miRNA-regulated delivery of lincRNA-p21 suppresses β-catenin signaling and tumorigenicity of colorectal cancer stem cells
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Jun Wang1, Zeng-jie Lei1, Yan Guo1, Tao Wang1, Zhong-yi Qin1, Hua-liang Xiao2, Li-lin Fan1, Dong-feng Chen1, Xiu-wu Bian3, Jia Liu4, Bin Wang1
1Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
2Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
3Institute 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
4Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
Bin Wang, e-mail: [email protected]
Jia Liu, e-mail: [email protected]
Keywords: β-catenin signaling, colorectal cancer, cancer stem cells, lncRNA, miRNA
Received: March 29, 2015 Accepted: October 06, 2015 Published: October 16, 2015
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.
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