Dataset Information

F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a.

ABSTRACT: FBXO31, a subunit of the SCF ubiquitin ligase, played a crucial role in neuronal development, DNA damage response and tumorigenesis. Here, we investigated the expression and prognosis value of FBXO31 in human primary gastric cancer (GC) samples. Meanwhile, the biological role and the regulation mechanism of FBXO31 were evaluated. We found that FBXO31 mRNA and protein was decreased dramatically in the GC tissue compared with the adjacent non-cancerous tissues. FBXO31 expression was significantly associated with tumor size, tumor infiltration, clinical grade and patients' prognosis. FBXO31 overexpression significantly decreased colony formation and induced a G1-phase arrest and inhibited the expression of CyclinD1 protein in GC cells. Further evidence was obtained from knockdown of FBXO31. Ectopic expression of FBXO31 dramatically inhibited xenograft tumor growth in nude mice. miR-20a and miR-17 mimics inhibited, whereas the inhibitor of miR-20a and miR-17 increased, the expression of FBXO31, respectively. miR-20a and miR-17 directly bind to the 3'-UTR of FBXO31. The level of miR-20a and miR-17 in GC tissue was significantly higher than that in surrounding normal mucosa. Moreover, a highly significant negative correlation between miR-20a (miR-17) and FBXO31 was observed in these GC samples. Therefore, effective therapy targeting the miR-20a (miR-17)-FBXO31-CyclinD1 pathway may help control GC progression.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4171621 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a.

Zhang Xinchao X Kong Ye Y Xu Xia X Xing Huaixin H Zhang Yingjie Y Han Fengjuan F Li Wenjuan W Yang Qing Q Zeng Jiping J Jia Jihui J Liu Zhifang Z

Oncotarget 20140801 15

FBXO31, a subunit of the SCF ubiquitin ligase, played a crucial role in neuronal development, DNA damage response and tumorigenesis. Here, we investigated the expression and prognosis value of FBXO31 in human primary gastric cancer (GC) samples. Meanwhile, the biological role and the regulation mechanism of FBXO31 were evaluated. We found that FBXO31 mRNA and protein was decreased dramatically in the GC tissue compared with the adjacent non-cancerous tissues. FBXO31 expression was significantly ...[more]

PMID: 25115392

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Project description:BackgroundGastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with H. Pylori infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.ResultsInvitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.ConclusionsIn this study, we document a diminished expression of miR-449 in Gastrin KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.

Project description:In response to DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Studies have shown that oncogene-induced senescence, which provides a barrier to tumour development, involves activation of the DDR. Using a genome-wide RNA interference (RNAi) screen, we have identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31, a candidate tumour suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular and prostate cancers. Here we study the cellular role of FBXO31, identify its target substrate and determine the basis for its growth inhibitory activity. We show that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at Thr 286, which is known to be required for cyclin D1 proteolysis. The involvement of the DDR in oncogene-induced senescence prompted us to investigate the role of FBXO31 in DNA repair. We find that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DDR-initiating kinase ATM. RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, we show that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Our results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest.

Dataset Information

F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a.

Publications

F-box protein FBXO31 is down-regulated in gastric cancer and negatively regulated by miR-17 and miR-20a.

Similar Datasets

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