Abstract
Prostate cancer is the most commonly diagnosed cancer in men with African American men disproportionally suffering from the burden of this disease. Biomarkers that could discriminate indolent from aggressive and drug resistance disease are lacking. MicroRNAs are small non-coding RNAs that affect numerous physiological and pathological processes, including cancer development and have been suggested as biomarkers and therapeutic targets. In the present study, we investigated the role of miR-214 on prostate cancer cell survival/migration/invasion, cell cycle regulation, and apoptosis. miR-214 was differentially expressed between Caucasian and African American prostate cancer cells. Importantly, miR-214 overexpression in prostate cancer cells induced apoptosis, inhibiting cell proliferation and colony forming ability. miR-214 expression in prostate cancer cells also inhibited cell migration and 3D spheroid invasion. Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. Our data indicates that miR-214 could act as a tumor suppressor in prostate cancer and could potentially be utilized as a biomarker and therapeutic target.
Highlights
Prostate cancer (PCa) is the most common form of cancer and the second leading cause of cancer-related deaths among men in the US, with an estimated 1.3 million cases and 359,000 deaths reported between 2017 and 20181,2
To explore the potential role of miR-214 in the PCa progression, RWPE-2, PC3, DU145, MDA-PCa-2b, and LNCaP cells were transiently transfected with miR-214 or Negative Control (NC) mimics, and the expression levels of miR-214 were measured by RT/qPCR
The results of a cell proliferation/viability assay 48 h post-transfection revealed that miR-214 overexpression dramatically suppressed the proliferation and viability of PC3, DU145, and MDA-PCa-2b cells compared with the NC mimic group, while proliferation was significantly increased in the LNCaP and RWPE-2 cells (Fig. 1C)
Summary
Prostate cancer (PCa) is the most common form of cancer and the second leading cause of cancer-related deaths among men in the US, with an estimated 1.3 million cases and 359,000 deaths reported between 2017 and 20181,2. Altered miRNA expression plays a significant role in diverse cancers, including PCa, and may critically affect its modulation/progression[4,7,8] MiR-214 overexpression induces both oncogenic activity by targeting the PTEN-PI3K/AKT signaling pathway[29] and tumor suppressor activity by regulating the RFWD2-p53 cascade[30], inhibiting cell proliferation and migration, and promoting apoptosis[31]. Protein tyrosine kinase 6 (PTK6), called breast tumor kinase (BRK/PTK6), is a non-receptor intracellular tyrosine kinase that is expressed in various normal epithelia, including the linings of the gastrointestinal tract, skin, oral cavity, and prostate In these regions, PTK6 expression is anti-oncogenic in signaling pathways that control cell survival, cell cycle, and differentiation[32,33,34]. Activation of membranous PTK6 promotes epithelial-mesenchymal transition (EMT) by activating AKT41
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