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

• Published in: Oncotarget Vol. 8; no. 30; pp. 49807 - 49823
• Main Authors: Ren, Dong, Lin, Bihua, Zhang, Xin, Peng, Yao, Ye, Ziyu, Ma, Yan, Liang, Yangfang, Cao, Longbin, Li, Xiangyong, Li, Ronggang, Sun, Lixia, Liu, Qiongru, Wu, Jinhua, Zhou, Keyuan, Zeng, Jincheng
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 25.07.2017
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Exosomes - metabolism; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2 - metabolism; Mice; MicroRNAs - genetics; Models, Biological; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Prognosis; Research Paper; Signal Transduction; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 1 Protein - genetics; Suppressor of Cytokine Signaling 3 Protein - genetics; Xenograft Model Antitumor Assays; STAT3 signaling pathway; cancer stem cell; CRC; chemotherapeutic resistance; miR-196b-5p
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.17971

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.