Regulation and signaling of SNX10, a tumor suppressor in hepatocellular carcinoma

Abstract

SNX10 is a protein belonging to the “Sorting Nexin” family, characterized by the presence of the PX phosphoinositide binding domain. SNX10 is involved in endosomal regulation and may act as a tumor suppressor in cancer, as it is underexpressed in a rat model of chemical hepatocarcinogenesis and in colon cancer. In colorectal carcinoma, SNX10 serves as a negative regulator of chaperone-mediated autophagy (CMA). However, recent studies have also indicated its pro-oncogenic properties in cancer development. In this study, we investigated the role of SNX10 in hepatocellular carcinoma (HCC), the cancer type responsible for the third highest number of cancer deaths worldwide. Our findings revealed that SNX10 expression is lower in HCC tumors than in healthy tissue in both patients and an animal model. Moreover, SNX10 expression is markedly reduced in HCC cell lines with mesenchymal traits when compared with epithelial traits cells, suggesting that decreased SNX10 expression is associated with disease progression. SNX10 negatively regulates LAMP2A and consequently CMA but positively regulates the CMA target proteins p21 and IκBα in HCC cells. It also downregulates AFP, BCL-2, and DKK1 transcription. Additionally, miR-30d and SNX10 exhibit an inverse relationship in HCC cells, with miR-30d identified as a negative regulator of SNX10 in this context. Through these mechanisms, SNX10 functions as a tumor suppressor by inhibiting proliferation, migration, invasion, and tumorigenesis of HCC.