Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis
SCIE
SCOPUS
- Title
- Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis
- Authors
- KIM, EUNJEONG; KIM, DONG HYO; LEE, JEON SOO; JEE, HYUN YOE; JONGMIN, PARK; Chang-Jin Kim; Dongjun Jeong; KIM, SANGUK; LEE, YOONTAE
- Date Issued
- 2018-01
- Publisher
- WILEY-BLACKWELL
- Abstract
- Hepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signaling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor Capicua/CIC as a suppressor of HCC progression and a potential therapeutic target. Expression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. The levels of PEA3 group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETV4 is the most significantly upregulated gene in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, ETV4 induces expression of MMP1, the MMP gene highly relevant to HCC progression, in HCC cells, and knockdown of MMP1 completely blocks the CIC deficiency-induced HCC cell proliferation and invasion.
CONCLUSION:
Our study demonstrates that the CIC-ETV4-MMP1 axis is a novel regulatory module controlling HCC progression. This article is protected by copyright. All rights reserved.
- Keywords
- capicua; ETS translocation variant 4; interstitial collagenase; messenger RNA; suppressor factor; transcription factor; transcription factor PEA3; unclassified drug; CIC protein, human; E1A protein; ETV4 protein, human; interstitial collagenase; MMP1 protein, human; oncoprotein; repressor protein; animal experiment; animal model; animal tissue; Article; cancer growth; cancer survival; cell invasion; cell migration; cell proliferation; controlled study; disease severity; gene; gene expression regulation; genetic transcription; hepatocellular carcinoma cell line; histopathology; human; human cell; immunohistochemistry; in vitro study; in vivo study; lethality; liver cell carcinoma; lung metastasis; male; MHCC97-H cell line; MMP1 gene; mouse; nonhuman; overall survival; priority journal; promoter region; SK-HEP-1 cell line; survival analysis; survival rate; tissue microarray; upregulation; animal; disease exacerbation; liver cell carcinoma; liver tumor; physiology; Adenovirus E1A Proteins; Animals; Carcinoma, Hepatocellular; Disease Progression; Humans; Liver Neoplasms; Matrix Metalloproteinase 1; Mice; Proto-Oncogene Proteins; Repressor Proteins
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/41188
- DOI
- 10.1002/hep.29738
- ISSN
- 0270-9139
- Article Type
- Article
- Citation
- HEPATOLOGY, vol. 67, no. 6, page. 2287 - 2301, 2018-01
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