MiR-203 enhances let-7 biogenesis by targeting LIN28B to suppress tumor growth in lung cancer

Yong Zhou,Hongwei Liang,Zhicong Liao,Yanbo Wang,Zhibin Hu,Lin Xu,Xi Chen,Xiuting Hu

doi:10.1038/srep42680

Yong Zhou, Hongwei Liang + Show 6 more

Open Access

https://doi.org/10.1038/srep42680

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Abstract

Human cancers often exhibit increased microRNA (miRNA) biogenesis and global aberrant expression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-203 enhances the biogenesis of tumor suppressor let-7 in lung cancer by directly targeting LIN28B. Specially, we found that the LIN28B protein levels were dramatically increased in lung cancer tissues, but its mRNA levels did not differ significantly, suggesting that a post-transcriptional mechanism is involved in LIN28B regulation. Interestingly, miR-203 overexpression was accompanied by massive upregulation of a group of miRNAs, especially let-7, and the let-7 expression level was concordant with the miR-203 expression in lung cancer tissues, implying its biological relevance. Furthermore, we showed that miR-203 played a critical role in inhibiting the proliferation and promoting the apoptosis of lung cancer cells by suppressing LIN28B and enhancing let-7 biogenesis. In summary, our results establish a novel mechanism by which miR-203, LIN28B and let-7 are tightly linked to form a regulatory network in lung cancer cells. The findings shed light on the role of a specific miRNA as a modulator of miRNA biogenesis and provide basis for developing new strategies for lung cancer therapy.

Highlights

In this study, we discovered that miR-203 directly targets LIN28B in lung cancer cells, thereby disrupting the Lin28/let-7 circuit, enhancing let-7 biogenesis and inhibiting the proliferation and promoting the apoptosis of lung cancer cells
After measuring the expression levels of the LIN28B protein in seven pairs of non-small cell lung cancer (NSCLC) tissues and corresponding normal adjacent tissues via Western blotting, we observed that the LIN28B protein levels were significantly higher in the cancer tissues (Fig. 1A and B)
Recent studies have discovered that LIN28 and let-7 family miRNAs tend to play opposing roles in many cellular processes, in particular those involved in cancer development and progression[12]

Summary

Introduction

We discovered that miR-203 directly targets LIN28B in lung cancer cells, thereby disrupting the Lin28/let-7 circuit, enhancing let-7 biogenesis and inhibiting the proliferation and promoting the apoptosis of lung cancer cells. The overexpression of miR-203 significantly suppressed the LIN28B protein levels in A549 and 95D cells (Fig. 3B). The expression of the LIN28B protein was increased in A549 and 95D cells transfected with the miR-203 antagomir (Fig. 3B), leading to the subsequent downregulation of let-7 in A549 and 95D cells (Fig. 3C).

Results

Conclusion