Identification of the Expression and Clinical Significance of E2F Family in Clear Cell Renal Cell Carcinoma

Abstract

Background: Multiple studies have identified that E2F transcriptions act as important regulators for the tumorigenesis and progression of several human cancers. However, little is known about the function of E2Fs in clear cell renal cell carcinoma (ccRCC). Methods: We firstly investigated the expression levels, genetic alteration, and biological function of E2Fs in patients with ccRCC and the connections between the immune cell infiltration and the overall survivals of ccRCC patients with the E2Fs expression levels based on UALCAN, The Cancer Genome Atlas database, Gene Expression Profiling Interactive Analysis, TIMER, STRING, GSCALite and cBioPortal databases. Results: Results revealed that the expression levels of E2F1/2/3/4/6/7/8 were markedly upregulated in patients with ccRCC, while the expression of E2F5 displayed an opposite trend. We also experimentally validated the overexpression of E2F3/4/7 in human ccRCC tissues and ccRCC cell lines. Furthermore, the high E2F1/2/3/4/7/8 expression levels were clearly associated with worse pathological characteristics of ccRCC, including high pathological stage, poor molecular subtypes and high tumor grade. Meanwhile, high expression levels of E2F1/2/4/7/8 were evidently associated with worse overall survivals (OSs) and progression-free survivals (PFSs) of patients harboring ccRCC. Univariate and multivariate analyses illustrated that the expressions of E2F4/5/7 were independent factors associated with the OSs and PFSs of patients with ccRCC. Meanwhile, the mutations in E2Fs were also significantly related to poor OSs and PFSs of patients with ccRCC. Mechanically, the E2Fs genes synergistically promoted the progression of ccRCC by accelerating the cell cycle and inhibiting DNA damage response and apoptosis after performing the protein structure, functional enrichment, and PPI network analyses. In addition, E2Fs genes were also significantly associated with tumor immune cells infiltration and the drug sensitivity in ccRCC. Conclusion:As a result, E2F4/7 were highly expressed in ccRCC and significantly associated with worse pathological characteristics of ccRCC, including high pathological stage, poor molecular subtypes and high tumor grade, tumor immune cell infiltration, and drug sensitivity, consequently translating into poor OSs and PFSs of patients with ccRCC. Our results indicated that E2F4/7 could be potential biomarkers and therapeutic targets of ccRCC patients.

Vimentin‐positive invasive breast carcinoma of no special type: A breast carcinoma with lethal biological characteristics

“…In the KEGG pathway analyses, eight coding RNAs of the cell cycle and seven RNAs involved in cellular senescence were identified as probably the key‐coding RNAs involved in significantly heightening the malignant potential of vimentin‐positive IBC‐NSTs. Among these, since MYC, CDK6 , and E2F3 which were significantly upregulated are involved in both the cell cycle and cellular senescence pathways, these coding RNAs are probably especially closely involved in heightening the malignant potential of vimentin‐positive IBC‐NSTs 37–39 . Thirteen GO terms consisted of many important coding RNAs that could play very important roles in heightening the malignant potential of vimentin‐positive IBC‐NSTs; among these, the 12 coding RNAs that were significantly upregulated in three or more GO terms may be especially important coding RNAs (Table 4).…”

“…Among these, since MYC, CDK6, and E2F3 which were significantly upregulated are involved in both the cell cycle and cellular senescence pathways, these coding RNAs are probably especially closely involved in heightening the malignant potential of vimentinpositive IBC-NSTs. [37][38][39] Thirteen GO terms consisted of many important coding RNAs that could play very important roles in heightening the malignant potential of vimentin-positive IBC-NSTs; among these, the 12 coding RNAs that were significantly upregulated in three or more GO terms may be especially important coding RNAs (Table 4). [40][41][42][43][44][45][46][47][48][49][50][51] This study clearly demonstrated a higher Ki67 labeling index of vimentin-positive IBC-NSTs than that of vimentin-negative IBC-NSTs; since all of the 12 coding RNAs play important roles in…”

GSDMB: A novel, independent prognostic marker and potential new therapeutic target in clear cell renal cell carcinoma

“…In order to assess relative gene expression, the 2 -ΔΔCq method was used. Additionally, the GAPDH gene was used as a reference gene and each of the analyses was performed in triplicate (22).…”