Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background: In many cancer types, aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) has been found to be associated with tumor cell proliferation and prognosis. However, the role of ARNT2 in clear cell renal cell carcinoma (ccRCC) has not been completely elucidated. In this study, the potential role of ARNT2 in ccRCC development was characterized. Methods: A pan-cancer dataset (TCGA-TARGET-GTEx) was accessed from UCSC Xena Data Browser. ARNT2 expression in normal and tumor samples was compared. Univariate Cox regression was performed to evaluate the prognostic value of ARNT2. Single sample gene set enrichment analysis (ssGSEA) was used to estimate the enrichment of functional pathways and gene signatures. CIBERSORT and ESTIMATE methods evaluated the immune infiltration. The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot. Results: ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types. Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators, immune cell infiltration, and genomic alternations. In ccRCC patients, the low-ARNT2 expression group had higher immune infiltration, CD8 T cells, and programmed cell death ligand 1 expression, as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group. Low-ARNT2 expression group was more responsive to immunotherapy. Moreover, low ARNT2 expression was observed in ccRCC tissue and cell lines. Conclusions: Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment. ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.