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Upregulation of amphiregulin by retinoic acid and Wnt signalling promotes liver cancer cell proliferation
Author(s) -
Lin HsuanHwai,
Peng YiJen,
Tsai MingJiun,
Wu YiYing,
Tsai TsungNeng,
Huang HsinHung,
Shih YuLueng,
Chang WeiKuo,
Hsieh TsaiYuan
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29088
Subject(s) - amphiregulin , hccs , wnt signaling pathway , hepatic stellate cell , retinoic acid , cancer research , cell growth , downregulation and upregulation , medicine , biology , beta catenin , hepatocellular carcinoma , cancer , cell culture , endocrinology , epidermal growth factor receptor , signal transduction , microbiology and biotechnology , genetics , biochemistry , gene
Activated hepatic stellate cells promote hepatocellular carcinoma (HCC) progression. Hepatic stellate cells play a key role in retinoid metabolism, and activation of stellate cells increases retinoic acid (RA) in the liver. However, the role of RA in HCC proliferation remains unclear. We aimed to analyse the mechanism of RA in HCC proliferation. Thirty‐eight patients who had undergone hepatic resection for HCCs were recruited. Paired non‐tumour tissues, adjacent and distal to HCCs, were collected, and the RA levels in the tissues were analysed. The mechanisms of RA and HCC proliferation were assessed in liver cancer cell lines by protein and gene expression analyses. Early recurrence of HCC was significantly higher in patients with a higher RA concentration than in those with a lower RA concentration in tissues adjacent to HCCs (61.1% vs. 20%, p = .010). RA promoted HCC cell proliferation and activated the expression of Amphiregulin, a growth factor in hepatocarcinogenesis. The promoter of Amphiregulin contained the binding sites of the RA receptor, RXRα. Wnt signalling also activated the expression of Amphiregulin, and the RA and Wnt pathways acted synergistically to increase the expression of Amphiregulin. Furthermore, RXRα interacted with β‐catenin and then translocated to the nucleus to activate Amphiregulin. An increased RA concentration in the tissues adjacent to the tumour was associated with an early recurrence of HCC. RA activated the expression of Amphiregulin, and then promoted HCC proliferation, which might partly contribute to early recurrence of HCC after hepatic resection.