Prostate cancer small extracellular vesicles participate in androgen-independent transformation of prostate cancer by transferring let-7a-5p.

Objectives: Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PCa). However, after 2-3 years ADT treatment, prostate cancer inevitably transits from androgen-dependent PCa (ADPC) to androgen-independent PCa (AIPC), which has a poor prognosis owing to its unclear mechanism and lack of effective therapeutic targets. Small extracellular vesicles (sEVs) play a vital role in the development of cancer. However, the role of PCa sEVs in the transformation of AIPC remains poorly understood. Materials and methods: Two different cell models were employed and compared. sEVs from ADPC cells (LNCaP) and AIPC cells (LNCaP-AI + F cells) were isolated and characterized. After co-culture of LNCaP-AI + F sEVs with LNCaP cells and of LNCaP sEVs with LNCaP-AI + F cells, androgen-independent transformation was determined respectively. Mechanically, small RNA sequencing was performed. Androgen-independent transformation was examined by the upregulation and downregulation of miRNA and downstream pathways were analyzed. Results: LNCaP-AI + F sEVs promoted the androgen-independent transformation of LNCaP cells. Interestingly, LNCaP sEVs exhibited a capacity to reverse the process.Let-7a-5p transfer was demonstrated. Furthermore, let-7a-5p overexpression promotes the androgen-independent transformation and let-7a-5p down-regulation reverses the process. Androgen receptor (AR) and PI3K/Akt pathways were identified and demonstrated by both let-7a-5p regulation and PCa sEVs coculture. Conclusions: PCa sEVs are intimately involved in the regulation of androgen-independent transformation of prostate cancer by transferring the key sEVs molecular let-7a-5p and then activating the AR and PI3K/Akt signaling pathways. Our results provide new perspectives for the development of sEVs and sEVs molecular targeted treatment approaches for AIPC patients.