MicroRNA-106a regulates autophagy-related cell death and EMT by targeting TP53INP1 in lung cancer with bone metastasis

Lei Han,Zunxian Tan,Jiadai Tang,Ya Zhang,Lijuan Ye,Dongqi Li,Cao Wang,Zuozhang Yang,Yan Liu,Zeyong Huang,Zhihong Yao,Hang Yang

doi:10.1038/s41419-021-04324-0

Abstract

Bone metastasis is one of the most serious complications in lung cancer patients. MicroRNAs (miRNAs) play important roles in tumour development, progression and metastasis. A previous study showed that miR-106a is highly expressed in the tissues of lung adenocarcinoma with bone metastasis, but its mechanism remains unclear. In this study, we showed that miR-106a expression is dramatically increased in lung cancer patients with bone metastasis (BM) by immunohistochemical analysis. MiR-106a promoted A549 and SPC-A1 cell proliferation, migration and invasion in vitro. The results of bioluminescence imaging (BLI), micro-CT and X-ray demonstrated that miR-106a promoted bone metastasis of lung adenocarcinoma in vivo. Mechanistic investigations revealed that miR-106a upregulation promoted metastasis by targeting tumour protein 53-induced nuclear protein 1 (TP53INP1)-mediated metastatic progression, including cell migration, autophagy-dependent death and epithelial–mesenchymal transition (EMT). Notably, autophagy partially attenuated the effects of miR-106a on promoting bone metastasis in lung adenocarcinoma. These findings demonstrated that restoring the expression of TP53INP1 by silencing miR-106a may be a novel therapeutic strategy for bone metastatic in lung adenocarcinoma.

Highlights

Lung cancer has the highest morbidity and mortality rate in the world
We found that miR-106a was highly expressed in lung adenocarcinoma tissues with bone metastasis (BM)
We found that miR-106a was highly expressed in the clinical samples of lung adenocarcinoma with BM compared to primary lung adenocarcinoma samples

Summary

INTRODUCTION

Lung cancer has the highest morbidity and mortality rate in the world. Approximately 25% of cancer-related deaths are caused by lung cancer. The transfection of miR-106a mimics alone did not affect the essential autophagy, but notably inhibition of TP53INP1 overexpression increased the number of GFP-LC3 fluorescent puncta of A549 and SPC-A1 cells (Fig. 5E–G) This result was confirmed by western blot analysis for the accumulation of LC3II and the decrease of p62 (Fig. 5H). Another study reported that autophagy inhibition could promote EMT in alveolar epithelial cells, which contributes to the distant metastasis of tumours [27, 28] It indicates that autophagy might play an important role in miR-106a/TP53INP1 regulation of BM in lung cancer. The migration and invasion of lung adenocarcinoma cells promoted by miR-106a were significantly attenuated by Atg short hairpin RNA or 3-MA, which indicated that the pro-metastatic role of miR106a was partially dependent on autophagy (Fig. 6A–D). These data indicated miR-106a promoting BM in lung adenocarcinoma partly depended on autophagy

DISCUSSION

CONCLUSIONS

MATERIALS AND METHODS

Findings

ETHICS APPROVAL AND CONSENT TO PARTICIPATE