Expressão da MTHFD2 e CAIX em carcinoma de células renais

Abstract

Introduction: Renal cell carcinoma (RCC) is the most common neoplasm in the kidneys. Due to its asymptomatic nature, one third of cases are diagnosed in advanced stages. Although there are no prognostic markers used in diagnostic practice, carbonic anhydrase IX (CA9 for the gene and CAIX for the protein) and MTHFD2 have been identified as potential indicators of tumor progression and survival respectively. However, the role of both in RCC still needs to be clarified. This study aimed to investigate the expression of carbonic anhydrase 9 and MTHFD2 according to prognostic factors and tumor aggressiveness in RCC. Methodology: Gene expression was assessed in relation to pathological characteristics and patient survival using the KM-Plotter platform. Two databases were used with samples of tumors, non-neoplastic tissues (NN) and metastases. The protein expression of the enzymes was investigated in a RCC cohort from HC-UFTM using immunohistochemistry, establishing associations with prognosis, clinical, epidemiological and histopathological data. Results: CA9 gene expression revealed higher levels in tumour tissue and tissue with metastases than in NN tissue, with the histological subtypes Clear Cell (ccRCC) and Papillary (pRCC) showing higher levels than NN tissue. Low CA9 expression was associated with lower overall survival in ccRCC cases and higher survival in the pRCC cohort. CAIX protein labelling was positive in all cases, with greater expression in Fuhrman grade 4 and in patients undergoing radical nephrectomy. Patients with moderate CAIX expression had lower survival compared to the group with strong expression (non-significant difference). Similarly, MTHFD2 showed higher expression in tumors and metastatic samples, with distinct gene expression patterns according to histological type, compared to the NN group. High MTHFD2 expression was associated with lower overall survival for ccRCC and pRCC, and lower recurrence-free survival for pRCC. MTHFD2 protein expression varied between histological subtypes, being lower in ccRCC compared to pRCC and ccRCC. There was an association between high MTHFD2 expression, tumors larger than 7cm and high Fuhrman grades. Although not statistically significant, patients with high expression tended to have lower overall survival. Conclusions: Gene expression of both enzymes was high in RCC and in metastatic samples, showing potential prognostic value for the CCRcc and CCRp subtypes. While CAIX protein expression showed fewer associations with tumor aggressiveness parameters, the MTHFD2 pattern in immunolabelling was more relevant, suggesting tumor progression (high Fuhrman grade, larger tumors), even with variability in expression between tumor histological types. The prognostic value of both markers, by analysing immunolabelling, has not been confirmed. Therefore, investigations in larger cohorts are needed to confirm the evidence observed by the overall survival curves.