Early studies indicated that the androgen receptor (AR) might play important roles in the regulating of the initiation and progression of hepatocellular carcinoma (HCC), but its linkage to the surrounding macrophages and their impacts on the HCC progression remain unclear. Here we found that macrophages in liver cancer might function via altering the microRNA, miR-92a-2-5p, in exosomes to decrease liver cancer cells AR expression, which might then lead to increase the liver cancer cells invasion. Mechanism dissection revealed that miR-92a-2-5p from the exosomes could target the 3′UTR of AR mRNA to suppress AR translation, altering the PHLPP/p-AKT/β-catenin signaling to increase liver cancer cells invasion. Preclinical studies demonstrated that targeting this newly identified signaling with miR-92a-2-5p inhibitors led to suppress liver cancer progression. Together, these findings suggest that macrophages in the liver cancer tumor microenvironment may function via exosomes to regulate liver cancer progression, and targeting this newly identified macrophages/exosomes-miR-92a-2-5p/AR/PHLPP/p-AKT/β-catenin signaling may help in the development of novel treatment strategies to better suppress liver cancer progression.

早期研究表明，雄激素受体（AR）可能在调节肝细胞癌（HCC）的发生和进展中发挥重要作用，但其与周围巨噬细胞的联系及其对HCC进展的影响仍不清楚。在这里，我们发现肝癌中的巨噬细胞可能通过改变外泌体中的微小RNA miR-92a-2-5p来发挥作用，降低肝癌细胞AR的表达，从而可能导致肝癌细胞侵袭增加。机制剖析表明，外泌体中的 miR-92a-2-5p 可以靶向 AR mRNA 的 3'UTR 来抑制 AR 翻译，改变 PHLPP/p-AKT/β-catenin 信号传导以增加肝癌细胞的侵袭。临床前研究表明，用 miR-92a-2-5p 抑制剂针对这一新发现的信号传导可抑制肝癌进展。总之，这些发现表明肝癌肿瘤微环境中的巨噬细胞可能通过外泌体发挥作用来调节肝癌进展，并靶向这种新发现的巨噬细胞/外泌体-miR-92a-2-5p/AR/PHLPP/p-AKT/β-连环蛋白信号传导可能有助于开发新的治疗策略，以更好地抑制肝癌进展。