Theranostics 2019; 9(9):2460-2474. doi:10.7150/thno.31097

Research Paper

HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis

Lin Jiang1,2, Ranran Wang3, Li Fang4, Xiaolu Ge1,2, Lingna Chen1,2, Ming Zhou1,2, Yanhong Zhou1,2, Wei Xiong1,2, Yerong Hu3, Xianming Tang3, Guiyuan Li1,2, Zheng Li1,2,5✉

1. The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
2. The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
3. Department of Thoracic and Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
4. Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
5. High Resolution Mass Spectrometry Laboratory of Advanced Research Center, Central South University, Changsha, Hunan, China

Abstract

Introduction: Transforming growth factor-beta (TGFβ) signaling plays a vital role in lung adenocarcinoma (LUAD) progression. However, the involvement of TGFβ-regulated long non-coding RNAs (lncRNAs) in metastasis of LUAD remains poorly understood.

Methods: We performed bioinformatic analyses to identify putative lncRNAs regulated by TGF-β/SMAD3 and validated the results by quantitative PCR in LUAD cells. We performed luciferase reporter and chromatin immunoprecipitation assays to demonstrate the transcriptional regulation of the lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) we decided to focus on. Stable HCP5 knockdown and HCP5-overexpressing A549 cell variants were generated respectively, to study HCP5 function and understand its mechanism of action. We also confirmed our findings in mouse xenografts and metastasis models. We analyzed the correlation between the level of lncRNA expression with EGFR, KRAS mutations, smoke state and prognostic of LUAD patients.

Results: We found that the lncRNA HCP5 is induced by TGFβ and transcriptionally regulated by SMAD3, which promotes LUAD tumor growth and metastasis. Moreover, HCP5 is overexpressed in tumor tissues of patients with LUAD, specifically in patients with EGFR and KRAS mutations and current smoker. HCP5 high expression level is positively correlated with poor prognosis of patients with LUAD. Finally, we demonstrated that upregulation of HCP5 increases the expression of Snail and Slug by sponging the microRNA-203 (miR-203) and promoting epithelial-mesenchymal transition (EMT) in LUAD cells.

Conclusions: Our work demonstrates that the lncRNA HCP5 is transcriptionally regulated by SMAD3 and acts as a new regulator in the TGFβ/SMAD signaling pathway. Therefore, HCP5 can serve as a potential therapeutic target in LUAD.

Keywords: SMAD3, Long non-coding RNA, HCP5, lung adenocarcinoma, metastasis.

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How to cite this article:
Jiang L, Wang R, Fang L, Ge X, Chen L, Zhou M, Zhou Y, Xiong W, Hu Y, Tang X, Li G, Li Z. HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis. Theranostics 2019; 9(9):2460-2474. doi:10.7150/thno.31097. Available from http://www.thno.org/v09p2460.htm