ArticleOncogene2022
Elevated expression of RIT1 hyperactivates RAS/MAPK signal and sensitizes hepatocellular carcinoma to combined treatment with sorafenib and AKT inhibitor.
Article in Oncogene, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 42 citations in OpenAlex.
- Targeted Gene Therapy for Mutated H-ras and C-raf.1 Genes Exhibited Variable Efficacy in Inhibiting Hepatocellular Carcinoma in Rats: A Mechanistic Approach.Pharmaceutical research · 2026Article
- Ubiquitin-independent pathway regulates the RIT1-MAPK pathway in chordoma progression.Cell death & disease · 2025Article
- Selumetinib promotes coronary collateral circulation by inducing M2-like macrophage polarization following myocardial infarction.Acta pharmacologica Sinica · 2025Article
- Ellipticine targets FGFR3 to mediate the RAS/MAPK-P38 signalling pathway to induce apoptosis in hepatocellular carcinoma cells.3 Biotech · 2025Article
- Ras-MAPK pathway in patients with lupus nephritis.Lupus science & medicine · 2025Article
- Networks of pre-diagnostic circulating RNA in testicular germ cell tumour.Scientific reports · 2025Article
- Uncovering novel pathogenic variants and pathway mutations in triple-negative breast cancer among the endogamous mizo tribe.Breast cancer research and treatment · 2025Article
- RIT1 Promotes the Proliferation of Gliomas Through the Regulation of the PI3K/AKT/c-Myc Signalling Pathway.Journal of cellular and molecular medicine · 2025Article
- Article
- Single-cell and genome-wide Mendelian randomization identifies causative genes for gout.Arthritis research & therapy · 2024Article
- A Model to Predict Prognosis of Renal Cell Clear Cell Carcinoma Based on 3 Angiogenesis-related Long Non-coding RNAs.Journal of Cancer · 2024Article
- RIT1 regulates mitosis and promotes proliferation by interacting with SMC3 and PDS5 in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2023Article
- RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.Science advances · 2023Article
- Metformin Induces Lipogenesis and Apoptosis in H4IIE Hepatocellular Carcinoma Cells.Development & reproduction · 2023Article
- Establishing a prognostic model of chromatin modulators and identifying potential drug candidates in renal clear cell patients.BMC bioinformatics · 2023Article
- Link of sorafenib resistance with the tumor microenvironment in hepatocellular carcinoma: Mechanistic insights.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
21 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperactivation of RAS/MAPK signaling is commonly observed in hepatocellular carcinoma (HCC). Gain-of-function mutations of canonical RAS genes, however, are rarely detected and it remains unclear how the activity of this pathway is turned on during hepatocarcinogenesis. We performed a comprehensive analysis of RAS superfamily genetic alterations across ten subfamilies, 152 members in 377 HCC patients from the Cancer Genome Atlas database. RIT1 (Ras-like without CAAX 1) was the most frequently altered RAS member amplified in 13% of the HCC cohort. Both genomic amplification and CREB-mediated transcriptional activation contributed to the elevated RIT1 expression, and its overexpression correlated with RAS/MAPK activation and poor prognosis. Then, we found that RIT1-induced angiogenesis via the MEK/ERK/EIF4E/HIF1-α/VEGFA axis. MAP3K11 and MAP3K12, in addition to CRAF, could mediate this process by binding to RIT1. Moreover, RIT1 increased the phosphorylation of p38 MAPK and AKT to promote cell survival under reactive oxygen species stress. Based on this mechanistic understanding, we treated RIT1-overexpressing HCC with combined regimen sorafenib plus AKT inhibitor, and achieved enhanced antitumor effects in vivo. Our study reveals RAS "orphan" member RIT1 as the most common genetic alteration of RAS family in HCC and combination of sorafenib with AKT inhibitor might be a promising treatment strategy for RIT1-overexpressing HCC.
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