LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription

Abstract

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods : A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo . Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. Results : miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo . Conclusions : Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

“…The low level of miR-378a-3p is demonstrated in sorafenib-resistant cells. While, overexpression of this miRNA reversed sorafenib sensitivity in HCC sorafenib-resistant cells [ 241 ]. Taken together, the results suggest that downregulation of miRNA leads to overexpression of the IGF-1R gene and triggers sorafenib resistance in HCC cells.…”

Hepatic miR-378 modulates serum cholesterol levels by regulating hepatic bile acid synthesis

“…Notably, excluding the let-7 family members, miR-378 ranked the 1 st among the rest of differentially expressed miRNAs in the liver of hypothyroid mice after T3 injection, indicating that miR-378 might be crucial for the regulatory role of TH (Figure 1 A and Figure S1 A). As miR-378 has been implicated in multiple metabolic processes 25 - 29 , we then chose miR-378 for further investigation. First of all, the expression of hepatic miR-378 was examined in the liver of mice under different thyroid status.…”

UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma

“…Understanding the molecular mechanisms of sorafenib resistance may provide novel therapeutic targets and more insights for combination therapies for the management of HCC. Although multiple studies have demonstrated possible mechanisms underlying sorafenib resistance, 24 , 25 , 39 , 40 the role of metabolic reprogramming and redox homeostasis in the process of sorafenib resistance has remained unknown.…”