Transcription Factors BARX1 and DLX4 Contribute to Progression of Clear Cell Renal Cell Carcinoma via Promoting Proliferation and Epithelial–Mesenchymal Transition

Abstract

Dysregulation of transcription factors contributes to the carcinogenesis and progression of cancers. However, their roles in clear cell renal cell carcinoma remain largely unknown. This study aimed to evaluate the clinical significance of TFs and investigate their potential molecular mechanisms in ccRCC. Data were accessed from the cancer genome atlas kidney clear cell carcinoma cohort. Bioinformatics algorithm was used in copy number alterations mutations, and differentially expressed TFs’ analysis. Univariate and multivariate Cox regression analyses were performed to identify clinically significant TFs and construct a six-TF prognostic panel. TFs’ expression was validated in human tissues. Gene set enrichment analysis (GSEA) was utilized to find enriched cancer hallmark pathways. Functional experiments were conducted to verify the cancer-promoting effect of BARX homeobox 1 (BARX1) and distal-less homeobox 4 (DLX4) in ccRCC, and Western blot was performed to explore their downstream pathways. As for results, many CNAs and mutations were identified in transcription factor genes. TFs were differentially expressed in ccRCC. An applicable predictive panel of six-TF genes was constructed to predict the overall survival for ccRCC patients, and its diagnostic efficiency was evaluated by the area under the curve (AUC). BARX1 and DLX4 were associated with poor prognosis, and they could promote the proliferation and migration of ccRCC. In conclusion, the six-TF panel can be used as a prognostic biomarker for ccRCC patients. BARX1 and DLX4 play oncogenic roles in ccRCC via promoting proliferation and epithelial–mesenchymal transition. They have the potential to be novel therapeutic targets for ccRCC.

Identification and Verification of m7G Modification Patterns and Characterization of Tumor Microenvironment Infiltration via Multi-Omics Analysis in Clear Cell Renal Cell Carcinoma

“…BARX homeobox 1 (BARX1), a transcription factor, is involved in craniofacial development ( 82 ) and in hepatocellular carcinoma metastasis ( 83 ). BARX1 has recently been reported for the first time to be associated with proliferation and epithelial-mesenchymal transition in ccRCC ( 84 ). GJB6 encoding Cx30 is a member of beta-connexins.…”

DNA methylation-mediated differential expression of DLX4 isoforms has opposing roles in leukemogenesis

“…showed that DLX4 induced CD44 expression by stimulating interleukin (IL)-1β-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, thereby promoting peritoneal metastasis of ovarian cancer [ 35 ]. Moreover, DLX4 played an oncogenic role in clear cell renal cell carcinoma via inducing proliferation and EMT, and was associated with poor prognosis [ 36 ]. DLX4 isoform BP1 overexpression promoted cell proliferation, migration in endometrial cancer with clinically prognostic effect [ 37 ].…”

A New Thinking: Deciphering the Aberrance and Clinical Implication of IGF Axis Regulation Pattern in Clear Cell Renal Cell Carcinoma

“…Niinivirta et al found that the combined expression of PKLR and CUBN could more accurately predict drug the responsiveness of sunitinib and sorafenib (43). Sun et al indicated that transcription factor BARX1 contributed to the progression of ccRCC via promoting proliferation and epithelial-mesenchymal transition (44). A recent report found that SCX regulated Twist1 and Snai1 expression in the epithelialto-mesenchymal transition (45).…”