血小板反應素-4在膀胱癌細胞侵襲之角色和其臨床應用之潛力
林宜佳1 、陳栢均2、楊尚哲2、蔡德甫1、陳宏恩1、仇光宇1、黃一勝1,2,3,4
1新光醫院 外科部 泌尿科、2新光醫院 中央研究室、3台北醫學大學 醫學院、4輔仁大學 醫學院
Role of Thrombospondin-4 (THBS4/TSP4) in bladder cancer cell invasion and its clinical application potential
Yi-Chia Lin1, Po-Chun Chen2, Shan-Che Yang2, Te-Fu Tsai 1, Hung-En Chen1, Kuang-Yu Chou1, and Thomas I-Sheng Hwang1,2,3,4
Department of Urology, Shin Kong Wu Ho-Su Memorial Hospital1, Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital2, Department of Urology, Taipei Medical University3, Division of Urology, School of Medicine, Fu-Jen Catholic University4, Taipei, Taiwan.
Background: Bladder cancer (BC) is the fifth most diagnosed tumor and the second leading cause of death in patients with genitourinary tract malignancies. Approximately 80% of patients will present with nonmuscle-invasive bladder cancer (NMIBC), but nearly a quarter have muscle-invasive disease (MIBC) at the time of diagnosis. However, patients with NMIBC are at risk of recurrence to progress into MIBC, and the prognosis of patients with MIBC is determined by the presence of metastasis. Thrombospondin-4 (THBS4/TSP4), a secreted matricellular glycoprotein participates cell-to-extracellular matrix attachment and regulates various physiological and pathological processes. However, little is known about the prognostic role of TSP4 and its role in bladder cancer progression.
Materials and methods: The expression level of TSP4 and its prognostic value in BC specimens was evaluated in online database GEPIA. Moreover, the protein expression level of TSP4 in BC and normal tissue was investigated in the tumor tissue array by the immunohistochemistry. The pro-invasive role of TSP4 in BC was examined by in vitro cell migration and invasion assay. Finally, The molecular mechanism of TSP4 on BC metastasis was defined by using Western blot and QPCR analyses.
Results: Based on the results of meta-analysis in GEPIA database and immunohistochemistry, we found that expression level of TSP4 was in accordance with the progression of BC, especially in MIBC. Interestingly, its expression is positively correlated with the matrix metalloproteinase-9 (MMP-9) expression, which are two well-characterized invasive markers in BC. Incubation with recombinant TSP4 dramatically promoted BC cell migration, invasion and MMP-9 expression.
Conclusion: Conclusively, our present study first describes the prognostic role of TSP4 in BC and defines its pro-invasive role in BC via promoting MMP-9 expression. TSP-2 may represent a novel promising new biomarker and therapeutic target for treating BC.
Key words: TSP4, MMP-9, invasion, metastasis, bladder cancer