miRNA-regulated delivery of lincRNA-p21 suppresses β-catenin signaling and tumorigenicity of colorectal cancer stem cells

Abstract

// Jun Wang 1 , Zeng-jie Lei 1 , Yan Guo 1 , Tao Wang 1 , Zhong-yi Qin 1 , Hua-liang Xiao 2 , Li-lin Fan 1 , Dong-feng Chen 1 , Xiu-wu Bian 3 , Jia Liu 4 , Bin Wang 1 1 Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China 2 Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China 3 Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 4 Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China Correspondence to: Bin Wang, e-mail: wb_tmmu@126.com Jia Liu, e-mail: dadaliujia@gmail.com Keywords: β-catenin signaling, colorectal cancer, cancer stem cells, lncRNA, miRNA Received: March 29, 2015      Accepted: October 06, 2015      Published: October 16, 2015 ABSTRACT Cancer stem cells (CSCs) are key cellular targets for effective cancer therapy, due to their critical roles in cancer progression and chemo/radio-resistance. Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are important players in the biology of cancers. However, it remains unknown whether lncRNAs could be exploited to target CSCs. We report that large intergenic non-coding RNA p21 (lincRNA-p21) is a potent suppressor of stem-like traits of CSCs purified from both primary colorectal cancer (CRC) tissues and cell lines. A novel lincRNA-p21-expressing adenoviral vector, which was armed with miRNA responsive element (MRE) of miR-451 (Ad-lnc-p21-MRE), was generated to eliminate CRC CSCs. Integration of miR-451 MREs into the adenovirus efficiently delivered lincRNA-p21 into CSCs that contained low levels of miR-451. Moreover, lincRNA-p21 inhibited the activity of β-catenin signaling, thereby attenuating the viability, self-renewal, and glycolysis of CSCs in vitro . By limiting dilution and serial tumor formation assay, we demonstrated that Ad-lnc-p21-MRE significantly suppressed the self-renewal potential and tumorigenicity of CSCs in nude mice. Importantly, application of miR-451 MREs appeared to protect normal liver cells from off-target expression of lincRNA-p21 in both tumor-bearing and naïve mice. Taken together, these findings suggest that lncRNAs may be promising therapeutic molecules to eradicate CSCs and MREs of tumor-suppressor miRNAs, such as miR-451, may be exploited to ensure the specificity of CSC-targeting strategies.