Abstract
BackgroundWe 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.MethodsThe 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.ResultsFSTL1 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).ConclusionsFSTL1 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.
Highlights
We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly downregulated in metastatic clear-cell renal cell carcinoma
In our previous study investigating global profiling of gene expression in Renal cell carcinoma (RCC) cells with different metastatic potential, we found that follistatin-like protein 1 (FSTL1) was frequently down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC) [19]; and the C allele of rs1259293 in the coding region of FSLT1 was associated with an increased risk and unfavorable postoperative prognosis of RCC, possibly by down-regulating FSTL1 expression in renal tissues [20]
NRCC and MRCC ccRCC cell lines were established from two Chinese ccRCC patients in our laboratory [30]. 786-O cells were grown in RPMI-1640 media (Hyclone, Pittsburgh, PA, USA) supplied with 10% fetal bovine serum (FBS) (GIBCO, Grand Island, NY, USA), 100 U/ mL penicillin, and 100 μg/mL streptomycin (Invitrogen, Carlsbad, CA, USA)
Summary
We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly downregulated in metastatic clear-cell renal cell carcinoma (ccRCC). Renal cell carcinoma (RCC) is the seventh most common cancer worldwide and the tenth most common cancer in the urban areas of China [1]. Early-stage RCC has an asymptomatic clinical course; 25%–30% of patients appear with metastatic disease [2]. 30% of RCC patients who undergo curable resection of localized tumors eventually develop distant metastases [2]. A percentage of metastatic RCC is sensitive to immunotherapy and targeted therapy [4,5,6,7]. To improve postoperative survival of RCC patients, it is important to identify the factors that have prognostic or predictive values, leading to monitoring for disease recurrence and opportunities for targeted and/or immunotherapy. D9S168 microsatellite alteration in tumors [8], intratumoral neutrophil [9], intratumoral expression of proteins including
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