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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Haiyan Zhai1, Andrew Fesler1, Yufeng Ba2, Song Wu3, Jingfang Ju1
1Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794 USA
2Department of Thoracic Surgery, The Cancer Hospital of Henan, Zhengzhou, Henan 450008 China
3Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794 USA
Jingfang Ju, e-mail: [email protected]
Keywords: hsa-miR-140-5p, smad2, autophagy, metastasis, colon cancer stem cell
Received: February 10, 2015 Accepted: April 15, 2015 Published: April 27, 2015
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 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.
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