Abstract
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 not yet fully understood in the metastasis of PCa. Here, we discovered an exosomal lncRNA HOXD-AS1 is upregulated in castration resistant prostate cancer (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). This 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 to guide the detection and treatment of metastatic PCa.
Highlights
Prostate cancer (PCa) is the second commonly diagnosed malignancy and one of the leading cause of male cancer-related death worldwide [1]
It has been reported that cellular communication by direct contact, hormones and metabolites in the tumor microenvironment (TME) participates in cancer metastasis, the significance of cellular interaction by exosomal long noncoding RNA (lncRNA) in PCa remains elusive
We demonstrated that a exosomal lncRNA HOXD-AS1 is involved in the metastasis of PCa
Summary
Prostate cancer (PCa) is the second commonly diagnosed malignancy and one of the leading cause of male cancer-related death worldwide [1]. Despite almost all patients respond to the initial treatment, disease progression is often inevitable after 18–24 months [2]. The mechanism of PCa metastasis is not fully understood. Accumulating evidence support the theories that pre-existing castration resistant PCa cells, as well as adaptive genetic or epigenetic alteration, concomitantly contribute to the metastasis of PCa [3,4,5]. Recent studies revealed that tumor microenvironment (TME), which promotes the conversion of PCa cell phenotypes through various ways, plays important roles in the metastasis of PCa [6, 7]. The mechanism underlying how PCa cells acquire metastatic features during evolving remains elusive.
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