The novel role of LDHA/LDHB in the prognostic value and tumor-immune infiltration in clear cell renal cell carcinoma

Abstract

Lactate dehydrogenase (LDH) is a crucial glycolytic enzyme which mediates the metabolic plasticity of cancer cells, however its clinical significance in renal cell carcinoma (RCC) is poorly understood. Herein, we examined the prognostic significance of the two primary components of LDH, i.e., LDHA and LDHB, in clear cell RCC (ccRCC) patients and further explored their association with immune infiltration in ccRCC. In this study, the expression levels of LDHA and LDHB were examined in ccRCC and adjacent normal tissues by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, and western blotting (WB) analyses, and their prognostic values were estimated in 150 ccRCC and 30 adjacent normal tissues by immunohistochemistry (IHC) analysis. The relationship to immune infiltration of LDHA and LDHB genes was further investigated using tumor immune estimation resource 2 (TIMER2) and Tumor-Immune System Interactions and DrugBank (TISIDB) databases, respectively. Public databases and WB analyses demonstrated higher LDHA and lower LDHB in ccRCC than in non-tumor tissues. IHC analysis revealed that LDHA and LDHB expression profiles were significantly associated with tumor grade, stage, size, and overall survival (OS). Univariate survival analysis displayed that high grade, advanced stage, large tumor, metastasis, high LDHA, and low LDHB expression were significantly associated with a poorer OS, and multivariate analysis revealed tumor stage and LDHB were identified as independent predictors for OS in patients with ccRCC. Further TIMER2 and TISIDB analyses demonstrated that LDHA and LDHB expression was significantly related to multiple immune cells and immune inhibitors in over 500 ccRCC patients. These findings revealed that LDHB was an independent favorable predictor, and LDHA and LDHB correlated with tumor immune infiltrates in ccRCC patients, which indicated LDHA/LDHB could be implicated in the tumorigenesis of ccRCC and might be potential therapeutic targets for patients with ccRCC.