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

// Haiyan Zhai 1 , Andrew Fesler 1 , Yufeng Ba 2 , Song Wu 3 , Jingfang Ju 1 1 Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794 USA 2 Department of Thoracic Surgery, The Cancer Hospital of Henan, Zhengzhou, Henan 450008 China 3 Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794 USA Correspondence to: Jingfang Ju, e-mail: jingfang.ju@stonybrookmedicine.edu Keywords: hsa-miR-140-5p, smad2, autophagy, metastasis, colon cancer stem cell Received: February 10, 2015 Accepted: April 15, 2015 Published: April 27, 2015 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-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.