Osteoblast-derived exosomal miR-140-3p targets ACER2 and increases the progression of prostate cancer via the AKT/mTOR pathway-mediated inhibition of autophagy.

Advanced prostate cancer (aPCa) often results in bone metastases (BM). However, the mechanism underlying its progression and metastasis to bones remains unclear. Therefore, we examined whether exosomal miR-140-3p affects prostate cancer (PCa) progression. We obtained from cell lines, clinical data analyses, and animal models consistently provide important evidence. Patients with PCa having BM had higher miR-140-3p expression in their serum exosomes than those without BM. Clinical investigations have manifested that the exosomal miR-140-3p overexpression connects with serum prostate-specific antigen (PSA) levels and Gleason grade in patients with PCa. Osteoblast-derived exosomal miR-140-3p targeting ACER2 activates the AKT/mTOR pathway in vitro, inhibits autophagy, and promotes PCa cell proliferation, invasion, and migration. miR-140-3p significantly increased tumorigenesis and metastasis of LNCaP in vitro. Bone metastatic PCa tissues exhibited elevated levels of miR-140-3p, p-GSK3, p-mTOR, p62, p-AKT (S473), and p-AKT (T308) contrasted with non-BM tissues. Moreover, their expression was intensified in the metastatic bone tissues. However, ACER2 and LC3 II showed opposite expression patterns. Based on our study outcomes, the evidence suggests that osteoblast-derived miR-140-3p inhibition of autophagy through the AKT/mTOR pathway is involved in PCa progression. Osteoblast-secreted exosomal miR-140-3p activates the AKT/mTOR pathway by targeting ACER2, inhibiting autophagy, and promoting the progression of PCa cells in vitro. Moreover, miR-140-3p induces the progression and metastasis of PCa in vivo.