Loss of androgen receptor promotes HCC invasion and metastasis via activating circ-LNPEP/miR-532–3p/RAB9A signal under hypoxia
Xiwu Ouyang, Lei Yao, Guodong Liu, Shiqing Liu, Liansheng Gong, Yao Xiao
Abstract
Development of novel targeted therapies remains the priority in hepatocellular carcinoma (HCC) treatments. Early reports have demonstrated that androgen receptor (AR) plays a suppressive role in HCC progression. However, the underlying mechanisms by which AR attenuates HCC development are still elusive, especially under hypoxic conditions. Herein, we demonstrated that AR/circ-LNPEP/miR-532-3p/RAB9A signaling axis was tightly involved in hypoxia-induced cell invasion of HCC cells. AR worked as a transcription factor to reduce circ-LNPEP expression level, which released its sponge potential of miR-532-3p, leading to the downregulation of RAB9A and inhibiting cell invasion of HCC cells. In vitro and in vivo animal model also confirmed that overexpression of circ-LNPEP could reverse the suppressive effect of AR on HCC cell invasion or tumor metastasis. Overall, our study supplements a critical mechanism by which AR suppresses HCC invasion/metastasis under hypoxic conditions, providing compelling rationale to develop novel therapy for better treatments of HCC.