首页|The CCCTC‐binding factor (CTCF)–forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma

The CCCTC‐binding factor (CTCF)–forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma

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  • NSTL
  • Wiley
Abstract CCCTC‐binding factor (CTCF) is a DNA‐binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non‐tumoural liver. Overexpression of CTCF was associated with shorter disease‐free survival of patients. Short hairpin RNA (shRNA)‐mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; these effects were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), the shelterin complex member telomerase repeat‐binding factor 1, and forkhead box protein M1 (FOXM1). In contrast, upregulation of CTCF was positively correlated with FOXM1 and TERT expression in clinical HCC biopsies. Depletion of CTCF resulted in reduced motility and invasiveness in HCC cells that could be reversed by ectopic expression of FOXM1, suggesting that FOXM1 is one of the important downstream effectors of CTCF in HCC. Reporter gene analysis suggested that depletion of CTCF is associated with reduced FOXM1 and TERT promoter activity. Chromatin immunoprecipitation (ChIP)–polymerase chain reaction (PCR) analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo . Importantly, depletion of CTCF by shRNA significantly inhibited tumour progression and metastasis in HCC mouse models. Our work uncovered a novel functional role of CTCF in HCC pathogenesis, which suggests that targeting CTCF could be further explored as a potential therapeutic strategy for HCC. ? 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

CTCFHCCFOXM1TERTchromatin immunoprecipitationmetastasis

Zhang Yajing、Zou Xiaoping、Chan Anthony WH、Zhang Rui、Lee Terence Kin‐Wah、Liu Hang、Lau Eunice Yuen‐Ting、Ho Nicole Pui‐Yu、Lai Paul BS、Cheung Yue‐Sun、To Ka‐Fai、Wong Hoi Kin、Choy Kwong Wai、Keng Vincent W、Chow Larry MC、Chan Kenrick KY、Cheng Alfred S、Ko Ben CB、Zhang Bin

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The Hong Kong Polytechnic University Shenzhen Research InstituteShenzhen,PR China

Department of Gastroenterology, Nanjing Drum Tower HospitalNanjing UniversityNanjing,PR China

Department of Anatomical and Cellular PathologyThe Chinese University of Hong KongHong Kong,SAR,PR

Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong

Department of SurgeryThe Chinese University of Hong KongHong Kong,SAR,PR China

Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong Kong,SAR,PR China

School of Biomedical SciencesThe Chinese University of Hong KongHong Kong,SAR,PR China

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2017

10.1002/path.4976

Journal of Pathology

Journal of Pathology

ISTP
ISSN：0022-3417
年,卷(期)：2017.243(4)
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