scholarly journals The tumor suppressor miR-642a-5p targets Wilms Tumor 1 gene and cell-cycle progression in prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dianne J. Beveridge ◽  
Kirsty L. Richardson ◽  
Michael R. Epis ◽  
Rikki A. M. Brown ◽  
Lisa M. Stuart ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Wilms Tumor ◽  
Tumor Model ◽  
Negative Control ◽  
Wilms Tumor 1

AbstractRNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.

scholarly journals Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1384 ◽  
Author(s):  
Shang-Tse Ho ◽  
Chi-Chen Lin ◽  
Yu-Tang Tung ◽  
Jyh-Horng Wu
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Lung Adenocarcinoma ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Microtubule Dynamics ◽  
Cycle Progression ◽  
Human Lung Adenocarcinoma

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G2/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics.

scholarly journals Cyclin D3-CDK6 Complex Facilitates Tumorigenesis by Regulating the C-Myc/miR-15a/16 Axis in a Feedback Loop in Gastric Cancer

2020 ◽  
Author(s):  
Yeting Hong ◽  
Wei He ◽  
Jianbin Zhang ◽  
Lu Shen ◽  
Chong Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Feedback Loop ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cyclin D3 ◽  
Luciferase Reporter

Abstract Background: Cyclin D3-CDK6 complex is a component of the core cell cycle machinery that regulates cell proliferation. By using Human Protein Atlas database, a higher expression level of this complex was found in gastric cancer. However, the function of this complex in gastric cancer remain poorly understood. This study aims to determine the expression pattern of this complex in gastric cancer and to investigate its biological role during tumorigenesis.Methods: To demonstrate that Cyclin D3-CDK6 regulate the c-Myc/miR-15a/16 axis in a feedback loop in gastric cancer, a series of methods were conducted both in vitro and in vivo experiments, including qRT-PCR, western blot analysis, EdU assay, flow cytometry, luciferase reporter assay and immunohistochemical staining. SPSS and Graphpad prism software were used for data analysis.Results: In this study, we found that Cyclin D3 and CDK6 were significantly upregulated in gastric cancer and correlated with poorer overall survival. Further study proved that this complex significantly promoted cell proliferation and cell cycle progression in vitro and accelerated xenografted tumor growth in vivo. Furthermore, we explored the molecular mechanisms through which the complex mediated Rb phosphorylation and then promoted c-Myc expression in vitro, we also found c-Myc could suppress miR-15a/16 expression in gastric cancer cell. Finally, we found that miR-15a/16 can simultaneously regulate Cyclin D3 and CDK6 expression as direct target genes.Conclusions: Our findings uncover the Cyclin D3-CDK6/c-Myc/miR-15a/16 feedback loop axis as a pivotal role in the regulation of gastric cancer tumorigenesis, and this regulating axis may provide a potential therapeutic target for gastric cancer treatment.

scholarly journals TRIM59 is Suppressed by Androgen Receptor and Acts to Promote Lineage Plasticity and Neuroendocrine Differentiation in Prostate Cancer

2021 ◽  
Author(s):  
Liancheng Fan ◽  
Yiming Gong ◽  
Yuman He ◽  
Wei-Qiang Gao ◽  
Baijun Dong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Neuroendocrine Differentiation ◽  
Tumor Model ◽  
Strongly Correlated ◽  
Neuroendocrine Prostate Cancer ◽  
In Vitro Effects

Abstract Background: The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of second-generation androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Methods: TRIM59 expression was evaluated in PCa samples from patients at first diagnosis or at relapse stage post ARPI treatment by immunohistochemistry; in vitro effects of TRIM59 were determined by cell proliferation, sphere formation and cell migration assays; while in vivo analysis was performed using subcutaneous tumor model. Western blot, qPCR assay, dual luciferase assessment, chromatin immunoprecipitation and RNA sequencing were applied for mechanistic exploration.Results: Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Conclusion: Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.

scholarly journals Wilms’ Tumor 1-Associating Protein Promotes Prostate Cancer Proliferation via Upregulation of CDK4 Transcript

2020 ◽  
Author(s):  
Lei Zhang ◽  
Yiren Gao ◽  
Jun Wang ◽  
Linghui Liang ◽  
Yifei Cheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Wilms Tumor ◽  
Cancer Cell Lines ◽  
Prostate Cancer Cell Lines ◽  
Wilms Tumor 1 ◽  
Cancer Tissues

Abstract Background: Wilms’ tumor 1-associating protein (WTAP) plays an important role in cell physiological function and have attracted increased interest in cancer research recently. Cyclin-dependent protein kinases (CDKs) are known to participate in regulating the cell cycle and often connected to many malignancies in tumor. We aim to explore whether WTAP or CDKs could play an role in the initiation and progression of prostate cancer(PCa) and hope to provide new insights into PCa treatment and prognostic. Methods: Quantitative real-time PCR, western blotting and immunohistochemistry were performed to explore the expression of WTAP and CDK4 in prostate cancer tissues and cell lines. The survival analysis was used to investigate the association between WTAP expression and the clinical outcomes of prostate cancer. Prostate cancer cell lines were stably transfected with lentivirus approach. CCK-8 assay, colony formation assay, cell invasion and migration assay, cell cycle assay and tumorigenesis in nude mice were performed to study the effect of WTAP in prostate cancer cell lines. RNA immunoprecipitation assay, dual-luciferase reporter assay and siRNA transfection were performed to verify the direct binding sites of WTAP with CDK4 transcript.Results: In prostate cancer tissues and cell lines, WTAP was significantly up-regulated and high expression of WTAP was connected to poor clinical outcomes. Additionally, cell function test indicated that overexpression of WTAP in prostate cancer cell lines could promote cell proliferation, while knocking down showed an opposite results. Subcutaneous xenograft tumor model revealed that overexpression of WTAP could induce tumorigenesis in vivo. Mechanism study showed that CDK4 expression could regulate the expression level of WTAP. Moreover, WTAP could directly bind to 3’-UTR of CDK4 transcript and enhance its stability. Furthermore, specific inhibitors of CDK4 as well as small interfering RNA (siRNA) of CDK4 reversed the promotion of proliferation induced by WTAP.Conclusions: These data indicated that WTAP may act as an oncogenic in prostate cancer by directly binding to CDK4 3’-UTR and stabilizing its transcript which might provide new insights into prostate cancer treatment and prognostic.

scholarly journals Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1

2019 ◽  
Vol 116 (19) ◽  
pp. 9423-9432 ◽  
Author(s):  
Wantae Kim ◽  
Yong Suk Cho ◽  
Xiaohui Wang ◽  
Ogyi Park ◽  
Xueyan Ma ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mitotic Cell ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Large Tumor ◽  
Cycle Progression ◽  
Signaling Regulation

The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)Cdh1 E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in Drosophila eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/CCdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.

scholarly journals FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
Maomao Guo ◽  
Weiwan Wang ◽  
Weican Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers. Methods We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity. Results FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion. Conclusions Our findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

scholarly journals Evaluation of Terpenes Psiadin, Plectranthone, and Saudinolide as Selective Anti-Cancer Agents against Hepatic Carcinoma Cells

2020 ◽  
Author(s):  
Khaled Y. Orabi ◽  
Mohamed S. Abaza ◽  
Rajaa Al-Attiyah ◽  
Yunus A. Luqmani
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Isolation And Purification

: Plant-derived terpenes have aroused considerable interest as chemotherapeutic agents for a variety of diseases. This study aimed at the isolation and purification of the scarce terpenes psiadin, plectranthone and saudinolide from their respective plants, followed by the determination of antiproliferative activity, against hepatic cancer cell lines (HepG2, Hep3B), and the potential molecular mechanisms. Time- and dose-dependent cytotoxicity, evaluated using MTT and colony-forming assays, were exhibited by psiadin and plectranthone against the cancer cells. Flow cytometry showed that these two terpenes blocked cell cycle progression and induced mitochondrial-mediated apoptosis, particularly through increased cytochrome c and disruption of mitochondrial membrane potential. Additionally, they initiated the generation of reactive oxygen species as well as inhibiting NF-B. Psiadin lowered several essential cyclins and cyclin-dependent kinases and reduced RB activation. It was concluded that psiadin, in particular, has a significant therapeutic potential with the biggest advantage of differentiating between cancer and normal cells which is acutely lacking in current cytotoxic drugs. Its precise mode of action needs further investigation but appears predominantly to cause cell cycle arrest by interfering with cyclin production. It will be important to determine, in future studies, whether these terpenes will similarly inhibit other cancer cell lines and retain its activity against tumors in vivo.

scholarly journals FOXM1  modulates docetaxel resistance in prostate cancer by regulating KIF20A

2020 ◽  
Author(s):  
Hongbo Yu ◽  
Zheng Xu ◽  
Maomao Guo ◽  
Weiwan Wang ◽  
Weican Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Docetaxel Resistance ◽  
Apoptosis Protein

Abstract Background: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.Methods: We monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using the ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.Conclusions: Our findings indicate highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

scholarly journals Wilms’ Tumor 1-associating Protein Promotes Prostate Cancer Proliferation via Upregulation of CDK4 Transcript

2020 ◽  
Author(s):  
Lei Zhang ◽  
Yiren Gao ◽  
Jun Wang ◽  
Linghui Liang ◽  
Yifei Cheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Wilms Tumor ◽  
Cancer Cell Lines ◽  
Prostate Cancer Cell Lines ◽  
Wilms Tumor 1 ◽  
Cancer Tissues

Abstract Background: Wilms’ tumor 1-associating protein (WTAP) plays an important role in cell physiological function and have attracted increased interest in cancer research recently. Cyclin-dependent protein kinases (CDKs) are known to participate in regulating the cell cycle and often connected to many malignancies in tumor. We aim to explore whether WTAP or CDKs could play an role in the initiation and progression of prostate cancer(PCa) and hope to provide new insights into PCa treatment and prognostic. Methods: Quantitative real-time PCR, western blotting and immunohistochemistry were performed to explore the expression of WTAP and CDK4 in prostate cancer tissues and cell lines. The survival analysis was used to investigate the association between WTAP expression and the clinical outcomes of prostate cancer. Prostate cancer cell lines were stably transfected with lentivirus approach. CCK-8 assay, colony formation assay, cell invasion and migration assay, cell cycle assay and tumorigenesis in nude mice were performed to study the effect of WTAP in prostate cancer cell lines. RNA immunoprecipitation assay, dual-luciferase reporter assay and siRNA transfection were performed to verify the direct binding sites of WTAP with CDK4 transcript.Results: In prostate cancer tissues and cell lines, WTAP was significantly up-regulated and high expression of WTAP was connected to poor clinical outcomes. Additionally, cell function test indicated that overexpression of WTAP in prostate cancer cell lines could promote cell proliferation, while knocking down showed an opposite results. Subcutaneous xenograft tumor model revealed that overexpression of WTAP could induce tumorigenesis in vivo. Mechanism study showed that CDK4 expression could regulate the expression level of WTAP. Moreover, WTAP could directly bind to 3’-UTR of CDK4 transcript and enhance its stability. Furthermore, specific inhibitors of CDK4 as well as small interfering RNA (siRNA) of CDK4 reversed the promotion of proliferation induced by WTAP.Conclusions: These data indicated that WTAP may act as an oncogenic in prostate cancer by directly binding to CDK4 3’-UTR and stabilizing its transcript which might provide new insights into prostate cancer treatment and prognostic.

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