The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals

Abstract

The androgen receptor (AR) was found to suppress hepatocellular carcinoma (HCC) metastasis at late stages. Due to this discovery, we searched for some AR enhancers to increase the efficacy of Sorafenib chemotherapy, and identified the microRNA (miR)-367-3p, whose expression is positively correlated with AR expression in advanced HCC, as an HCC metastasis suppressor. Combining miR-367-3p with Sorafenib showed better efficacy to suppress HCC cell invasion in vitro and in vivo. Mechanism dissection revealed that miR-367-3p could increase AR expression via directly targeting the 3′UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FKBP5 and PHLPP, thus dephosphorylating and inactivating AKT and ERK, to suppress the HCC cell invasion. Interestingly, the suppression of pAKT by miR-367-3p could subsequently attenuate the phosphorylation of AR and MDM2, giving rise to additional enhancement of AR protein expression, effectively forming a positive feedback loop. Together, these results suggest that miR-367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FKBP5/PHLPP/(pAKT and pERK) signals to better suppress HCC metastasis. Successful development of this newly combined chemotherapy in the future may help us to better suppress the HCC metastasis at late stages.

MicroRNA‐367‐3p overexpression represses the proliferation and invasion of cervical cancer cells through downregulation of SPAG5‐mediated Wnt/β‐catenin signalling

“…Currently, an increasing number of studies have suggested miR‐367‐3p is a critical cancer‐related miRNA that is dysregulated in a wide range of cancers . However, whether miR‐367‐3p is dysregulated in cervical cancer and, further, participates in the progression of cervical cancer remains unclear.…”

“…Currently, an increasing number of studies have suggested miR-367-3p is a critical cancer-related miRNA that is dysregulated in a wide range of cancers. [25][26][27][28] However, whether miR-367-3p is dysregulated in cervical cancer and, further, participates in the progression of cervical cancer remains unclear. The present study was aimed to investigate the expression status and biological function of miR-367-3p in cervical cancer and elucidate the potential underlying mechanism of miR-367-3p action.…”

MiR-1202 functions as a tumor suppressor in glioma cells by targeting Rab1A

“…Depending on their mRNA targets, miRNAs can act as oncogenes or tumor suppressor genes. 26,27 The changes of miRNA are involved in most aspects of cancer biology, including proliferation, apoptosis, migration, and invasion. [28][29][30] Therefore, miRNAs are usually viewed as a potential diagnostic and therapeutic tool.…”

Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks

“…Interestingly, miR‐193b has been shown to specifically sensitize HBV‐infected HCC cells to sorafenib and full‐length hepatitis C virus reportedly increases its expression . Moreover, miR‐486 and miR‐367‐3p regulate cell proliferation and invasion by targeting CITRON, Claudin10, and androgen receptor signals, thus increasing the efficacy of sorafenib . Apart from these mechanisms, few miRNAs also exploit other cellular pathways to increase sorafenib sensitivity.…”

“…64,65 Moreover, miR-486 and miR-367-3p regulate cell proliferation and invasion by targeting CITRON, Claudin10, and androgen receptor signals, thus increasing the efficacy of sorafenib. 66,67 Apart from these mechanisms, few miRNAs also exploit other cellular pathways to increase sorafenib sensitivity. MicroRNA-338-3p sensitizes HCC cells to sorafenib in vitro and in mice models possibly by directly targeting hypoxia-induced factor 1α, hence increasing cell death.…”