关键词: 肾透明细胞癌, PDK1, PTEN, 分子机制, 预后

Abstract:

Background and purpose: The aberrant activation of pyruvate dehydrogenase kinase 1 (PDK1) drives tumor microenvironment remodeling and metastasis through mediating the Warburg effect. As a critical tumor-suppressive phosphatase, phosphatase and tensin homolog deleted on chromoseme ten (PTEN) activates PDK1 via loss of expression to induce aerobic glycolysis and accelerate tumor progression. The molecular interplay between PDK1 and PTEN in kidney renal clear cell carcinoma (KIRC) urgently requires systematic elucidation. This study aimed to clarify how PTEN regulates PDK1 to inhibit malignant phenotypes in KIRC. Methods: Bioinformatics analysis was conducted to compare PTEN and PDK1 expression levels as well as their prognostic correlations in the Cancer Genome Atlas (TCGA)-KIRC datasets. KIRC cell models was established by either silencing PDK1 or enhancing its expression, subsequently evaluating their malignancy characteristics through cell counting kit-8 (CCK-8) proliferation, colony formation, cell migration, and invasion assays. To validate the regulatory interactions, we used PDK1-overexpressing cells treated with a PTEN-specific inhibitor. Western blot was used to dectect the protein expression. Results: The TCGA-KIRC analysis found significantly higher mRNA levels of PTEN and PDK1 in tumor tissues compared to normal controls (P<0.05), yet this high expression was associated with improved overall survival (P<0.01). Besides, a strong positive correlation was observed between PTEN and PDK1 expressions (r=0.52, P<0.001). Functional assays demonstrated that PDK1 knockdown markedly promoted cell proliferation, migration, and invasion, whereas PDK1 overexpression exhibited opposing effects. Mechanistically, inhibiting PTEN worsened malignant behaviors (P<0.01), however, these effects were reversed by overexpressing PDK1. Conclusion: This study presents the first evidence of the dual tumor-suppressive function of the PTEN-PDK1 biological axis in renal cancer, which supports the development of precision treatment strategies based on novel targets.

Key words: Clear cell renal cell carcinoma, PDK1, PTEN, Molecular mechanisms, Prognosis