HnRNPR/CCNB1/CENPF Axis Contributes to Gastric Cancer Proliferation and Metastasis

Abstract

Backgroud: Gastric cancer (GC) has a high mortality rate worldwide, this calls for urgent novel therapies targeting specific underlying oncogenic events. However, the potential function and mechanism of hnRNPR in GC remains unknown. Methods: Data from The Cancer Genome Atlas (TCGA) and GEO database were used to investigate the expression of hnRNPR in multiple cancers. The functional effects of up/down-regulated hnRNPR levels were assessed via in vitro and in vivo assays (CCK-8, colony formation, wound scratch, transwell, subcutaneous tumor model and metastasis model). Gene Set Enrichment Analysis (GSEA) were performed to identify hnRNPR-downstream signaling pathways in TCGA GC cohort. RNA immunoprecipitation-PCR was used to validate the direct binding between hnRNPR and the downstream genes. Findings: The expression of hnRNPR is significantly overexpressed in multiple cancers. Functionally, hnRNPR increased cancer cell proliferation, migration, and invasion. Concordantly, in in vivo orthotopic mice models, knockdown of hnRNPR was associated with decreased features of tumor aggressiveness and metastasis. Mechanistically, hnRNPR leads to typical oncogenic pathways activated via stabilizing CCNB1 and CENPF mRNA. Knockdown pf CCNB1 and CENPF abolished the hnRNPR-induced cell growth and invasion. Furthermore, the protein level of hnRNPR in the tumor was positively correlated with the expression of CCNB1 and CENPF in clinical samples. Interpretation: The results indicated that overexpression of hnRNPR facilitated GC aggressiveness by stabilizing CCNB1 and CENPF mRNA. HnRNPR/CCNB1/CENPF axis may represent a potential therapeutic target for GC treatment. This finding casts new light on developing more rational therapies to treat this highly aggressive tumor. Funding: This work was supported by the National Natural Science Foundation of China (81502003) and the Shanghai Science and Technology Commission (17411951400, 15411961900). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The study was approved by the Research Ethics Committee of Zhongshan Hospital.