MicroRNAs and epithelial-mesenchymal transition in prostate cancer

Abstract

Prostate cancer (PCa) is a leading cause of male cancer-related deaths. A significant fraction of prostate tumors are very aggressive, often metastasizing to bone, causing significant morbidity and mortality. Also, PCa is associated with high rates of recurrence, often attributed to the existence of cancer stem cells. Epithelial-mesenchymal transition (EMT), a process characterized by decreased expression of epithelial genes and increased expression of mesenchymal genes, plays a critical role in tumor invasion, metastasis and recurrence. In PCa, EMT has been implicated particularly in the context of metastatic disease and microRNAs have emerged as critical post-transcriptional regulators of PCa EMT. In this review, we summarize the role of miRNAs in PCa EMT that play a role in progression, metastasis and recurrence. Studies till date suggest that microRNAs mediate efficient and reversible control of PCa EMT via multiple mechanisms including either by (i) directly repressing single or multiple EMT-TFs or regulating cytoskeletal components (epithelial/mesenchymal genes) or (ii) regulating key signaling pathways involved in EMT. Oncogenic microRNAs often act as EMT promoters by repressing epithelial characteristics and tumor suppressive miRNAs act by inhibiting mesenchymal progression. Further, EMT is mechanistically linked to stem cell signatures in PCa and several miRNAs implicated in EMT have been reported to influence PCa stem cells. Loss of EMT-inhibiting miRNAs and/or gain of EMT promoting miRNAs lead to induction of PCa EMT, leading to tumor progression, metastasis and recurrence. Restoring expression of tumor suppressive miRNAs and inhibiting oncogenic miRNAs represent potential therapeutic opportunities to prevent disease metastasis and recurrence.

EMT: Present and future in clinical oncology

“…Additionally, in endometrial carcinosarcomas, miR‐200f expression is restricted to the carcinoma area, but absent in the sarcomatous regions (Castilla et al ., ), validating the key role of miR‐200 members in maintaining the epithelial phenotype in vivo . Moreover, a link between miRNA signatures and expression of specific EMT‐TFs has also been described in carcinosarcomas (Diaz‐Martin et al ., ) and PCa (Sekhon et al ., ). Significantly, in experimental cancer models, the upregulation of miR‐200f influences the cancer cell secretome favoring metastasis associated with the reacquisition of epithelial traits (Korpal et al ., ).…”

Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention

“…The tumor suppressor miRNAs are generally downregulated in cancer cells, including PCa cells, and promote proliferation, metastasis, and cell invasiveness. In PCa miR-143, miR-145, and members of the miR-200 family play a major role in cell migration and tumorigenesis due to the fact that their downregulation activates epithelial-mesenchymal transition (EMT) [103,104]. EMT is a process through which epithelial cells assume the features of mesenchymal stem cells, able to differentiate in a broad range of cells, thus acquiring invasive and migratory properties.…”

Association of Micro RNA (MiRNA) with Drug Resistance in Malignancies

“…A significant fraction of prostate tumors are very aggressive, often metastasizing to the bone, and causing significant morbidity and mortality. Epithelialmesenchymal transition (EMT) plays a major role, particularly in the context of metastatic disease and microRNAs have emerged as critical post-transcriptional regulators of prostate cancer EMT [31][32][33].…”