miR-145-5p Mimic Inhibits Bone Metastasis of Prostate Cancer Via the Regulation of Epithelial Mesenchymal Transition

Abstract Background: The bone is the most common site of distant metastasis in prostate cancer. However, treatments for the bone metastasis of prostate cancer remain unsatisfactory. MicroRNAs (miRNAs) are small noncoding RNAs that play a variety of critical roles in tumor development and progression. Studies have confirmed that miRNA mimics could regulate the response to therapy in many cancers. Methods: In this study, a set of forty-four miRNAs were reduced in prostate cancer patients with bone metastases by high-throughput sequencing analysis. Wound healing, transwell assays and western blotting analysis were used to explore the role of miRNA mimic in prostate cancer bone metastasis. Results: Further gene ontology and pathway analysis showed that these miRNAs target genes are mainly involved in cellular metabolic process, intracellular membrane-bounded organelle, as well as proteoglycans in cancer and focal adhesion. Therefore, these down-regulated miRNAs may play a key role for prostate cancer bone metastasis treatment, including hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-133a-3p, hsa-miR-222-5p, hsa-miR-204-3p, hsa-miR-145-5p, hsa-miR-3681-5p, hsa-miR-184, hsa-miR-144-3p, hsa-miR-204-5p, and hsa-miR-221-5p. To further investigate the role of these miRNA mimics on prostate cancer bone metastasis, miR-145-5p was randomly selected for validation. Bioinformatics analysis showed that miR-145-5p target genes significantly affected TGF-beta and adherens junction signaling pathway. Wound healing and transwell assays and western blotting analysis revealed that miR-145-5p mimic inhibited proliferation, migration and invasion. Importantly, miR-145-5p mimic increased the expression of E-cadherin and reduced the expression of matrix metalloproteinase 2 and 9. These results revealed that miR-145-5p mimic mediated epithelial mesenchymal transition. Meanwhile, miR-145-5p mimic enhanced the level of caspase 9, which is an important promoter of apoptosis. Conclusions: These results indicate that miR-145-5p mimic could inhibit the progress of prostate cancer bone metastasis via regulation of epithelial mesenchymal transition. In addition, miR-145-5p mimic could induce the apoptosis of prostate cancer cells with bone metastases. In summary, the miR-145-5p mimic is expected to become a novel strategy for the treatment of tumor metastasis.

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Magnesium Chloride is an Effective Therapeutic Agent for Prostate Cancer

Functional Foods in Health and Disease ◽

10.31989/ffhd.v8i1.368 ◽

2018 ◽

Vol 8 (1) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Julianna Maria Santos ◽

Fazle Hussain

Keyword(s):

Prostate Cancer ◽

Magnesium Chloride ◽

Epithelial Mesenchymal Transition ◽

Chromatin Condensation ◽

Myosin Ii ◽

In Vivo Studies ◽

Migration Speed ◽

Mesenchymal Transition

Background: Reduced levels of magnesium can cause several diseases and increase cancer risk. Motivated by magnesium chloride’s (MgCl2) non-toxicity, physiological importance, and beneficial clinical applications, we studied its action mechanism and possible mechanical, molecular, and physiological effects in prostate cancer with different metastatic potentials.Methods: We examined the effects of MgCl2, after 24 and 48 hours, on apoptosis, cell migration, expression of epithelial mesenchymal transition (EMT) markers, and V-H+-ATPase, myosin II (NMII) and the transcription factor NF Kappa B (NFkB) expressions.Results: MgCl2 induces apoptosis, and significantly decreases migration speed in cancer cells with different metastatic potentials. MgCl2 reduces the expression of V-H+-ATPase and myosin II that facilitates invasion and metastasis, suppresses the expression of vimentin and increases expression of E-cadherin, suggesting a role of MgCl2 in reversing the EMT. MgCl2 also significantly increases the chromatin condensation and decreases NFkB expression.Conclusions: These results suggest a promising preventive and therapeutic role of MgCl2 for prostate cancer. Further studies should explore extending MgCl2 therapy to in vivo studies and other cancer types.Keywords: Magnesium chloride, prostate cancer, migration speed, V-H+-ATPase, and EMT.

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Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽

10.1038/s41388-021-01887-2 ◽

2021 ◽

Author(s):

Kaisa-Mari Launonen ◽

Ville Paakinaho ◽

Gianluca Sigismondo ◽

Marjo Malinen ◽

Reijo Sironen ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Protein A ◽

Chorioallantoic Membrane ◽

Chromatin Accessibility ◽

Castration Resistant Prostate Cancer ◽

Novel Therapy ◽

Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

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Correction to: Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129-5p in epithelial–mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2

Cancer Cell International ◽

10.1186/s12935-021-01945-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhenming Jiang ◽

Yuxi Zhang ◽

Xi Chen ◽

Pingeng Wu ◽

Dong Chen

Keyword(s):

Prostate Cancer ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Inhibitory Role

An amendment to this paper has been published and can be accessed via the original article.

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Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽

10.3390/cancers13112795 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2795

Author(s):

Sofia Papanikolaou ◽

Aikaterini Vourda ◽

Spyros Syggelos ◽

Kostis Gyftopoulos

Keyword(s):

Prostate Cancer ◽

Cancer Therapy ◽

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Therapy Resistance ◽

Cellular Process ◽

Cell Plasticity ◽

Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

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The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis

Cancers ◽

10.3390/cancers11040434 ◽

2019 ◽

Vol 11 (4) ◽

pp. 434 ◽

Cited By ~ 22

Author(s):

Wenjuan Mei ◽

Xiaozeng Lin ◽

Anil Kapoor ◽

Yan Gu ◽

Kuncheng Zhao ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Current Evidence ◽

Target Cells ◽

Mesenchymal Transition ◽

Prostate Cancer Stem Cells

Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial–mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types.

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Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129-5p in epithelial–mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2

Cancer Cell International ◽

10.1186/s12935-019-0977-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Zhenming Jiang ◽

Yuxi Zhang ◽

Xi Chen ◽

Pingeng Wu ◽

Dong Chen

Keyword(s):

Prostate Cancer ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Common Disease ◽

Vascular Endothelial ◽

Mesenchymal Transition ◽

Du145 Cells ◽

Endothelial Growth Factor ◽

E Cadherin

Abstract Background Prostate cancer (PCa) is a common disease that often occurs among older men and a frequent cause of malignancy associated death in this group. microRNA (miR)-129-5p has been identified as an essential regulator with a significant role in the prognosis of PC. Therefore, this study aimed to investigate roles of miR-129-5p in PCa. Methods Microarray analysis was conducted to identify PCa-related genes. The expression of miR-129-5p and ZIC2 in PCa tissues was investigated. To understand the role of miR-129-5p and ZIC2 in PCa, DU145 cells were transfected with mimic or inhibitor of miR-129-5p, or si-ZIC2 and the expression of Wnt, β-catenin, E-cadherin, vimentin, N-cadherin, vascular endothelial growth factor (VEGF), and CD31, as well as the extent of β-catenin phosphorylation was determined. In addition, cell proliferation, migration, invasion, angiogenesis, apoptosis and tumorigenesis were detected. Results miR-129-5p was poorly expressed and ZIC2 was highly expressed in PCa tissues. Down-regulation of ZIC2 or overexpression of miR-129-5p reduced the expression of ZIC2, Wnt, β-catenin, N-cadherin, vimentin, and β-catenin phosphorylation but increased the expression of E-cadherin. Importantly, miR-129-5p overexpression significantly reduced cell migration, invasion, angiogenesis and tumorigenesis while increasing cell apoptosis. Conclusions The findings of the present study indicated that overexpression of miR-129-5p or silencing of ZIC2 could inhibit epithelial–mesenchymal transition (EMT) and angiogenesis in PCa through blockage of the Wnt/β-catenin signaling pathway.

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Role of androgens and the androgen receptor in epithelial‐mesenchymal transition and invasion of prostate cancer cells

The FASEB Journal ◽

10.1096/fj.09-136994 ◽

2009 ◽

Vol 24 (3) ◽

pp. 769-777 ◽

Cited By ~ 131

Author(s):

Meng‐Lei Zhu ◽

Natasha Kyprianou

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Prostate Cancer Cells ◽

Mesenchymal Transition

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Wnt and β-Catenin Signaling in the Bone Metastasis of Prostate Cancer

Life ◽

10.3390/life11101099 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1099

Author(s):

Zachary Kaplan ◽

Steven P. Zielske ◽

Kristina G. Ibrahim ◽

Frank C. Cackowski

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Blood Stream ◽

Primary Tumor Site ◽

Mesenchymal Transition ◽

Protein Ligands ◽

Wnt Ligands ◽

Canonical Pathways

Wnt family proteins and β-catenin are critical for the regulation of many developmental and oncogenic processes. Wnts are secreted protein ligands which signal using a canonical pathway, and involve the transcriptional co-activator β-catenin or non-canonical pathways that are independent of β-catenin. Bone metastasis is unfortunately a common occurrence in prostate cancer and can be conceptualized as a series of related steps or processes, most of which are regulated by Wnt ligands and/or β-catenin. At the primary tumor site, cancer cells often take on mesenchymal properties, termed epithelial mesenchymal transition (EMT), which are regulated in part by the Wnt receptor FZD4. Then, Wnt signaling, especially Wnt5A, is of importance as the cells circulate in the blood stream. Upon arriving in the bones, cancer cells migrate and take on stem-like or tumorigenic properties, as aided through Wnt or β-catenin signaling involving CHD11, CD24, and Wnt5A. Additionally, cancer cells can become dormant and evade therapy, in part due to regulation by Wnt5A. In the bones, E-selectin can aid in the reversal of EMT, a process termed mesenchymal epithelial transition (MET), as a part of metastatic tumorigenesis. Once bone tumors are established, Wnt/β-catenin signaling is involved in the suppression of osteoblast function largely through DKK1.

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Potential clinical use of miRNA molecules in the diagnosis of prostate cancer

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0015.0030 ◽

2021 ◽

Vol 75 ◽

pp. 491-501

Author(s):

Paweł Porzycki

Keyword(s):

Prostate Cancer ◽

Gene Expression Regulation ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Process ◽

Specific Antigen ◽

Digital Rectal Examination ◽

Diagnostic Tools ◽

Transcriptional Level ◽

Mesenchymal Transition

Prostate cancer (PCa) is the most common type of cancer among men in Europe and this applies to almost the whole world. Current recommendations for screening and diagnosis are based on prostate specific antigen (PSA) measurements and the digital rectal examination (DRE). Both of them trigger the prostate biopsy. Limited specificity of the PSA test brings, however, a need to develop new and better diagnostic tools. In the last few years, new approaches for providing significantly better biomarkers, an alternative to PSA, have been introduced. Modern biomarkers show improvement not only as a diagnostic procedure, but also for staging, evaluating aggressiveness and managing the therapeutic process. The most promising group are molecular markers; among them microRNAs (miRNAs, miRs) are most frequent. miRNAs represent a class of about 22 nucleotides long, small non-coding RNAs, which are involved in gene expression regulation at the post-transcriptional level. This article reports a revision about the role of miRNAs in PCa including data of Adreno Receptor (AR) signaling, cell cycle, epithelial mesenchymal transition (EMT) process, cancer stem cells (CSCs) regulation and even the role of miRNAs as PCa therapeutic tool. Finding better PCa biomarkers, replacing the current PSA measurement, is firmly needed in modern oncology practice.

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