Abstract
IntroductionGap junction protein, alpha 1 (GJA1), which is correlated with recurrences and unfavorable prognoses in hepatocellular carcinomas (HCCs), is one of the specific proteins expressed by activated hepatic stellate cells (HSCs).MethodsExpression of GJA1 was compared between HCCs and nontumor tissues (NTs), between hepatic cirrhosis and NTs, and between primary and metastatic HCCs using transcriptomic datasets from the Gene Expression Omnibus and the Integrative Molecular Database of Hepatocellular Carcinoma. The in vitro activities of GJA1 were investigated in cultured HSCs and HCC cells. The underlying mechanism was characterized using Gene Set Enrichment Analysis and validated by western blotting.ResultsThe expression of GJA1 was significantly increased in HCCs and hepatic cirrhosis compared to that in NTs. GJA1 was also overexpressed in pulmonary metastases from HCCs when compared with HCCs without metastasis. Overexpression of GJA1 promoted while knockdown of GJA1 inhibited proliferation and transforming growth factor (TGF)-β-mediated activation and migration of cultured HSCs. Overexpression of GJA1 by lentivirus infection promoted proliferation and migration, while conditioned medium from HSCs overexpressing GJA1 promoted migration but inhibited proliferation of Hep3B and PLC-PRF-5 cells. Lentivirus infection with shGJA1 or conditioned medium from shGJA1-infected HSCs inhibited the proliferation and migration of HCCLM3 cells that had a high propensity toward lung metastasis. Mechanistically, GJA1 induced the epithelial–mesenchymal transition (EMT) in HSCs and HCCLM3 cells.ConclusionGJA1 promoted HCC progression by inducing HSC activation and the EMT in HSCs. GJA1 is potentially regulated by TGF-β and thus may be a therapeutic target to inhibit HCC progression.
Highlights
Hepatocellular carcinoma (HCC) is one of the most predominant and fatal malignancies worldwide [1]
By analyzing one dataset consisting of 5 nontumor tissues (NTs), 10 primary HCCs without metastasis (p-HCC), and 12 pulmonary metastases from HCCs (m-HCC), we found that GJA1 expression was significantly increased in pulmonary metastases from HCCs compared to that in NTs or primary HCCs without metastasis (Figure 1c)
In another dataset that contained 22 primary HCCs without metastasis (P0), 17 primary lesions (P1) and 12 metastases (M1) from HCCs with intrahepatic spread metastasis, and 9 primary lesions (P2) and 7 metastases (M2) from HCCs with portal vein tumor thrombus metastasis, the expression of GJA1 was significantly decreased in P2 and M2 samples while decreased with no significance in P1 and M1 samples, compared to that in P0 samples (Figure 1d)
Summary
Hepatocellular carcinoma (HCC) is one of the most predominant and fatal malignancies worldwide [1]. Immunization with vaccines against the hepatitis B virus could dramatically decrease the incidence of HCC in highrisk populations [2], this malignancy remains a huge health threat due to the high probability of metastasis [3]. Activation of hepatic stellate cells (HSCs) initiates HCC recurrence and metastasis [4,5,6,7]. Stimulated by various profibrotic factors such as transforming growth factor (TGF)-β, HSCs are activated and transdifferentiated into myofibroblasts that secrete extracellular matrix proteins into the stroma to promote the development of hepatic fibrosis and cirrhosis, which are predisposed to and often interact with HCCs [7,8,9,10]. Activated HSCs express a number of specific genes that facilitate HCC recurrence [4,5]. By inhibiting HSC activation and minimizing the adverse effects of profibrotic factors, fibrotic and cirrhotic liver diseases may be effectively treated [9,10,11], and HCC progression may be inhibited
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