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Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy.

ABSTRACT: Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-? signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreased cell invasion and proliferation, and increasing cell cycle arrest. Ectopic expression of hsa-miR-140-5p in colorectal CSCs inhibited CSC growth and sphere formation in vitro by disrupting autophagy. We have systematically identified targets of hsa-miR-140-5p involved in autophagy. Furthermore, overexpression of hsa-miR-140-5p in CSCs abolished tumor formation and metastasis in vivo. In addition, there is a progressive loss of hsa-miR-140-5p expression from normal colorectal mucosa to primary tumor tissues, with further reduction in liver metastatic tissues. Higher hsa-miR-140 expression is significantly correlated with better survival in stage III and IV colorectal cancer patients.The functional and clinical significance of hsa-miR-140-5p suggests that it is a key regulator in CRC progression and metastasis, and may have potential as a novel therapeutic molecule to treat CRC.

SUBMITTER: Zhai H

PROVIDER: S-EPMC4637317 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy.

Zhai Haiyan H Fesler Andrew A Ba Yufeng Y Wu Song S Ju Jingfang J

Oncotarget 20150801 23

Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-β signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreas ...[more]

PMID: 25980495

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Project description:BackgroundCompeting endogenous RNA (ceRNA) networks play important roles in the mechanism and development of a variety of diseases. This study aimed to construct a ceRNA network of hypertrophic cardiomyopathy (HCM).MethodsWe searched the Gene Expression Omnibus (GEO) database and then analyzed the RNAs of 353 samples to explore differentially expressed lncRNAs (DELs), microRNAs (miRNAs; DEMs), and messenger RNAs (DEmRNAs) during the progression of HCM. Weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and transcription factor (TF) prediction of miRNAs were also performed, and the GO terms, KEGG pathway terms, protein-protein interaction (PPI) network, and Pearson correlation network of the DEGs were visualized with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and through Pearson analysis. In addition, a ceRNA network related to HCM was constructed on the basis of the DELs, DEMs, and DEs. Finally, the function of the ceRNA network was explored via GO and KEGG enrichment analyses.ResultsThrough our analysis, 93 DELs (77 upregulated and 16 downregulated), 163 DEMs (91 upregulated and 72 downregulated), and 432 DEGs (238 upregulated and 194 downregulated) were screened. The functional enrichment analysis results for miRNAs showed that the miRNAs were mainly related to the VEGFR signaling network and the INFr pathway and were mainly regulated by TFs such as SOX1, TEAD1, and POU2F1. Gene set enrichment analysis (GSEA), GO analysis, and KEGG enrichment analysis showed that the DEGs were enriched in the Hedgehog signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. In addition, a ceRNA network including 8 lncRNAs (e.g., LINC00324, SNHG12, and ALMS1-IT1), 7 miRNAs (e.g., hsa-miR-217, hsa-miR-184, and hsa-miR-140-5p), and 52 mRNAs (e.g., IGFBP5, TMED5, and MAGT1) was constructed. The results revealed that SNHG12, hsa-miR-140-5p, hsa-miR-217, TFRC, HDAC4, TJP1, IGFBP5, and CREB5 may form an important network involved in the pathology of HCM.ConclusionsThe novel ceRNA network that we have demonstrated will provide new research points about molecular mechanisms of HCM.

Dataset Information

Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy.

Publications

Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy.

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