SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway

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.

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

“…Autophagy is also called programed cell death type II, which is different from the apoptotic type I death pathway (Choi et al, 2013). It is a highly conserved catabolic process that maintains cellular homeostasis by targeting damaged proteins or organelles to lysosomal compartments for degradation (Zhang et al, 2019). Autophagy has potential roles in radioresistance of cancer cells such as colorectal cancer, breast cancer, glioma, and pancreatic cancer (Yao et al, 2003;Chaachouay et al, 2011Chaachouay et al, , 2015Wang et al, 2013;Koukourakis et al, 2016).…”

Aurora-B Knockdown Inhibits Osteosarcoma Metastasis by Inducing Autophagy via the mTOR/ULK1 Pathway

“…These ndings indicate that autophagy plays an essential role in the process of Aurora-B affecting the ability of motility and invasive in OS cells. Autophagy is reported to inhibit cell migration by accelerating the degradation of MMP family proteins (26,27), therefore, we sought to determine the MMP2 protein levels in Aurora-Bknockdown OS cells with or without CQ treatment. Results showed that the suppression of MMP2 expression due to Aurora-B knockdown could be restored by CQ treatment (Fig.…”

Inhibition of HIF1A-AS1 promoted starvation-induced hepatocellular carcinoma cell apoptosis by reducing HIF-1α/mTOR-mediated autophagy

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