Follistatin-like protein 1 plays a tumor suppressor role in clear-cell renal cell carcinoma

Cancer Communications

Hongwei Zhang¹  Xiaojie Tan¹  Xiaomei Hou¹  Ling Wang¹  Jianhua Yin¹  Xi Chen¹  Yan Liu¹  Yibo Ding¹  Wenbin Liu¹  Guangwen Cao¹  Yongwei Yu²  Dan Shen³  Jianguo Hou³  Timothy C. Thompson⁴ 

[1] Department of Epidemiology, Second Military Medical University, Shanghai, P. R. China;Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, P. R. China;Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, P. R. China;Genitourinary Medical Oncology-Research, University of Texas MD Anderson Cancer Center, Houston, USA

关键词: Follistatin-like protein 1;    Clear cell renal cell carcinoma;    NF-κB;    HIF-2α;    Prognosis;    Tumor suppressor;   

DOI  :  10.1186/s40880-018-0267-2

学科分类：肿瘤学

来源: Springer

【 摘 要 】

We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients. FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118–0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = − 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.

【 授权许可】

CC BY