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.
Highlights
Accumulating evidence demonstrates that cancer stem cells (CSCs) reside at the apex of tumor cell hierarchy and play crucial roles in growth of primary tumors and their metastases to distal organs [1,2]
We report that large intergenic noncoding RNA p21 is a potent suppressor of stem-like traits of Cancer stem cells (CSCs) purified from both primary colorectal cancer (CRC) tissues and cell lines
Application of miR-451 miRNA responsive element (MRE) appeared to protect normal liver cells from off-target expression of lincRNA-p21 in both tumor-bearing and naïve mice. These findings suggest that long non-coding RNAs (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
Summary
Accumulating evidence demonstrates that cancer stem cells (CSCs) reside at the apex of tumor cell hierarchy and play crucial roles in growth of primary tumors and their metastases to distal organs [1,2]. The stemlike traits of CRC CSCs are maintained or acquired by the activation of several developmental pathways, especially the Wntless (Wnt)/β-catenin signaling [9]. In this regard, 90% of CRC contain a mutation in the adenomatous polyposis coli (APC) gene or other essential regulators of www.impactjournals.com/oncotarget
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