Abstract
BackgroundHepatocellular carcinoma (HCC) is still the most common cause of cancer-related mortality worldwide and accumulating studies report that HCC is frequently linked to chronic inflammation. G-protein alpha-subunit (GNAS)-activating mutations have recently been reported to form a rare subgroup of inflammatory liver tumors. In this study, we investigated the roles of GNAS in inflammation-related HCC progression and its underlying mechanism.MethodsLipopolysaccharides (LPS) and diethylnitrosamine were employed to stimulate HCC cells to an induced inflammatory response. qRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of GNAS in HCC tissues and cell lines. Expression levels of proinflammatory cytokines were detected by qRT-PCR and ELISA. N6-methyladenosine (m6A) methylation of GNAS mRNA was detected by RNA-binding protein immunoprecipitation (RIP). Transcription factors activation profiling plate array was performed to investigate the underlying mechanism in GNAS promoting interleukin-6 (IL-6) expression in HCC cells. HCC cell invasion was determined by transwell assay in vitro, and tumorigenesis was assessed with a subcutaneous xenograft mouse model of HCC.ResultsWe found that LPS stimulation promotes GNAS expression in HCC cells through increasing m6A methylation of GNAS mRNA. The high expression level of GNAS promotes LPS-induced HCC cell growth and invasion by interacting with signal transducer and activator of transcription 3 (STAT3). Furthermore, GNAS knockdown inhibits LPS induced-IL-6 expression in HCC cells by suppressing STAT3 activation. Moreover, we found that GNAS promotes LPS-induced STAT3 activation in HCC cells through inhibiting long non-coding RNA TPTEP1 interacting with STAT3. In addition, GNAS expression promotes HCC development in mice and is related to poor survival.ConclusionsOur findings for the first time indicate a tumor-promoting role of GNAS in inflammation-related HCC progression and provide a novel potential target for HCC therapy.
Highlights
Hepatocellular carcinoma (HCC) is still the most common cause of cancer-related mortality worldwide and accumulating studies report that HCC is frequently linked to chronic inflammation
We found that G-protein alpha-subunit (GNAS) promotes LPS-induced signal transducer and activator of transcription 3 (STAT3) activation in HCC cells through inhibiting long non-coding RNA TPTEP1 interacting with STAT3
LPS stimulation promotes GNAS expression in HCC cells, and GNAS knockdown inhibits LPS-induced IL-6 expression HCC is frequently linked to chronic inflammation [6,7,8], and GNAS-activating mutations have been reported to form a rare subgroup of inflammatory liver tumors [23]
Summary
Hepatocellular carcinoma (HCC) is still the most common cause of cancer-related mortality worldwide and accumulating studies report that HCC is frequently linked to chronic inflammation. Inflammation in the tumor microenvironment promotes tumorous cell proliferation and metastasis, and triggers chemotherapy tolerance [11,12,13] Cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β), are the major mediators which are responsible for interchanging among cells in the tumor microenvironment [14,15,16]. Exploring the pathological mechanisms of tumor-related inflammatory responses attracts much attention, the molecular mechanisms in inflammation-related HCC progression are still not completely known
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