Sp1‐regulated transcription of Ras<scp>GRP</scp>1 promotes hepatocellular carcinoma (<scp>HCC</scp>) proliferation

Zhang, Xinran; Zhuang, Hao; Han, Feng; Shao, Xiaowen; Liu, Yun; Ma, Xuda; Wang, Zun; Qiang, Zhaoyan; Li, Yongmei

doi:10.1111/liv.13757

Cited by 31 publications

(21 citation statements)

References 35 publications

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“…Upregulated RASGRP1 expression correlates with improved clinical outcomes in patients with colorectal cancer, and may induce a negative feedback loop to suppress proliferative epidermal growth factor receptor/son of sevenless homolog 1/Ras signaling (64). RASGRP1 may be a novel therapeutic target for the treatment of hepatocellular carcinoma (66). Wang et al (67) reported a positive correlation between RASGRP1 overexpression and survival in triple-negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the lncRNA‑associated competing endogenous RNA network in breast cancer

Wang¹,

Huang

Song

et al. 2019

Oncol Rep

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Long noncoding RNAs (lncRNAs) have been confirmed to be potential prognostic markers in a variety of cancers and to interact with microRNAs (miRNAs) as competing endogenous RNAs (ceRNAs) to regulate target gene expression. However, the role of lncRNA-mediated ceRNAs in breast cancer (BC) remains unclear. In the present study, a ceRNA network was generated to explore their role in BC. The expression profiles of mRNAs, miRNAs and lncRNAs in 1,109 BC tissues and 113 normal breast tissues were obtained from The Cancer Genome Atlas database (TCGA). A total of 3,198 differentially expressed (DE) mRNAs, 150 differentially DEmiRNAs and 1,043 DElncRNAs were identified between BC and normal tissues. A lncRNA-miRNA-mRNA network associated with BC was successfully constructed based on the combined data obtained from RNA databases, and comprised 97 lncRNA nodes, 24 miRNA nodes and 74 mRNA nodes. The biological functions of the 74 DEmRNAs were further investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The results demonstrated that the DEmRNAs were significantly enriched in two GO biological process categories; the main biological process enriched term was ‘positive regulation of GTPase activity’. By KEGG analysis, four key enriched pathways were obtained, including the ‘MAPK signaling pathway’, the ‘Ras signaling pathway’, ‘prostate cancer’, and the ‘FoxO signaling pathway’. Kaplan-Meier survival analysis revealed that six DElncRNAs (INC AC112721.1, LINC00536, MIR7-3HG, ADAMTS9-AS1, AL356479.1 and LINC00466), nine DEmRNAs (KPNA2, RACGAP1, SHCBP1, ZNF367, NTRK2, ORS1, PTGS2, RASGRP1 and SFRP1) and two DEmiRNAs (hsa-miR-301b and hsa-miR-204) had significant effects on overall survival in BC. The present results demonstrated the aberrant expression of INC AC112721.1, AL356479.1, LINC00466 and MIR7-3HG in BC, indicating their potential prognostic role in patients with BC.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the lncRNA‑associated competing endogenous RNA network in breast cancer

Wang¹,

Huang

Song

et al. 2019

Oncol Rep

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“…Other Rap GEFs such as EPAC1/2 could contribute to regulate Rap activity. Although there are no data about them, EPAC1/2 regulate liver fibrosis [51] [Table 1], a previous step towards HCC development.…”

Section: C3g and Other Ras Gefs In Liver Cancermentioning

confidence: 99%

Contribution of C3G and other GEFs to liver cancer development and progression

Porrás¹,

Sequera²,

Bragado³

et al. 2021

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Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide, due to their high morbidity, late diagnosis and lack of effective treatments. Hepatocellular carcinoma (HCC) represents 80% and cholangiocarcinoma (CCA) 15% of liver cancers. Several genetic and epigenetic gene alterations (e.g., TERT, TP53 or CTNNB1) are HCC drivers, although many additional gene alterations contribute to HCC initiation and/or progression. Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators (GEFs) have recently emerged as putative key players in liver cancer. The Ras GEF, C3G (RAPGEF1), a GEF mainly for Rap proteins, has recently been uncovered as a relevant gene in HCC. Its upregulation promotes tumor growth, although a decrease in C3G levels favors migration/invasion and lung metastasis. Rap1A/1B/2A/2B are overexpressed in HCC tumors, but their effects are controversial and not equivalent to those of C3G. The C3G partner, CRKL, is also overexpressed in HCC, promoting proliferation, migration and invasion. Various Rho GEFs are also deregulated in liver cancer. Tiam1 and Tiam2 expression is upregulated in HCC, promoting proliferation, migration and metastasis. In addition, ARHGEF-10L/9/19/39 are overexpressed in HCC tumors, facilitating migration, invasion, metastasis and proliferation. Another Rho GEF, Vav2, is also involved in metastasis. Little is known about the participation of these GEFs and GTPases in CCA. However, analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes, in both CCA and HCC. Hence, GEFs

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“…RasGRP1 is a Ras guanine nucleotide releasing factor that activates Ras and its downstream ERK and AKT signalling pathways 48, 49 . However, the function of RasGRP1 in tumorigenesis has been debated 50 . EGFR signalling-driven ERK and AKT signalling cascades are critical for the development and tumorigenesis of hepatocellular carcinoma, lung cancer, breast cancer and others 51–53 .…”

Section: Discussionmentioning

confidence: 99%

Ras guanine nucleotide exchange factor RasGRP1 promotes acute inflammatory response and restricts inflammation-contributed cancer cell growth

Wang

et al. 2021

Preprint

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Acute inflammatory response needs to be tightly regulated for promoting the elimination of pathogens and preveting the risk of tumorigenesis, but the mechanism has not been fully elucidated. Here, we report that Ras guanine nucleotide releasing protein 1 (RasGRP1) plays a bifunctional regulator that promotes acute inflammation and inhibits inflammation-associated cancer. At the mRNA level, RasGRP1 strengthens the inflammatory response by functioning as a competing endogenous RNA to specifically promote IL-6 expression by sponging let-7a. In vivo overexpression of the RasGRP1 3' untranslated region significantly aggravated lipopolysaccharide-induced systemic inflammation and dextran sulphate sodium-induced colitis in IL-6+/+ mice but not in IL-6-/- mice. At the protein level, RasGRP1 restricts the growth of inflammation-contributed cancer cells by impairing EGFR-SOS1-Ras-AKT signalling. Tumour patients with high RasGRP1 expression showed a better clinical outcome than those with low expression. Considering acute inflammation rarely leads to tumorigenesis, this work reveals that RasGRP1 is an essential bifunctional regulator for acute inflammatory response.

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Sp1‐regulated transcription of RasGRP1 promotes hepatocellular carcinoma (HCC) proliferation

Abstract: RasGRP1 is upregulated in HCC and promotes HCC cell proliferation. Thus, RasGRP1 may be a novel therapeutic target for HCC.

Cited by 31 publications

References 35 publications

Comprehensive analysis of the lncRNA‑associated competing endogenous RNA network in breast cancer

Comprehensive analysis of the lncRNA‑associated competing endogenous RNA network in breast cancer

Contribution of C3G and other GEFs to liver cancer development and progression

Ras guanine nucleotide exchange factor RasGRP1 promotes acute inflammatory response and restricts inflammation-contributed cancer cell growth

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