Roles for the Nerve Growth Factor-Farnesoid X Receptor-Retinol Dehydrogenase 16 Axis in Hepatocellular Carcinoma Prognosis and Chemosensitivity

Abstract

Nerve growth factor (NGF) has been shown to upregulate expression of retinol dehydrogenase 16 (RDH16) and farnesoid X receptor (FXR), thereby conferring hepatoprotection against cholestatic and oxidative injury. This study investigated the expression levels of NGF, RDH16, and FXR in human hepatocellular carcinoma (HCC) tissues and explored their relationships, as well as their roles in tumorigenesis and resistance to antitumor chemotherapy. Transcriptomic data set and Kaplan-Meier survival analyses revealed that HCC patients with higher NGF and RDH16 expression exhibited better survival rates. Clinically, NGF protein expression was positively correlated with RDH16 levels in human HCC tissues, whereas RDH16 showed a negative correlation with proliferating cell nuclear antigen levels. In vitro experiments demonstrated that recombinant NGF treatment modestly increased proliferation of SK-Hep1 HCC cells. However, NGF pretreatment significantly enhanced cisplatin-induced and doxorubicin-induced cytotoxicity, accompanied by preserved constitutive FXR expression under chemotherapeutic stress, suggesting an association between NGF-regulated FXR expression and enhanced chemosensitivity in HCC cells. Chromatin immunoprecipitation-qPCR analysis further confirmed that FXR directly binds to the RDH16 promoter, providing mechanistic evidence of transcriptional regulation. The correlation between higher FXR expression and improved HCC patient survival, along with the in vitro enhancement of chemosensitivity by FXR agonist GW4064, supported the tumor-suppressive role of FXR in HCC. Conversely, small interfering RNA-mediated FXR gene silencing significantly induced drug resistance and completely abolished the NGF-enhanced chemosensitivity. In conclusion, hepatic NGF expression may maintain higher FXR and RDH16 levels, thereby modulating drug metabolism machinery and survival signaling in HCC cells.

Keywords: chemosensitivity; farnesoid X receptor; hepatocellular carcinoma; nerve growth factor; retinol dehydrogenase 16.