長鏈非編碼核醣核酸OIP5-AS1藉由調控miR-340-5p/versican路徑進而調節上泌尿道上皮癌細胞的遷移和侵襲能力
吳奕儒¹、徐偉齊²、連培因³、吳文正^{1, 2, 4}、李怡琛^{4, 5}、詹鎮豪^1,6,7、李威明^1,2,4,8、
李經家^1,2,4、張玲麗^{4, 9}、黃阿梅^{6, 10}、林慧惠¹、柯宏龍^1,2,4,11*

高雄醫學大學附設醫院 泌尿部 ¹ ; 高雄醫學大學 醫學系 泌尿學科 ²; 高雄醫學大學附設醫院 病理部 ³; 高雄醫學大學醫學系 醫學研究所 ⁴，解剖學科 ⁵，臨床醫學研究所 ⁶ ; 高雄市立小港醫院 泌尿科 ⁷ ; 衛生福利部屏東醫院泌尿科 ⁸ ; 高雄醫學大學醫學系 微生物與免疫學科 ⁹ ; 生物化學科 ¹⁰ ; 高雄市立大同醫院 泌尿科 ¹¹

Long non-coding RNA OIP5-AS1 modulates upper tract urothelial carcinoma cell migration and invasion through regulating miR-340-5p/versican axis
Yi-Ru Wu ¹, Wei-Chi Hsu ², Peir-In Liang ³, Wen-Jeng Wu ^1,2,4, Yi-Chen Lee ^4,5, Jhen-Hao Jhan ^1,6,7,
Wei-Ming Li ^1,2,4,8, Ching-Chia Li^1,2,4, Lin-Li Chang ^4,9, A-Mei Huang ^6,10, Hui-Hui Lin ¹,
Hung-Lung Ke ^1,2,4,11*

¹ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.² Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ³ Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. ⁴ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.⁵ Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ⁶ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.⁷ Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan. ⁸ Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan. ⁹ Department of Microbiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ¹⁰ Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ¹¹ Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.

Purpose: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different feature between Eastern and Western countries. Versican (VCAN) is a large chondroitin sulfate proteoglycan and a major component of the extracellular matrix. OIP5-AS1 is recognized as an oncogenic long non-coding RNA (lncRNA) and miR-340-5p regulates tumor suppressor functions in various tumors. We aimed to elucidate the molecular mechanism underlying the regulation of versican by OIP5-AS1 and miR-340-5p in UTUC.
Materials and methods: Versican expression was evaluated by immunohistochemistry in human UTUC tissues. We demonstrated the regulatory relationship between versican, miR-340-5p and OIP5-AS1 by real-time PCR, Western blot and dual luciferase reporter assay using UTUC cell lines. The role of the OIP5-AS1/miR-340-5p/versican signaling pathway in motility and invasion was analyzed in vitro.

Results: High versican expression was associated with stage, distant metastasis, cancer death and poor survival in UTUC patients. In vitro study, VCAN wild-type and knock-out cells were analyzed by next-generation sequencing (NGS) to identify a set of genes, which were found to be associated with collagen-containing extracellular matrix, cell adhesion, and cell-substrate junction. Knockdown of versican and OIP5-AS1 or overexpression of miR-340-5p suppressed UTUC cell migration and invasion. OIP5-AS1 was found to act as a competitive endogenous RNA to sponge miR-340-5p, which regulated versican expression in UTUC cells. The functional studies showed that versican overexpression reversed the OIP5-AS1 and miR-340-5p modulation of tumor cell migration and invasion.
Conclusion: These findings implicate the OIP5-AS1/miR-340-5p/versican regulatory axis, which may be future therapeutic targets for UTUC.