Upregulation of RASAL2 promotes proliferation and metastasis, and is targeted by miR-203 in hepatocellular carcinoma

Fang, Jianfeng; Zhao, Haiping; Wang, Zheng‐Fei; Zheng, Shusen

doi:10.3892/mmr.2017.6320

Cited by 19 publications

(24 citation statements)

References 29 publications

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“…RASAL2 was initially identified as a tumor suppressor [ 40 ] and the inactivation of RASAL2 promoted tumor progression and metastasis in luminal B breast, ovarian, and lung cancers [ 13 , 15 , 16 ]. However, other studies found that RASAL2 promoted mesenchymal invasion and metastasis [ 14 , 17 – 19 ]. A genome-wide study revealed that RASAL2 depletion inhibits cancer cell growth and invasiveness in liver and triple-negative breast cancers [ 14 , 17 ].…”

Section: Discussionmentioning

confidence: 96%

“…RASAL2 is a member of RAS GTPase-activating protein family (RAS GAP) that negatively regulates RAS by catalyzing the hydrolysis of RAS-GTP to RAS-GDP. The gene may exhibit pro-tumorigenic or anti-tumorigenic behavior depending on the cell context and/or type of stimulus in human cancers [ 12 – 19 ]. Therefore, the functional role of RASAL2 in CRC was still unclear.…”

Section: Introductionmentioning

confidence: 99%

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RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

et al. 2018

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BackgroundPatients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown.MethodsUsing array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays.ResultsIntegrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis.ConclusionsOur findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0853-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

et al. 2018

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“…Questions remain regarding RASAL2 deregulation in tumour tissues. Interestingly, recent studies revealed that RASAL2 expression is controlled by specific miRNAs, including miR‐136, miR‐135b‐5p, and miR‐203 . Considering that RASAL2 is overexpressed in colorectal cancer, we aimed to determine whether it is regulated by specific miRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent studies revealed that RASAL2 expression is controlled by specific miRNAs, including miR-136, miR-135b-5p, and miR-203. 17,40,41 Considering that RASAL2 is overexpressed in colorectal cancer, we aimed to determine whether it is regulated by specific miRNAs. Notably, we identified RASAL2 as a miR-876-5p target gene.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, RASAL2 exhibits oncogenic or tumour suppressive functions in different cancer types. RASAL2 is highly expressed in triple‐negative breast cancer and hepatocellular carcinoma, and it contributes to the malignant growth and metastasis of cancers . However, low RASAL2 expression occurs in bladder, ovarian, and lung cancers, and it correlates with the clinical stages and pathological grades .…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA‐876‐5p represses the cell proliferation and invasion of colorectal cancer through suppressing YAP signalling via targeting RASAL2

Ren

Zhang

Feng

et al. 2020

Clin Exp Pharma Physio

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Aberrant expression of microRNA‐876‐5p (miR‐876‐5p) is implicated in the progression of multiple human cancers. However, the potential role of miR‐876‐5p in colorectal cancer remains poorly understood. The purpose of the current study was to investigate the potential role of miR‐876‐5p in colorectal cancer. miR‐876‐5p expression was significantly downregulated in colorectal cancer tissues and cell lines compared with normal controls. Gain‐of‐function assays revealed that miR‐876‐5p overexpression effectively repressed the malignant behaviours of colorectal cancer cells, including cell proliferation, colony formation, and invasion. Bioinformatics analysis predicted that RAS protein activator like 2 (RASAL2), a potential oncogene for colorectal cancer, is a putative miR‐876‐5p target gene. A luciferase reporter assay confirmed that miR‐876‐5p directly binds to the 3′‐untranslated region (UTR) of RASAL2. Furthermore, both RASAL2 messenger RNA (mRNA) and protein expression were negatively modulated by miR‐876‐5p in colorectal cancer cells. Notably, there was an inverse correlation between miR‐876‐5p and RASAL2 expression in colorectal cancer tissue specimens. Moreover, miR‐876‐5p was involved in regulating the activation of Yes‐associated protein (YAP) signalling through inhibiting RASAL2. However, the miR‐876‐5p‐mediated antitumour effect on colorectal cancer cells was partially reversed by restoring RASAL2 expression. Notably, miR‐876‐5p upregulation impeded the tumour growth of colorectal cancer cells in vivo in nude mice. Overall, these results demonstrated that miR‐876‐5p exerts an antitumour function in colorectal cancer by targeting RASAL2 to suppress YAP signalling activation. These findings highlight the importance of the miR‐876‐5p/RASAL2/YAP axis in colorectal cancer progression and suggest that miR‐876‐5p is a potential therapeutic target for treating colorectal cancer.

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Inhibition of Ras protein activator like 2 produces antitumor effects in gastric cancer via the suppression of YAP1 activation

Zhang²,

Shi

et al. 2021

Environmental Toxicology

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Ras protein activator like 2 (RASAL2) has a cancer‐related function, but plays inconsistent roles in different malignancies. This project was designed to determine the role of RASAL2 in carcinogenesis in gastric cancer. The Cancer Genome Atlas data revealed high levels of RASAL2 in gastric cancer tissue, which was confirmed in clinical specimens of gastric cancer via real‐time quantitative PCR and western blotting assays. High RASAL2 was correlated with a reduced survival rate in gastric cancer patients. In gastric cancer cell lines, the silencing of RASAL2 restrained cellular proliferation, invasion and epithelial‐to‐mesenchymal transition, while enhancing chemosensitivity to cisplatin. Mechanistically, the silencing of RASAL2 was found to inhibit the activation of Yes‐associated protein 1 (YAP1), a pro‐oncogenic protein in gastric cancer, and decrease the expression of YAP1 target genes. The re‐expression of constitutively active YAP1 substantially reversed RASAL2‐silencing‐produced antitumor effects. Moreover, treatment with YAP1 inhibitors could diminish RASAL2‐overexpression‐evoked oncogenic effects in gastric cancer cells. Additionally, gastric cancer cells with RASAL2 silencing exhibited a reduced ability to form xenograft tumors in nude mice. Collectively, our data demonstrate that the silencing of RASAL2 has noteworthy antitumor effects in gastric cancer cells via the suppression of YAP1 activation. This project underscores a vital role of the RASAL2/YAP1 axis in gastric progression and indicates that targeting this oncogenic axis may be applied as a potential therapeutic option for gastric cancer.

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Upregulation of RASAL2 promotes proliferation and metastasis, and is targeted by miR-203 in hepatocellular carcinoma

Cited by 19 publications

References 29 publications

RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer

MicroRNA‐876‐5p represses the cell proliferation and invasion of colorectal cancer through suppressing YAP signalling via targeting RASAL2

Inhibition of Ras protein activator like 2 produces antitumor effects in gastric cancer via the suppression of YAP1 activation

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