The miR‐1908/SRM regulatory axis contributes to extracellular vesicle secretion in prostate cancer

Abstract

Targeting extracellular vesicle (EV) secretion can have potential clinical implications for cancer therapy, however the precise regulatory mechanisms of EV secretion are not fully understood. Recently, we have shown a novel pathway of EV biogenesis in PCa cell lines, PC3 and PC3M. However, as the characteristics of EVs are divergent even among PCa cell lines, we hypothesized that other pathways or common regulatory pathways of EV biogenesis still exist. Here, we performed quantitative high‐throughput screening to determine the key regulatory genes involved in EV biogenesis in 22Rv1 cells, which secrete a different type of EVs. In total, 1728 miRNAs were screened and miR‐1908 was selected as the potential miRNA regulating EV biogenesis in 22Rv1 cells. Subsequently, we investigated target genes of miR‐1908 using siRNA screening and identified that spermidine synthase (SRM) was the key regulator of EV secretion in 22Rv1 cells. Attenuation of SRM expression significantly inhibited secretion of EVs in 22Rv1 cells, and overexpression of SRM was confirmed in PCa tissues. Furthermore, we found that the number of endosome compartments was increased in cellular cytoplasm after knockdown of the SRM gene. In conclusion, our results showed that miR‐1908‐mediated regulation of SRM can control secretion of EVs in PCa. In addition, these data suggested that the EV secretion pathway was dependent on cellular characteristics.

miR-1908 Dysregulation in Human Cancers

“…miR-1908 also exhibits abnormal expression in a variety of pathological tissues and cells. In pathological tissues or disease cell lines, the abnormally high expression of miR-1908 is associated with glioma ( 8 , 13 ), osteosarcoma ( 9 , 12 ), breast cancer ( 37 ), prostate cancer ( 29 ), and hepatitis ( 25 ). However, the abnormally low expression of miR-1908 is also associated with a variety of diseases, including NSCLC ( 22 , 23 ), cervical cancer ( 26 ), high-grade serous ovarian cancer ( 28 ), chordoma ( 6 ), melanoma ( 36 ), acute myocardial infarction (AMI) ( 1 ), and renal fibrosis ( 7 ).…”

“…SRM can promote EV secretion in 22Rv1 cells, thereby regulating the cancer microenvironment and promoting cancer progression. miR-1908-5p can target SRM to regulate EV secretion and inhibit the pathogenesis of PCa ( 29 ). Exosomes are a type of EV, a new type of mediator for tumorigenesis and immune escape.…”

“…miR-1908-5p targets HDAC10 to promote the growth, invasion, and metastasis of cervical cancer cells (Ca-Ski, SiHa, and C-4I) ( 26 ). miR-1908-5p can target SRM to regulate extracellular vesicle (EV) secretion ( 29 ), thereby promoting PCa cancer progression ( 54 ). miR-1908-5p targets TGF-β1 and JunD in the MAPK pathway to promote the proliferation of chordoma tissue ( 6 ).…”

Urinary extracellular vesicles: a rising star in bladder cancer management

“…To overcome this dilemma, the mechanism of cancer-specific EV secretion should be investigated. Recently, we established a screening assay to comprehensively screen the regulator genes of EV secretion, which can be carried out in a short period of time and can be applied to all kinds of cancer (97,98). This highthroughput screening method can contribute to revealing the mechanism involved in EV secretion and contribute to the establishment of EV-based therapy targeting EV secretion.…”

Extracellular vesicles in urological malignancies

“…Using a combination of urinary EV mRNA levels of Erythroblast transformation-specific related gene (ERG), prostate cancer antigen 3 (PCA3) and PSA with patient characteristics including age, race and family history improved the diagnostic accuracy from AUC 0.6723 to 0.803 159 highlighting the applicability of ERG, PCA3 and PSA as diagnostic biomarkers [ 160 ]. In addition to the biomarker potential of microRNAs, miR-1908 interaction with spermidine synthase (SRM) was found to regulate EV release in prostate cancer cells, confirmed by reduced secretion following SRM knockdown [ 161 ].…”