Abstract
Our previous research indicated miR-410 played a critical role in promoting the tumorigenesis and development of NSCLC (non-small cells lung cancer). MiR-410 has been recently reported to be crucial for development and differentiation of embryonic stem cells. But it remains elusive whether miR-410 stimulates the stemness of cancer until now. Herein, we identify miR-410 induces the stemness and is associated with the progression of NSCLC. We demonstrate miR-410 increases the levels of stem cells marker Sox2, Oct4, Nanog, CXCR4 as well as lung cancer stem cells surface marker CD44 and CD166. MiR-410 promotes stem cells-like properties such as proliferation, sphere formation, metastasis and chemoresistance. Moreover, Gsk3β is directly targeted and post-transcriptionally downregulated by miR-410. Also, the expression levels of miR-410 and Gsk3β may be correlated to clinicopathological differentiation in NSCLC tumor specimens. Additionally, we demonstrate miR-410 induces stemness through inhibiting Gsk3β but increasing Sox2, Oct4, Nanog and CXCR4, which binds to β-catenin signaling. In conclusion, our findings identify the miR-410/Gsk3β/β-catenin signaling axis is a novel molecular circuit in inducing stemness of NSCLC.
Highlights
Despite drastic treatment strategies, including radiotherapy and chemotherapy, the 5-year survival rate of non-small cells lung cancer (NSCLC) remained a low level of 15% [1]
We demonstrated miR-410 was significantly upregulated in NSCLC cells and tumor tissues, and acted as oncogene which might be correlated to Wnt/β-catenin pathway [16]
The mRNA levels of chemokine receptor-4 (CXCR4), Nanog, Oct4, and Sox2 were remarkably increased in miR-410 overexpression stable A549 cells versus decreased in miR-410 knock-down stable A549 cells compared with their respective NC control cells by qRT-PCR (Figure 1C–1E and 1F)
Summary
Despite drastic treatment strategies, including radiotherapy and chemotherapy, the 5-year survival rate of NSCLC remained a low level of 15% [1]. Postoperative metastasis and chemoresistance accounted for its treatment failure and relapse. Emerging evidences suggested the enriched existence of tumor initiating cells, called cancer stem cells (CSCs), with the potency of self-renewal, differentiation and high oncogenicity, primarily accounted for the metastasis, reoccurrence, and chemoresistance in many tumors [2,3,4]. Cancer was acknowledged to originate from CSCs [5], and many tumors (including lung cancer [6, 7]) might progress because of CSCs. little was known about the regulating mechanism of lung cancer stemness. Little was known about the regulating mechanism of lung cancer stemness Revealing those regulating mechanisms of lung cancer stemness would contribute to uncovering the molecular mechanism of lung cancer tumorigenesis and development
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