Abstract
Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial–mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR-200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies and the third leading cause of cancer-related deaths.[1]
Zhang et al.[16] found that long noncoding RNAs (lncRNAs) CASC11 can interact with hnRNP-K and activate the WNT/β-catenin pathway to promote growth and metastasis in colorectal cancer (CRC)
We found that lncRNA XIST expression was upregulated in CRC tissues than adjacent normal tissues
Summary
LncRNA XIST expression is upregulated in CRC cell lines and tissues. First, the expression of lncRNA XIST was measured in CRC cell lines, compared with the normal colon epithelial cell line CCD-112CoN, and lncRNA XIST was significantly upregulated in CRC cell lines (*Po0.05, Figure 1a). lncRNA XIST expression was measured in 115 patients with CRC tissues and paired normal tissues. To explore the effect of lncRNA XIST on tumor metastasis, cells (sh-NC or sh-XIST, 2 × 106cells/mouse) were injected into the tail vein of nude mice, and after 6 weeks the mice were killed and the lung and liver were exercised. Western blot analysis indicated that ectopic expression of miR-200b-3p and/or knockdown of lncRNA XIST significantly reduced the protein level of ZEB1, whereas inhibition of miR-200b-3p increased the protein level of ZEB1 in CRC cells (Figure 6d). Knockdown of lncRNA XIST could significantly reduce the mRNA level of ZEB1 in CRC cells, and the reduced level of ZEB1 mRNA induced by lncRNA XIST knockdown could be restored by ectopic expression of ZEB1 or inhibition of miR-200b-3p (*Po0.05, Figure 7c). What’s more, the suppression of tumor phenotype by knockdown of lncRNA XIST could be restored by ectopic expression of ZEB1 or inhibition of miR-200b-3p (*Po0.05, Figures 7d and e)
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