Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma

Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting Enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal Cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC.

BCKDK; clear cell renal cell carcinoma; exosome; microRNA; vascular permeability.