ABSTRACT
Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC. SIGNIFICANCE: Intracellular SPARC boosts cholesterol availability to fuel invasion and drug resistance in hepatocellular carcinoma, providing a rational approach to improve the treatment of advanced liver cancer.
Subject(s)
Apolipoproteins E , Carcinoma, Hepatocellular , Cholesterol , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Liver Neoplasms , Neoplasm Invasiveness , Osteonectin , Sorafenib , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Osteonectin/metabolism , Osteonectin/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Humans , Sorafenib/pharmacology , Cholesterol/metabolism , Animals , Mice , Apolipoproteins E/metabolism , Apolipoproteins E/genetics , Epithelial-Mesenchymal Transition/drug effects , Cell Line, Tumor , Mice, Nude , Male , Xenograft Model Antitumor Assays , Antineoplastic Agents/pharmacology , Signal Transduction/drug effectsABSTRACT
Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury (AKI). However, the potential function of MSCs in chronic kidney disease remains elusive. Renal fibrosis is the common endpoint of chronic progressive kidney diseases and causes a considerable health burden worldwide. In this study, the protective effects of bone marrow mesenchymal stem cells (BM-MSCs) were assessed in repeated administration of low-dose cisplatin-induced renal fibrosis mouse model in vivo as well as a TGF-ß1-induced fibrotic model in vitro. Differentially expressed miRNAs in mouse renal tubular epithelial cells (mRTECs) regulated by BM-MSCs were screened by high-throughput sequencing. We found microRNA (miR)-146a-5p was the most significant up-regulated miRNA in mRTECs. In addition, the gene Tfdp2 was identified as one target gene of miR-146a-5p by bioinformatics analysis. The expression of Tfdp2 in the treatment of BM-MSCs on cisplatin-induced renal injury was evaluated by immunohistochemistry analysis. Our results indicate that BM-MSC attenuates cisplatin-induced renal fibrosis by regulating the miR-146a-5p/Tfdp2 axis in mRTECs.
