Theranostics 2019; 9(6):1599-1613. doi:10.7150/thno.30372

Research Paper

Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance

Bin Li1,2,3, Pan Hong3, Can-Can Zheng3, Wei Dai4, Wen-You Chen5, Qing-Sheng Yang5, Liang Han2, Sai Wah Tsao2, Kin Tak Chan6, Nikki Pui Yue Lee6, Simon Law6, Li Yan Xu7, En Min Li7, Kwok Wah Chan1,8, Yan Ru Qin9, Xin Yuan Guan4, Maria Li Lung4, Qing-Yu He3, Wen Wen Xu10,1,2✉, Annie LM Cheung1,2,✉

1. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China
2. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
3. Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
4. Department of Clinical oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
5. Department of Thoracic Surgery, First Affiliated Hospital, Jinan University, Guangzhou 510632, China
6. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
7. The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China
8. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
9. Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
10. Institute of Biomedicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.

Abstract

Rationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance. This study aims to identify miRNAs that are associated with fluorouracil (5-FU) chemoresistance in esophageal squamous cell carcinoma (ESCC). The potential of miR-29c as a novel diagnostic, prognostic and treatment-predictive marker in ESCC, and its mechanisms and therapeutic implication in overcoming 5-FU chemoresistance were explored.

Methods: The miRNA profiles of an ESCC cell model with acquired chemoresistance to 5-FU were analyzed using a Taqman miRNA microarray to identify novel miRNAs associated with 5-FU chemoresistance. Quantitative real-time PCR was used to determine miR-29c expression in tissue and serum samples of patients. Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression. The potential of systemic miR-29c oligonucleotide-based therapy in overcoming 5-FU chemoresistance was evaluated in tumor xenograft model.

Results: MiR-29c, under the regulatory control of STAT5A, was frequently downregulated in tumor and serum samples of patients with ESCC, and the expression level was correlated with overall survival. Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK. Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo.

Conclusions: MiR-29c modulates chemoresistance by interacting with FBXO31, and is a promising non-invasive biomarker and therapeutic target in ESCC.

Keywords: diagnosis and prognosis, chemoresistance, p38 signaling, STAT5A, microRNA therapy

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How to cite this article:
Li B, Hong P, Zheng CC, Dai W, Chen WY, Yang QS, Han L, Tsao SW, Chan KT, Lee NPY, Law S, Xu LY, Li EM, Chan KW, Qin YR, Guan XY, Lung ML, He QY, Xu WW, Cheung AL. Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance. Theranostics 2019; 9(6):1599-1613. doi:10.7150/thno.30372. Available from http://www.thno.org/v09p1599.htm