Long-chain perfluoroalkyl carboxylates induce cytoskeletal abnormalities and activate epithelial-mesenchymal transition in both renal cell carcinoma 3D cultures and Caki-1 xenografted mouse model

Abstract

Exposure to perfluorooctanoate (PFOA; a type of perfluoroalkyl carboxylates [PFACs]) may be correlated with the incidence of kidney cancer in individuals exposed to high levels of PFOA. However, mechanistic studies on the influence of PFACs on renal cell carcinoma (RCC) development are lacking. We explored the effects of five types of PFACs on RCC using in vitro and in vivo models to fill this knowledge gap and provide information for environmental/usage regulations. Using 2D/3D cultures of Caki-1 cells, a human clear cell RCC line, we examined the effects of short-chain (SC) PFACs and long-chain (LC) PFACs on RCC physio/pathological markers, including the cytoskeleton, epithelial-mesenchymal transition (EMT)-related proteins, and Na⁺/K⁺-ATPase. We also administered three different PFACs orally to mice harboring Caki-1 xenografts to assess the impact of these compounds on engrafted RCC in vivo. Compared with the effects of SCPFACs, mice with Caki-1 xenografts treated with LCPFACs showed increased EMT-related protein expression and exhibited liver toxicity. Therefore, LCPFACs induced EMT, influencing cancer metastasis activity, and displayed higher toxicity in vivo compared with SCPFACs. These findings improve our understanding of the effects of PFACs on RCC development and their corresponding in vivo toxicity, which is crucial for regulating these substances to protect public health.

Keywords: Epithelial–mesenchymal transition-related protein; F-actin abnormality; Na(+)/K(+)-ATPase; Perfluoroalkyl carboxylate; Renal cell carcinoma.