Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

Abstract

Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs. Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic Kras G12D . Bioinformatics and gain- or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations. Transcriptional profiling was used to identify biomarker for the subtype of HCC. The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model. Results: Oncogenic Kras G12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis. Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity. Paternally expressed 3 (PEG3) was responsible for Kras/Erk- and mTOR-driven HCC. Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation- and metastasis-related proteins. Targeting mTOR significantly inhibited these actions in vitro and in vivo . Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation. Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.

Co‐expression pattern of SLC transporter genes associated with the immune landscape and clinical outcomes in gastric cancer

“…Additionally, some genes used to model SLC scores have also been studied in gastric and other cancers. Particularly, high expression levels of RBPMS2 , 31 DZIP1 , 32 PEG3 , 33 TSPYL5 34 and MAGEA4 35 , 36 in gastric cancer or other tumour tissues have been associated with a poor prognosis, while high expression levels of CXCL3 and TNFRSF11A in gastric cancer have been associated with a better prognosis 37 , 38 ; these observations are consistent with our findings. Thus, the clinical translational potential of SLC family gene members can be realized using the SLC score, which has good reproducibility and clinical applicability for predicting prognosis and guiding therapeutic strategies.…”

Tanshinone IIA regulates CCl4 induced liver fibrosis in C57BL/6J mice via the PI3K/Akt and Nrf2/HO‐1 signaling pathways

“…Thus, the PI3K/Akt signaling pathway is worth exploring. Meanwhile, it was found that the role of KRAS protein in the early stage of tumor development has always been a focus of attention, [ 41–43 ] but its mechanism in the fibrosis stage was still unclear. The occurrence and development of LF are often accompanied by oxidative stress, which is defined as the imbalance between free radicals and reactive metabolites, playing an important role in the pathogenesis of LF and being eliminated by the antioxidant system.…”

Identification of metabolism terms significantly affecting hepatocellular carcinoma immune microenvironment and immunotherapy response

“…However, the effectiveness of these therapies can be influenced by various factors, including the genetic background of the tumour and the tumour's microenvironment 33 . KRAS is an oncogene involved in cell signalling pathways that regulate proliferation, differentiation and survival 34 . In HCC, KRAS mutations are rare but its pathway can be activated via other mechanisms, contributing to tumour development and progression 35,36 .…”

“…33 KRAS is an oncogene involved in cell signalling pathways that regulate proliferation, differentiation and survival. 34 In HCC, KRAS mutations are rare but its pathway can be activated via other mechanisms, contributing to tumour development and progression. 35,36…”

“… 33 KRAS is an oncogene involved in cell signalling pathways that regulate proliferation, differentiation and survival. 34 In HCC, KRAS mutations are rare but its pathway can be activated via other mechanisms, contributing to tumour development and progression. 35 , 36 E2F targets refer to genes regulated by the E2F family of transcription factors, critical for cell cycle regulation and DNA synthesis.…”