Abstract
SOCS5 is a member of the suppressor of cytokine signaling (SOCS) protein family with important yet incompletely understood biological functions in cancer. In hepatocellular carcinoma (HCC), controversial tumor-promoting and tumor-suppressive roles of SOCS5 have been reported. Our study aims to unravel novel functions of SOCS5 in HCC, especially that affecting metastasis. We examined the expression levels of SOCS5 in HCC using publicly available datasets, and in our patient cohort, using quantitative real-time PCR, western blotting, and immunohistochemistry. The association of SOCS5 expression with clinical pathological data of HCC patients was examined and that with the mTOR pathway was predicted. We further studied the effects of SOCS5 on PI3K/Akt/mTOR activity; HCC cell autophagy, migration, and invasion; and HCC cell metastasis in vitro and in vivo. We observed that SOCS5 was significantly overexpressed in HCC tissues, compared to adjacent non-tumor liver tissues, in both the public datasets and in our patient cohort. SOCS5 overexpression was significantly and inversely correlated with HCC patient prognosis. Moreover, SOCS5 overexpression promoted HCC cell migration and invasion in vitro by inactivating PI3K/Akt/mTOR-mediated autophagy. Conversely, SOCS5 inhibition suppressed HCC cell migration and invasion in vitro by activating PI3K/Akt/mTOR-mediated autophagy. Dual inhibition of SOCS5 and mTOR further enhanced autophagy and the subsequent anti-metastatic effects on HCC cells. In vivo, stable knockdown of SOCS5 reduced HCC cell metastasis. Overall, our study revealed a novel metastasis-promoting function of SOCS5 in HCC, acting via the PI3K/Akt/mTOR-mediated autophagy pathway. Combined inhibition of SOCS5 and mTOR may be a potential therapeutic approach to inhibit HCC metastasis and prolong patient survival.
Highlights
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide and the third leading cause of cancer mortality in China[1,2]
High Suppressor of cytokine signaling 5 (SOCS5) expression predicts poor prognosis in hepatocellular carcinoma (HCC) Using published datasets from the Oncolnc database, we found that HCC patients with high SOCS5 mRNA expression had significantly worse median overall survival (OS) than patients with low SOCS5 (OS: 1372 vs. 2131 days, respectively; Fig. 1d)
SOCS5 expression levels affect HCC cell autophagy Since SOCS5 can regulate the phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and affect p-ULK1/p-ATG13, which play an important role in affecting autophagy[19,20,21], we further examined the relationship between SOCS5 and autophagy-related protein expression in HCC cells that were transfected with GV141-SOCS5 or siSOCS5 #3 for 12, 24, or 48 h
Summary
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide and the third leading cause of cancer mortality in China[1,2]. Members of the suppressor of cytokine signaling (SOCS) protein family play key roles in the regulation of Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2019)10:612 cytokine signaling[4,5,6] and aberrant expression levels of SOCS members have been reported to contribute to disease development and progression[7]. Yoon et al reported that SOCS5 was upregulated in the three liver cancer tissues[7]. The data from this limited sample set require validation in a larger liver cancer patient cohort. In a recent study using liver cancer cell lines, SOCS5 was shown to have tumorsuppressive role[12]. Our study aims to fill in the gaps in understanding the contribution of SOCS5 to HCC development and/or progression, which may form the basis for developing new therapeutic strategies for HCC
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