Sodium-Glucose Cotransporter 2 (SGLT2) as a Potential Biomarker and Target in Papillary Renal Cell Carcinoma

Abstract

Background

SGLT2 is selectively expressed in the human kidney. SGLT2 inhibitors have markedly changed diabetes, heart failure, and kidney disease treatment, and are under investigation in cancer. However, the role of SGLT2 in papillary renal cell carcinoma (pRCC) is not known.

Methods

We investigated the SGLT2 gene expression, associated clinical-molecular features, and overall survival (OS) in pRCC. The Cancer Genome Atlas Program and Gene Expression Omnibus data were utilized. mRNA expression z-scores of the SGLT2 gene relative to normal samples (log-RNASeqV2-RSEM, threshold ± 2) were analyzed (low, unaltered, high expression).

Results

273 patients were involved. As per mRNA expression, 180 patients (66%) had low, and the remaining had unaltered expression. High correlation (r > 0.6) with SGLT2 was observed in IRX5, STRIP2, LINC00899, SATB2-AS1, FOXC1, IRX3, SLC22A8, SH3BP5 genes (P < .001,q < 0.001 for all) and with the HIF-2α (r:0.43, P < .001,q < 0.001). Tumor mutational burden (P = .365) and aneuploidy scores (P = .976) did not differ, however, among the genes with the highest alteration frequency, SETD2 alterations (15.63% vs. 1.07%, P < .00, q = 0.046) were more frequent in the unaltered-expression group. Differential protein expression analysis showed highly separated proteins (ERBB2, AR, MAPK14, VHL, TGM2 in the low and SHC1, SQSTM1, MYH14, and CDH1 in the unaltered group). The median OS has not reached the median in both groups [Hazard Ratio(HR) for the unaltered group:2.658, 95% Confidence Interval(CI):1.401-5.043, P = .003]. SGLT2 expression remained a significant prognostic factor in multivariable analysis [HR:2.446 (95%CI: 1.199-4.990), P = .014].

Conclusions

This study reveals the first data that SGLT2 might have a role in pRCC as a pathogenic factor and biomarker. Confirmatory mechanistic studies are needed.