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KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma.

ABSTRACT: KDF1 has been identified as a key regulator of epidermal proliferation and differentiation, but it is unknown whether KDF1 is involved in the pathogenesis of malignancy. No study has reported the expression and function of KDF1 in renal cancer. To explore the pathologic significance of KDF1 in clear cell renal cell carcinoma (ccRCC), the expression level of KDF1 protein in the tumor tissue of ccRCC patients was examined by immunohistochemistry and Western blot while the expression level of KDF1 mRNA was analyzed by using the data from TCGA database. In vitro cell experiments and allogeneic tumor transplantation tests were performed to determine the effects of altered KDF1 expression on the phenotype of ccRCC cells. Both the KDF1 mRNA and protein were found to be decreasingly expressed in the tumor tissue of ccRCC patients when compared with the adjacent non-tumor control tissue. The expression level of KDF1 in the tumor tissue was found to correlate negatively with the tumor grade. Patients with higher KDF1 in the tumor tissue were found to have longer overall survival and disease-specific survival time. KDF1 was shown to be an independent factor influencing the disease-specific survival of the ccRCC patients. Overexpression of KDF1 was found to inhibit the proliferation, migration and invasion of ccRCC cells, which could be reversed by decreasing the expression of KDF1 again. ccRCC cells with KDF1 overexpression were found to produce smaller transgrafted tumors. These results support the idea that KDF1 is involved in ccRCC and may function as a tumor suppressor.

SUBMITTER: Zheng JM

PROVIDER: S-EPMC8201614 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma.

Zheng Jing-Min JM Gan Mei-Fu MF Yu Hong-Yuan HY Ye Lu-Xia LX Yu Qing-Xin QX Xia Yu-Hui YH Zhou Han-Xi HX Bao Jia-Qian JQ Guo Yi-Qing YQ

Frontiers in oncology 20210531

KDF1 has been identified as a key regulator of epidermal proliferation and differentiation, but it is unknown whether KDF1 is involved in the pathogenesis of malignancy. No study has reported the expression and function of KDF1 in renal cancer. To explore the pathologic significance of KDF1 in clear cell renal cell carcinoma (ccRCC), the expression level of KDF1 protein in the tumor tissue of ccRCC patients was examined by immunohistochemistry and Western blot while the expression level of KDF1 ...[more]

PMID: 34136411

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Project description:Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of malignancy in adults. However, the clinical significance of tumor suppressor genes (TSG) is largely elusive. Herein, the expression profile TSGs and its clinical response in ccRCC were investigated. A total of 603 ccRCC samples from two cohorts (TCGA and ICGC) were retrieved in this study. Three molecular subtypes (C1, C2, and C3) were identified based on the TSGs expression profile in the TCGA dataset. Through Weighted Gene Correlation Network Analysis (WGCNA), six modules associated with three subtypes were identified. Pathway enrichment for the modules revealed that crucial pathways including p53 signaling and immune-related pathways were significantly enriched. We further focused on the relationship between immune infiltration level and subtypes, and found that subtype C1 was associated with higher immune infiltration level, subtype C2 was corresponding with medium immune infiltration level, whereas subtype C3 was correlated with lower immune infiltration level. Interestingly, C2 have a better survival outcome, while C1 and C3 showed a poor prognosis. Considering their survival difference, we then performed a differentially expression analysis between C2 and C1&3, and a total of 99 differentially expressed tumor suppressor genes (DETSGs) were identified. According to these DETSGs, 59 potential compounds with 28 mechanisms of action (MOA) were predicted using the Connectivity Map (CMap) database. Among these compounds, leflunomide, naftopidil, and ribavirin were the most prospective compounds for the treatment of ccRCC. In addition, we found that subtype C2 is more sensitive to sorafenib and sunitinib drugs, and C2 have more likelihood to be responded to immunotherapy. In summary, the three subtypes hinged on the tumor suppressor gene expression for ccRCC might contribute to understanding the underlying molecular mechanisms of ccRCC. Also, its potential compounds might offer guidelines for developing a novel treatment strategy of ccRCC.

Project description: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-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). CONCLUSIONS: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.

Dataset Information

KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma.

Publications

KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma.

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