Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway

// Dong Ren 1, 2, * , Bihua Lin 1, * , Xin Zhang 1, 3 , Yao Peng 4 , Ziyu Ye 1 , Yan Ma 1 , Yangfang Liang 5 , Longbin Cao 4 , Xiangyong Li 1 , Ronggang Li 3 , Lixia Sun 3 , Qiongru Liu 3 , Jinhua Wu 6 , Keyuan Zhou 1 and Jincheng Zeng 1 1 Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong Province, 523808, China 2 Department of Orthopedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510080, China 3 Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, 529030, China 4 Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510080, China 5 Department of Pathology, Dongguan Hospital Affiliated to Medical College of Jinan University, The Fifth People’s Hospital of Dongguan, Dongguan, Guangdong Province, 523905, China 6 Department of Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, Guangdong Province, 529030, China * These authors contributed equally to this work Correspondence to: Jincheng Zeng, email: zengjc@gdmu.edu.cn Keywords: miR-196b-5p, cancer stem cell, chemotherapeutic resistance, STAT3 signaling pathway, CRC Received: October 27, 2016      Accepted: May 04, 2017      Published: May 18, 2017 ABSTRACT Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR-196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo . Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC.