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

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.

LincRNA-p21 Inhibits the Wnt/β-Catenin Pathway in Activated Hepatic Stellate Cells via Sponging MicroRNA-17-5p

“…For instance, Wang et al . found that lincRNA-p21 suppresses β-catenin signaling and tumorigenicity of colorectal cancer stem cells [38]. In line with it, we found that lincRNA-p21 suppresses Wnt/β-catenin signal through sponging miR-17-5p.…”

Long non‐coding ribonucleic acid zinc finger antisense 1 promotes the progression of colonic cancer by modulating ZEB1 expression

“…Long non‐coding RNAs (lncRNAs) constitute a novel heterogeneous class of non‐coding RNAs, which range from 200 nucleotides to multiple kilobases and account for much of the transcribed genome . Increasing evidence has demonstrated the key roles of lncRNAs in regulating multiple major physiological and pathological processes, including proliferation, cell growth, apoptosis, metastasis, metabolism, development, differentiation, senescence, self‐renewal, stem‐cell pluripotency, immune response, and drug resistance . Epithelial‐to‐mesenchymal transition (EMT) is one of the underlying mechanisms of colonic cancer progression.…”

“…8 Increasing evidence has demonstrated the key roles of lncRNAs in regulating multiple major physiological and pathological processes, including proliferation, cell growth, apoptosis, metastasis, metabolism, development, differentiation, senescence, self-renewal, stem-cell pluripotency, immune response, and drug resistance. [9][10][11][12][13][14][15] Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of colonic cancer progression. LncRNA HOTAIR, H19, CCAT1, ATB, and BANCR, through a variety of mechanisms, can promote the EMT process, or its converse MET process, in colorectal cancers.…”

Inhibition of microRNA‐21‐3p suppresses proliferation as well as invasion and induces apoptosis by targeting RNA‐binding protein with multiple splicing through Smad4/extra cellular signal‐regulated protein kinase signalling pathway in human colorectal cancer HCT116 cells

“…Increasing evidence reports that multiple miRNAs are differently expressed and dysregulated in tumour tissues, or in colon cancer patients, compared with adjacent tissues or with healthy controls, respectively . Although previous studies have amply reported the role of miR‐21 (miR‐21‐5p) in the progress of CRC cells, which has been recognized as an oncogene associated with cancer initiation, progression, and metastasis, the role of the miR‐21 passenger strand (miR‐21‐3p) in the proliferation, apoptosis and invasion of CRC cells has not been fully clarified . This study aimed to investigate the role of miR‐21‐3p and its target gene in CRC cells.…”

“…MicroRNAs have been found to regulate many physiological development processes including cell proliferation, apoptosis and differentiation, and participate in various pathological processes including carcinogenesis and metastasis . MiRNA expression levels are found to be altered in especially most tumour types including CRC . Yang et al reported that miR‐21, which has been one of the best studied miRNAs, controls human telomerase reverse transcriptase via PTEN in human colorectal cancer cell proliferation.…”