WISP-3 Stimulates VEGF-C-Dependent Lymphangiogenesis in Human Chondrosarcoma Cells by Inhibiting miR-196a-3p Synthesis

Chih-Yang Lin; Shih-Wei Wang; Jeng-Hung Guo; Huai-Ching Tai; Wen-Chun Sun; Cheng-Ta Lai; Chen-Yu Yang; Shih-Chia Liu; Yi-Chin Fong; Chih-Hsin Tang

doi:10.3390/biomedicines9101330

WISP-3 Stimulates VEGF-C-Dependent Lymphangiogenesis in Human Chondrosarcoma Cells by Inhibiting miR-196a-3p Synthesis

Biomedicines. 2021 Sep 27;9(10):1330. doi: 10.3390/biomedicines9101330.

Authors

Chih-Yang Lin¹, Shih-Wei Wang^{2

3

4}, Jeng-Hung Guo^{5

6}, Huai-Ching Tai^{7

8}, Wen-Chun Sun^{2

9}, Cheng-Ta Lai^{3

9}, Chen-Yu Yang¹⁰, Shih-Chia Liu¹⁰, Yi-Chin Fong^{11

12}, Chih-Hsin Tang^{1

13

14}

Affiliations

¹ Department of Pharmacology, School of Medicine, China Medical University, Taichung 404022, Taiwan.
² Institute of Biomedical Sciences, Mackay Medical College, Taipei 104217, Taiwan.
³ Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan.
⁴ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
⁵ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404022, Taiwan.
⁶ Department of Neurosurgery, China Medical University Hospital, Taichung 404022, Taiwan.
⁷ School of Medicine, Fu-Jen Catholic University, New Taipei City 252005, Taiwan.
⁸ Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City 252005, Taiwan.
⁹ Department of Surgery, Division of Colon and Rectal Surgery, MacKay Memorial Hospital, Taipei 104217, Taiwan.
¹⁰ Department of Orthopedic Surgery, Division of Pediatric Orthopedics, MacKay Memorial Hospital, Taipei 104217, Taiwan.
¹¹ Department of Sports Medicine, College of Health Care, China Medical University, Taichung 404022, Taiwan.
¹² Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin 651012, Taiwan.
¹³ Department of Biotechnology, College of Health Science, Asia University, Taichung 413005, Taiwan.
¹⁴ Chinese Medicine Research Center, China Medical University, Taichung 404022, Taiwan.

Abstract

Chondrosarcoma is a malignant bone tumor with high metastatic potential. Lymphangiogenesis is a critical biological step in cancer metastasis. WNT1-inducible signaling pathway protein 3 (WISP-3) regulates angiogenesis and facilitates chondrosarcoma metastasis, but the role of WISP-3 in chondrosarcoma lymphangiogenesis is unclear. In this study, incubation of chondrosarcoma cells with WISP-3 increased the production of VEGF-C, an important lymphangiogenic factor. Conditioned medium from WISP-3-treated chondrosarcoma cells significantly enhanced lymphatic endothelial cell tube formation. WISP-3-induced stimulation of VEGF-C-dependent lymphangiogenesis inhibited miR-196a-3p synthesis in the ERK, JNK, and p38 signaling pathways. This evidence suggests that the WISP-3/VEGF-C axis is worth targeting in the treatment of lymphangiogenesis in human chondrosarcoma.

Keywords: VEGF-C; WISP-3; chondrosarcoma; lymphangiogenesis; miR-196a-3p.