Abstract
Simple SummaryProstate Cancer is the second leading cause of cancer-related deaths in the United States. In this study, we analyzed a molecule known as a microRNA, which regulates the expression of genes. microRNAs are involved in processes related to cancer onset and progression. Abnormal expression of microRNAs can promote prostate cancer. This study showed that knockdown of microRNA miR-214-3p enhanced the progression and of prostate cancer. In addition, miR-214 regulated the expression of many genes. These results are useful to better understand the function of miR-214-3p in prostate cancer and can be a useful target in the treatment of the disease.Abnormal expression of microRNA miR-214-3p (miR-214) is associated with multiple cancers. In this study, we assessed the effects of CRISPR/Cas9 mediated miR-214 depletion in prostate cancer (PCa) cells and the underlying mechanisms. Knockdown of miR-214 promoted PCa cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and increased resistance to anoikis, a key feature of PCa cells that undergo metastasis. The reintroduction of miR-214 in miR-214 knockdown cells reversed these effects and significantly suppressed cell proliferation, migration, and invasion. These in vitro studies are consistent with the role of miR-214 as a tumor suppressor. Moreover, miR-214 knockout increased tumor growth in PCa xenografts in nude mice supporting its anti-oncogenic role in PCa. Knockdown of miR-214 increased the expression of its target protein, Protein Tyrosine Kinase 6 (PTK6), a kinase shown to promote oncogenic signaling and tumorigenesis in PCa. In addition, miR-214 modulated EMT as exhibited by differential regulation of E-Cadherin, N-Cadherin, and Vimentin both in vitro and in vivo. RNA-seq analysis of miR-214 knockdown cells revealed altered gene expression related to PCa tumor growth pathways, including EMT and metastasis. Collectively, our findings reveal that miR-214 is a key regulator of PCa oncogenesis and is a potential novel therapeutic target for the treatment of the disease.
Highlights
Prostate cancer (PCa) is the most common cancer affecting men in the United States (U.S.) and is a second leading cause of cancer-related mortality in males [1]
After CRISPR/Cas9 targeting of miR-214 genomic sequences was performed in PC3 and MDA-prostate cancer (PCa)-2b cells, expression of miR-214 in the resulting miR-214KO cells was assessed by quantitative RT-PCR (qRT-PCR)
Protein Tyrosine Kinase 6 (PTK6) transcript levels were considerably increased in PC3 D2 clonal miR-214KO cells and MDA-PCa-2b miR-214KO cells, consistent with decreased activity of miR-214 in these cells (Figure 1D)
Summary
Prostate cancer (PCa) is the most common cancer affecting men in the United States (U.S.) and is a second leading cause of cancer-related mortality in males [1]. According to the Surveillance, Epidemiology, and End Results (SEER) database, the 5-year survival rate for men diagnosed with prostate cancer in the U.S is approximately 98% for localized PCa and 31% for metastatic PCa [2]. Since PCa tumor growth is primarily driven by androgen receptor (AR) signaling, treatments include the use of drugs that decrease androgen synthesis or block binding of androgens to AR, called androgen deprivation therapy (ADT) [3,4]. These interventions typically show initial success, but virtually all patients eventually relapse with a more aggressive form of prostate cancer called castration-resistant prostate cancer (CRPC). There is an urgent need to further understand molecular mechanisms underlying prostate cancer progression and metastasis and to identify novel therapies targeted to metastatic disease
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