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.
Recent studies have elucidated the role of lysine-specific demethylase 1 (LSD1), a member of the histone demethylases, in epigenetic regulation of tumor suppressing/promoting genes and neoplastic growth. However, the expression of LSD1 in patients with esophageal squamous cell carcinoma (ESCC) is still unknown. Here, we reported that LSD1 expression was elevated in cancerous tissue and correlated with lymph node metastasis and poorer overall survival in patients with ESCC. Compared to EC109 cells, LSD1 expression was unregulated in aggressive cancer cell lines KYSE450 and KYSE150. Knockdown of LSD1 using lentivirus delivery of LSD1-specific shRNA abrogated the migration and invasion of ESCC cells in vitro. Further, a LSD1 inhibitor, tranylcypromine, suppressed H3K4me2 demethylation and attenuated cellular motility and invasiveness in a dose-dependent manner. Taken together, these data suggested that LSD1 was a potential prognostic maker and may be a molecular target for inhibiting invasion and metastasis in ESCC.
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