GNAS promotes inflammation-related hepatocellular carcinoma progression by promoting STAT3 activation

Abstract

Background: 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. 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. Methods: Lipopolysaccharides (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 RNAbinding 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. Results: We 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. Conclusions: Our 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.

lncRNA TPTEP1 inhibits stemness and radioresistance of glioma through miR‑106a‑5p‑mediated P38 MAPK signaling

“…TPTeP1 acts as a tumor suppressor in hepatocellular carcinoma (33,34) and lung cancer (35), and has been reported to participate in the modulation of several biological functions, including cell proliferation, invasion, chemoresistance and inflammation (33)(34)(35) . In addition, bioinformatic analysis suggests that TPTeP1 may serve as a tumor suppressor in the development of GBM (36).…”

Identification of Potential Biomarkers of Prognosis-Related Long Non-Coding RNA (lncRNA) in Pediatric Rhabdoid Tumor of the Kidney Based on ceRNA Networks

“…The high expression of TPTEP1 can predict the prolonged overall survival of patients with lung cancer [ 21 ]. TPTEP1 overexpression suppressed cell proliferation and metastasis but did not affect cell apoptosis in hepatocellular carcinoma [ 22 ]. However, in our study, the survival rate of patients with TPTEP1 overexpression was low, which likely means that in RTK, TPTEP1 overexpression can promote tumor development, which needs to be further confirmed in future studies.…”

N6-Methyladenosine RNA Modification in Inflammation: Roles, Mechanisms, and Applications

“…Another study reported that LPS stimulation can increase m6A methylation of G-protein alpha-subunit (GNAS) mRNA to promote GNAS expression in HCC cells. Highly expressed GNAS promotes the growth and invasion of HCC cells by interacting with STAT3 (Ding et al, 2020). Intrahepatic cholangiocarcinoma (ICC) is the second most malignant type of primary liver cancer with a high degree of incidence and a very poor prognosis.…”

“…For instance, human HCC exhibits a characteristic increase in m6A modification, which is related to inflammation-mediated malignancy (Hou et al, 2019). Meanwhile, LPS stimulation can increase m6A levels and trigger inflammatory cytokine production and pathways in liver tumors and dental pup inflammation (Feng et al, 2018;Ding et al, 2020). Mechanistically, it has been reported that silencing Mettl3 could maintain LCFA absorption by blocking the TRAF6-dependent inflammation response (Zong et al, 2019).…”