TrkC-mediated inhibition of DJ-1 degradation is essential for direct regulation of pathogenesis of hepatocellular carcinoma

Abstract

Abstract None of the previous studies has systematically explored how upregulation of TrkC plays a central role in the pathogenesis of hepatocellular carcinoma (HCC) by regulating the underlying mechanisms that promote invasion and metastasis. In this report, we demonstrated the possible association between upregulation of TrkC and acquisition of cancer stem cells traits or chemoresistance in HCC. We show that upregulation of TrkC is closely associated with the survival and progression of HCC in vivo and in vitro. Most strikingly, activation of STAT3 by TrkC-mediated inhibition of DJ-1 degradation significantly enhances the efficacy of invasion and metastasis during the progression of HCC cells. Acquiring the traits of cancer stem cells (CSCs) by TrkC/DJ-1/STAT3 signaling pathway leads to the induction of chemoresistance via upregulation of ABC transporters and anti-apoptotic genes. Also, activating the epithelial-mesenchymal transition (EMT) program by inducing EMT-transcription factor (TF)s by TrkC/DJ-1/STAT3 signaling pathway is the direct cause of multiple tumor malignancies of HCC. Thus, understanding the mechanisms by which acquisition of anticancer drug resistance by TrkC-mediated inhibition of DJ-1 degradation can help enhance the efficacy of anticancer therapies.