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HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.

ABSTRACT: Gastric cancer (GC) is a common disease globally with high mortality rate. It is therefore necessary to develop novel therapies targeting specific events in the pathogenesis of GC. Some hnRNP family members are involved in multiple cancer biological behaviors. However, the potential function and mechanism of hnRNPR, a new molecule of hnRNP family in GC remains unknown. We found that the expression of hnRNPR was significantly overexpressed in multiple cancers compared to the normal tissues. Functionally, hnRNPR promoted cancer cell proliferation, migration, and invasion. Knockdown of hnRNPR in two type mice models, with two types of tumors models decreased the tumor aggressiveness and metastasis. Mechanistically, hnRNPR targeted oncogenic pathways by stabilizing the expression of CCNB1 and CENPF mRNA level. Knockdown of CCNB1 and CENPF abolished the hnRNPR-induced cell growth and invasion, respectively. Furthermore, the protein level of hnRNPR in the tumor was positively correlated with the expression of CCNB1 and CENPF in clinical samples. Together, these results indicate that overexpression of hnRNPR promoted the aggressiveness of GC by increasing the mRNA expression of CCNB1 and CENPF. HnRNPR-CCNB1/CENPF axis may be a potential therapeutic target for GC treatment.

SUBMITTER: Chen EB

PROVIDER: S-EPMC6782008 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.

Chen Er-Bao EB Qin Xuan X Peng Ke K Li Qian Q Tang Cheng C Wei Yi-Chou YC Yu Shan S Gan Lu L Liu Tian-Shu TS

Aging 20190916 18

Gastric cancer (GC) is a common disease globally with high mortality rate. It is therefore necessary to develop novel therapies targeting specific events in the pathogenesis of GC. Some hnRNP family members are involved in multiple cancer biological behaviors. However, the potential function and mechanism of hnRNPR, a new molecule of hnRNP family in GC remains unknown. We found that the expression of hnRNPR was significantly overexpressed in multiple cancers compared to the normal tissues. Funct ...[more]

PMID: 31527303

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Project description:BackgroundN6-methyladenosine (m6 A) modification is the most common modification that occurs in eukaryotes. Although substantial effort has been made in the prevention and treatment of gastric cancer (GC) in recent years, the prognosis of GC patients remains unsatisfactory. The regulatory mechanism between m6 A modification and GC development needs to be elucidated. In this study, we examined m6 A modification and the downstream mechanism in GC.MethodsDot blotting assays, The Cancer Genome Atlas analysis, and quantitative real-time PCR (qRT-PCR) were used to measure the m6 A levels in GC tissues. Methylated RNA-immunoprecipitation sequencing and RNA sequencing were performed to identify the targets of m6 A modification. Western blotting, Transwell, wound healing, and angiogenesis assays were conducted to examine the role of centromere protein F (CENPF) in GC in vitro. Xenograft, immunohistochemistry, and in vivo metastasis experiments were conducted to examine the role of CENPF in GC in vivo. Methylated RNA-immunoprecipitation-qPCR, RNA immunoprecipitation-qPCR and RNA pulldown assays were used to verify the m6 A modification sites of CENPF. Gain/loss-of-function and rescue experiments were conducted to determine the relationship between CENPF and the mitogen-activated protein kinase (MAPK) signaling pathway in GC cells. Coimmunoprecipitation, mass spectrometry, qRT-PCR, and immunofluorescence assays were performed to explore the proteins that interact with CENPF and elucidate the regulatory mechanisms between them.ResultsCENPF was upregulated in GC and facilitated the metastasis of GC both in vitro and in vivo. Mechanistically, increased m6 A modification of CENPF was mediated by methyltransferase 3, and this modified molecule could be recognized by heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), thereby promoting its mRNA stability. In addition, the metastatic phenotype of CENPF was dependent on the MAPK signaling pathway. Furthermore, CENPF could bind to FAK and promote its localization in the cytoplasm. Moreover, we discovered that high expression of CENPF was related to lymphatic invasion and overall survival in GC patients.ConclusionsOur findings revealed that increased m6 A modification of CENPF facilitates the metastasis and angiogenesis of GC through the CENPF/FAK/MAPK and epithelial-mesenchymal transition axis. CENPF expression was correlated with the clinical features of GC patients; therefore, CENPF may serve as a prognostic marker of GC.

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HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.

Publications

HnRNPR-CCNB1/CENPF axis contributes to gastric cancer proliferation and metastasis.

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