Theranostics 2019; 9(18):5134-5148. doi:10.7150/thno.34887

Research Paper

C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer

Hui Li1, Juan Liu1, Wenjie Cao2, Xiaojuan Xiao1, Long Liang1, Feng Liu-Smith1, Weiwei Wang2, Hong Liu3, Peng Zhou4, Ruoyun Ouyang5, Zhijun Yuan6, Jing Liu1,✉, Mao Ye7,✉, Bin Zhang2,✉

1. Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
2. Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha 410013, China.
3. The First Xiangya Hospital, Central South University, Changsha 410078, China.
4. Department of pathology, The Second Xiangya Hospital, Central south university, Changsha, 410011, China.
5. Department of Respiratory Medicine, Respiratory Disease Research Institute, The Second XiangYa Hospital, Central South University, Changsha, 410011, China.
6. Head & Neck Internal Medicine Area, Hunan Provincial Tumor Hospital, Changsha, 410013, China.
7. Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha 410082, China.

Abstract

Rationale: Lung cancer is the leading cause of cancer death worldwide, and treatment options are limited to mainly cytotoxic agents. Here we reveal a novel role of miR-150 in non-small cell lung cancer (NSCLC) development and seek potential new therapeutic targets.

Methods: The miR-150-mediated autophagy dysfunction in NSCLC cells were examined using molecular methods in vitro and in vivo. The upstream regulatory element and downstream target of miR-150 were identified in vitro and validated in vivo. Potential therapeutic methods (anti-c-myc or anti-miR-150) were tested in vitro and in vivo. Clinical relevance of the c-myc/miR-150/EPG5 axis in NSCLC was validated in human clinical samples and large genomics database.

Results: miR-150 blocked the fusion of autophagosomes and lysosomes through directly repressing EPG5. The miR-150-mediated autophagy defect induced ER stress and increased cellular ROS levels and DNA damage response, and promoted NSCLC cell proliferation and tumor growth. Knockdown of EPG5 promoted NSCLC cell proliferation, and attenuated the effects of miR-150. c-myc gene was identified as a miR-150 transcriptional factor which increased miR-150 accumulation, therefore pharmacologically or genetically inhibiting c-myc/miR-150 expression significantly inhibited NSCLC cell growth in vitro and in vivo. Both c-myc and miR-150 were significantly over-expressed in NSCLC, while EPG5 was down-regulated in NSCLC. Expression levels of these molecules were well correlated, and also well correlated with patient survival.

Conclusions: Our findings suggest that c-myc/miR-150/EPG5 mediated dysfunction of autophagy contributes to NSCLC development, which may provide a potential new diagnostic and therapeutic target in NSCLC.

Keywords: NSCLC, miR-150, EPG5, autophagy, tumorigenesis

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How to cite this article:
Li H, Liu J, Cao W, Xiao X, Liang L, Liu-Smith F, Wang W, Liu H, Zhou P, Ouyang R, Yuan Z, Liu J, Ye M, Zhang B. C-myc/miR-150/EPG5 axis mediated dysfunction of autophagy promotes development of non-small cell lung cancer. Theranostics 2019; 9(18):5134-5148. doi:10.7150/thno.34887. Available from http://www.thno.org/v09p5134.htm