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

ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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-?B (NF-?B) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-?-induced degradation of NF-?B inhibitor (I?B?) 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-2? expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = - 0.229, P = 0.044). Intratumoral expression of HIF-2?, rather than HIF-1?, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). CONCLUSIONS:FSTL1 plays a tumor suppression role possibly via repressing the NF-?B and HIF-2? signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5778637 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Liu Yan Y Tan Xiaojie X Liu Wenbin W Chen Xi X Hou Xiaomei X Shen Dan D Ding Yibo Y Yin Jianhua J Wang Ling L Zhang Hongwei H Yu Yongwei Y Hou Jianguo J Thompson Timothy C TC Cao Guangwen G

Chinese journal of cancer 20180122 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29357946

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Project description:BACKGROUND: Clinical outcome of patients with high-grade ccRCC (clear cell renal cell carcinoma) remains still poor despite recent advances in treatment strategies. Molecular mechanism of pathogenesis in developing high-grade ccRCC must be clarified. In the present study, we found that SAV1 was significantly downregulated with copy number loss in high-grade ccRCCs. Therefore, we investigated the SAV1 function on cell proliferation and apoptosis in vitro. Furthermore, we attempted to clarify the downstream signaling which is regulated by SAV1. METHODS: We performed array CGH and gene expression analysis of 8 RCC cell lines (786-O, 769-P, KMRC-1, KMRC-2, KMRC-3, KMRC-20, TUHR4TKB, and Caki-2), and expression level of mRNA was confirmed by quantitative RT-PCR (qRT-PCR) analysis. We next re-expressed SAV1 in 786-O cells, and analyzed its colony-forming activity. Then, we transfected siRNAs of SAV1 into the kidney epithelial cell line HK2 and renal proximal tubule epithelial cells (RPTECs), and analyzed their proliferation and apoptosis. Furthermore, the activity of YAP1, which is a downstream molecule of SAV1, was evaluated by western blot analysis, reporter assay and immunohistochemical analysis. RESULTS: We found that SAV1, a component of the Hippo pathway, is frequently downregulated in high-grade ccRCC. SAV1 is located on chromosome 14q22.1, where copy number loss had been observed in 7 of 12 high-grade ccRCCs in our previous study, suggesting that gene copy number loss is responsible for the downregulation of SAV1. Colony-forming activity by 786-O cells, which show homozygous loss of SAV1, was significantly reduced when SAV1 was re-introduced exogenously. Knockdown of SAV1 promoted proliferation of HK2 and RPTEC. Although the phosphorylation level of YAP1 was low in 786-O cells, it was elevated in SAV1-transduced 786-O cells. Furthermore, the transcriptional activity of the YAP1 and TEAD3 complex was inhibited in SAV1-transduced 786-O cells. Immunohistochemistry frequently demonstrated nuclear localization of YAP1 in ccRCC cases with SAV1 downregulation, and it was preferentially detected in high-grade ccRCC. CONCLUSIONS: Taken together, downregulation of SAV1 and the consequent YAP1 activation are involved in the pathogenesis of high-grade ccRCC. It is an attractive hypothesis that Hippo signaling could be candidates for new therapeutic target.

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

Publications

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

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