Loss of androgen receptor promotes HCC invasion and metastasis via activating circ-LNPEP/miR-532-3p/RAB9A signal under hypoxia.

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.