stage of esophageal squamous cell carcinoma.
Dis Esophagus 2011;
25:656-63. [PMID:
22121946 DOI:
10.1111/j.1442-2050.2011.01284.x]
[Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Matrix metallopeptidase 10 (MMP10) is frequently expressed and correlates closely with metastasis and poor prognosis in various human cancers. However, the significance of MMP10 expression in esophageal squamous cell carcinoma (ESCC) and its role in ESCC progression remains unclear. In this report, upregulation of MMP10 mRNA was detected in 39/60 (65.0%) of primary ESCC tissues compared with their paired nontumor esophageal tissues. Tissue microarray (TMA) study found protein overexpression of MMP10 in 188/239 (78.7%) of primary ESCC tissues but not in their corresponding nontumor esophageal tissues, suggesting that overexpression of MMP10 may play important roles in ESCC development and progression. Although the overexpression of MMP10 was not significantly associated with disease-specific survival rate (P= 0.182) for all tested ESCCs, it was significantly associated with poorer disease-specific survival (P= 0.001) in early stage of ESCCs (I-IIA). In addition, multivariate analysis found that MMP10 expression in tumor tissues was evaluated as a potential independent prognostic factor for early stage ESCC patients. These findings suggest that MMP10 plays an important role in ESCC progression in the early stage, and overexpression of MMP10 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of ESCC.
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Affiliation(s)
- H Liu
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, China
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48
Investigation of β-catenin and E-cadherin Expression in Dukes B2 Stage Colorectal Cancer with Tissue Microarray Method. Is It a Marker of Metastatic Potential in Rectal Cancer?
Pathol Oncol Res 2011;
18:429-37. [DOI:
10.1007/s12253-011-9463-y]
[Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Accepted: 09/14/2011] [Indexed: 01/20/2023]
49
Zhou WH, Tang F, Xu J, Wu X, Feng ZY, Li HG, Lin DJ, Shao CK, Liu Q. Aberrant upregulation of 14-3-3ơ expression serves as an inferior prognostic biomarker for gastric cancer.
BMC Cancer 2011;
11:397. [PMID:
21933426 PMCID:
PMC3184120 DOI:
10.1186/1471-2407-11-397]
[Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Accepted: 09/20/2011] [Indexed: 12/18/2022] Open
Abstract
Background
14-3-3ơ is an intracellular, phosphoserine binding protein and proposed to be involved in tumorigenesis. However, the expression dynamics of 14-3-3ơ and its clinicopathological/prognostic significance in human tumors are still controversial.
Methods
The method of immunohistochemistry (IHC) and Western blot were utilized to examine the protein expression of 14-3-3ơ in gastric cancer and paired normal adjacent gastric mucosal tissues. Receive operating characteristic (ROC) curve analysis was employed to determine a cutoff score for 14-3-3ơ expression in a training set (n = 66). For validation, the ROC-derived cutoff score was subjected to analysis of the association of 14-3-3ơ expression with patient outcome and clinical characteristics in a testing set (n = 86) and overall patients (n = 152).
Results
The expression frequency and expression levels of 14-3-3ơ were significantly higher in gastric cancer than in normal gastric mucosal tissues. Correlation analysis demonstrated that high expression of 14-3-3ơ in gastric cancer was significantly correlated with clinical stage and tumor invasion. Furthermore, in the testing set and overall patients, Kaplan-Meier analysis showed that elevated 14-3-3ơ expression predicted poorer overall survival (OS) and progression-free survival (PFS). Importantly, high 14-3-3ơ expression was also associated with shortened survival time in stage III and stage IV gastric cancer patients. Multivariate analyses revealed that 14-3-3ơ expression was an independent prognostic parameter in gastric cancer.
Conclusions
These findings provide evidence that high expression of 14-3-3ơ may be important in the tumor progression and servers as an independent molecular marker for poor prognosis of gastric cancer. Thus, overexpression of 14-3-3ơ identifies patients at high risk and is a novel therapeutic molecular target for this tumor.
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Affiliation(s)
- Wei-hua Zhou
- Department of Hematology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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50
Cai MY, Tong ZT, Zhu W, Wen ZZ, Rao HL, Kong LL, Guan XY, Kung HF, Zeng YX, Xie D. H3K27me3 protein is a promising predictive biomarker of patients' survival and chemoradioresistance in human nasopharyngeal carcinoma.
Mol Med 2011;
17:1137-45. [PMID:
21738951 DOI:
10.2119/molmed.2011.00054]
[Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 06/30/2011] [Indexed: 12/14/2022] Open
Abstract
Trimethylation of lysine 27 on histone H3 (H3K27me3) is an epigenetic change which plays a critical role in tumor development and/or progression. However, the molecular status of H3K27me3 and its clinicopathologic/prognostic significance in nasopharyngeal carcinoma (NPC) have not been elucidated. In this study, the methods of Western blotting and immunohistochemistry (IHC) were utilized to examine the expression of H3K27me3 protein in NPC tissues and nonneoplastic nasopharyngeal epithelial tissues. Receiver operating characteristic (ROC) curve analysis was used to determine the cutpoint for H3K27me3 high expression. High expression of H3K27me3 could be observed in 127/209 (60.8%) of NPCs and in 8/50 (16.0%) normal nasopharyngeal epithelial tissues (P < 0.001). Further correlation analysis demonstrated that high expression of H3K27me3 was positively associated with tumor later T classification, tumor metastasis, advanced clinical stage and chemoradioresistance (P < 0.05). Moreover, high expression of H3K27me3 was closely associated with NPC patient shortened survival time as evidenced by univariate and multivariate analysis (P < 0.05). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (H3K27me3 expression, distant metastasis and treatment regimen) was constructed. The model could stratify risk significantly (low, intermediate and high) for overall survival and progression-free survival (P < 0.0001). These findings provide evidence that H3K27me3 expression, as examined by IHC, has the potential to be used as an immunomarker to predict NPC chemoradiotherapy response and patient prognosis. The combined clinicopathologic prognostic model may become a useful tool for identifying NPC patients with different clinical outcomes.
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Affiliation(s)
- Mu-Yan Cai
- State Key Laboratory of Oncology in South China Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
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