Prognostic value of epithelial-mesenchymal transition markers in clear cell renal cell carcinoma

Abstract

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC. We further compared the mRNA expression of CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1 between ccRCC tumor samples and adjacent normal tissues respectively based on RNA-sequence data from TCGA database. Consistent with Oncomine data, CDH1 expression was lower in ccRCC primary tumors in comparison with adjacent normal tissues (Figure 1B). However, expression of mesenchymal markers, CDH2, SNAI1, VIM, TWIST1, were significantly higher in ccRCC primary tumors (Figure 1C-1G). Neighbor genes and hierarchical partitioning of hub genes from TCGA As was shown in Supplementary Figure 1, network of CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1 and their 49 frequently genetic altered neighbor genes was integrated and constructed using cBioPortal.

The Most Common VHL Point Mutation R167Q in Hereditary VHL Disease Interferes with Cell Plasticity Regulation

“…Importantly, our study provides supporting evidence that certain hypoxia-related genes are associated with a lower survival in RCC patients-that is, IRS2, ROR2, and ENO2 [35,38,39]. Moreover, the RNA-Seq analysis coupled with the interrogation of the TCGA KIRC dataset allowed the identification of novel candidates strongly associated with poor prognosis and the lethal evolution of RCC, including NUMBL, COL6A1, and ASPM, as well as SNAI2 [51]. The specific impact of each gene in the setting of RCC, hypoxic, and pseudo-hypoxic contexts should be investigated in future studies.…”

“…TGFB1 is known to have a central role in the regulation of EMT, fibrosis, stem cell maintenance, invasiveness and metastatic development [46][47][48]. SNAI2, also known as Slug, is a well-known EMT transcription factor that is critically involved in oncogenesis and in the maintenance of stemness and progenitor cells [49][50][51]. COL6A1 is a member of the collagen family that is involved in numerous biological processes, including apoptosis, autophagy, stemness, differentiation, and tumor progression, including in RCC [52,53].…”

The inhibitory effect of betulinic acid on epithelial–mesenchymal transition pathway in renal cell carcinoma

“…Krebs et al reported that ZEB1, an EMT transcription factor, is closely associated with tumor grade, invasion, metastasis and tumor progression in mouse pancreatic cancer model [30]. Studies have shown that higher expressions of Vimentin and TWIST1 and lower expression of E-cadherin are associated with high tumor grade, poor prognosis and worse progression-free survival in renal cancer patients [31,32]. In addition to triggering metastatic properties, EMT is also known to be associated with drug resistance in cancer cells.…”

CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug

“…Additionally, we found that the Slug gene, which is a potent regulator of the EMT pathway, has a speci c HOXA5-binding sequence in its promoter region. EMT, which plays a crucial role during embryogenesis [31], was rst described in the 1980s. Cells that undergo EMT lose their epithelial morphology and acquire stronger mobility, facilitating migration, and EMT may also regulate the invasion of cancer cells [32].…”