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

Autor: Zhang B; Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, PR China., Zhang Y; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, PR China.; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Zou X; Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, PR China., Chan AW; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Zhang R; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Lee TK; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Liu H; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Lau EY; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Ho NP; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Lai PB; Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Cheung YS; Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., To KF; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Wong HK; Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Choy KW; Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Keng VW; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Chow LM; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Chan KK; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China., Cheng AS; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, PR China., Ko BC; The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, PR China.; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong, SAR, PR China.
Jazyk: angličtina
Zdroj: The Journal of pathology [J Pathol] 2017 Dec; Vol. 243 (4), pp. 418-430. Date of Electronic Publication: 2017 Oct 27.
DOI: 10.1002/path.4976
Abstrakt: 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.
(© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)
Databáze: MEDLINE
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