Exosomal Long Noncoding RNA HOXD-AS1 Promotes Prostate Cancer Metastasis via miR-361-5p/FOXM1 Axis

Abstract

Background: Development of distant metastasis is the main cause of deaths in prostate cancer (PCa) patients. Understanding the mechanism of PCa metastasis is of utmost importance to improve its prognosis. The role of exosomal long noncoding RNA (lncRNA) has been reported yet fully understood in the metastasis of PCa. Methods: Co-culture assay, in-situ hybridization and quantitative PCR (qPCR) were applied to identify the presence of HOXD-AS1 overexpressing exosomes secreted by of castration resistant prostate cancer (CRPC) cells. Migration and wound healing assays were carried out to evaluate the biological function of exosomal HOXD-AS1. Then a mouse model was used to elucidate the effect of exosomal HOXD-AS1 on distant metastasis of PCa in vivo. Further RNA immunoprecipitation and luciferase assay were applied to identify the interaction between HOXD-AS1 and miR-361-5p. Moreover, rescue experiment was conducted to prove the binding of exosomal HOXD-AS1 and miR-361-5p. Last but not least, the application of serum exosomal HOXD-AS1 as a diagnostic and prognostic biomarker for PCa was evaluated. Results: We discovered the exosomal lncRNA HOXD-AS1 is upregulated in CRPC cell line derived exosomes and serum exosomes from metastatic PCa patients, which correlated with its tissue expression. Further investigation confirmed exosomal HOXD-AS1 promotes prostate cancer cell metastasis in vitro and in vivo by inducing metastasis associated phenotype. Mechanistically exosomal HOXD-AS1 was internalized directly by PCa cells, acting as competing endogenous RNA (ceRNA) to modulate the miR-361-5p/FOXM1 axis, therefore promoting PCa metastasis. In addition, we found that serum exosomal HOXD-AS1 was upregulated in metastatic PCa patients, especially those with high volume disease. And it is correlated closely with Gleason Score, distant and nodal metastasis, Prostatic specific antigen (PSA) recurrence free survival and progression free survival (PFS). Conclusions: Our study sheds a new insight into the regulation of PCa distant metastasis by exosomal HOXD-AS1 mediated miR-361-5p/FOXM1 axis, and provided a promising liquid biopsy biomarker as well as therapeutic target to the detection and treatment of metastatic PCa.

Study on the mechanism of miR-361-5p regulation of androgen receptor in castration-resistant transformation of prostate cancer

“…However, when the expression of miR-361-5p was arti cially increased, this malignant effect could be effectively eliminated, demonstrating the potential value of miR-361-5p in prostate cancer therapy. Gu P et al [20,21] demonstrated that lncRNA HOXD-AS1 was highly expressed in CRPC cells, and in vivo and ex vivo experiments veri ed that knockdown of HOXD-AS1 inhibited the proliferation and chemoresistance of CRPC cells. miR-361-5p, one of the most highly enriched mircoRNAs in PCa, showed a negative correlation between its expression level and that of the exosomal HOXD-AS1 (R = -0.21, P < 0.01), HOXD-AS1 was cells, HOXD-AS1 was directly internalized by PCa cells and acted as a competitive endogenous RNA (ceRNA) sponge adsorbed by miR-361-5p to upregulate the expression of FOXM1, which promoted distant metastasis in PCa cells.…”