Locally-invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging

AbstractHere we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.

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Locally invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging

PLoS ONE ◽

10.1371/journal.pone.0232807 ◽

2020 ◽

Vol 15 (9) ◽

pp. e0232807

Author(s):

Courtney Yong ◽

Devon L. Moose ◽

Nadine Bannick ◽

Wade R. Gutierrez ◽

Marion Vanneste ◽

...

Keyword(s):

Prostate Cancer ◽

Mouse Model ◽

Knockout Mouse ◽

Bioluminescent Imaging ◽

Double Knockout ◽

Knockout Mouse Model ◽

Non Invasive ◽

Double Knockout Mouse ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

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circSLC8A1 Acts as a Tumor Suppressor in Prostate Cancer via Sponging miR-21

BioMed Research International ◽

10.1155/2021/6614591 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Daoyuan Wang ◽

Shuxian Yan ◽

Lihui Wang ◽

Yunlong Li ◽

Baoping Qiao

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Epithelial To Mesenchymal Transition ◽

Direct Interaction ◽

Mapk Signaling ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Chemokine Signaling ◽

Chemokine Signaling Pathway

Background. There is more and more evidence showed that circRNAs played essentially role in the regulation of various biological processes. The role of circSLC8A1 in prostate cancer (PCa) is yet little known. Methods. The CircSLC8A1 expression in human prostate cancer was measured by qRT-PCR. The interplay between the specific circRNA, miRNA, and mRNA was investigated by RT-PCR and luciferase reporter assay. Through transient transfection of siRNA, the impacts of circSLC8A1 on PCa were discussed. Cell cycle evaluation, transwell assay, and CCK-8 assay were employed to determine its biological influences. Results. In this study, our data revealed that circSLC8A1 was downregulated in PCa tissues and cells. The reduction of circSLC8A1 resulted in the inhibition of cell proliferation and migration. In mechanism, circSLC8A1 exhibited a direct interaction with miR-21 and displayed as a miRNA sponge to inhibit PCa progression. The functional analysis revealed that the circSLC8A1/miR-21 axis may regulate the cell proliferation, angiogenesis, cell migration, epithelial to mesenchymal transition, MAPK signaling pathway, and chemokine signaling pathway. Conclusions. CircSLC8A1 functioned as an inhibitor of neoplasm via modulating the miR-21 and might serve as a prospective target for the treatment of PCa.

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The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

Prostate Cancer ◽

10.1155/2020/7938280 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Tanzila Khan ◽

Kieran F. Scott ◽

Therese M. Becker ◽

John Lock ◽

Mohammed Nimir ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanisms ◽

Oncogenic Signaling ◽

Mesenchymal Transition ◽

Development Of Resistance ◽

Castrate Resistant

Prostate cancer (PCa) is initially driven by excessive androgen receptor (AR) signaling with androgen deprivation therapy (ADT) being a major therapeutic approach to its treatment. However, the development of drug resistance is a significant limitation on the effectiveness of both first-line and more recently developed second-line ADTs. There is a need then to study AR signaling within the context of other oncogenic signaling pathways that likely mediate this resistance. This review focuses on interactions between AR signaling, the well-known phosphatidylinositol-3-kinase/AKT pathway, and an emerging mediator of these pathways, the Hippo/YAP1 axis in metastatic castrate-resistant PCa, and their involvement in the regulation of epithelial-mesenchymal transition (EMT), a feature of disease progression and ADT resistance. Analysis of these pathways in circulating tumor cells (CTCs) may provide an opportunity to evaluate their utility as biomarkers and address their importance in the development of resistance to current ADT with potential to guide future therapies.

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miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-14-1784 ◽

2014 ◽

Vol 20 (24) ◽

pp. 6559-6569 ◽

Cited By ~ 62

Author(s):

Murali Gururajan ◽

Sajni Josson ◽

Gina Chia-Yi Chu ◽

Chia-Lun Lu ◽

Yi-Tsung Lu ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition

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MicroRNA-144 Suppresses Prostate Cancer Growth and Metastasis by Targeting EZH2

Technology in Cancer Research & Treatment ◽

10.1177/1533033821989817 ◽

2021 ◽

Vol 20 ◽

pp. 153303382198981

Author(s):

Xin-bo Sun ◽

Yong-wei Chen ◽

Qi-sheng Yao ◽

Xu-hua Chen ◽

Min He ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Viability ◽

Cell Apoptosis ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Proliferation And Apoptosis ◽

High Incidence ◽

Inhibit Cell Proliferation

Background: Prostate cancer is a common malignant tumor with a high incidence. MicroRNAs (miRNAs) have been shown to be important post-transcriptional regulators during tumorigenesis. This study aimed to explore the effect of miR-144 on PCa proliferation and apoptosis. Material and Methods: The expression of miR-144 and EZH2 were examined in clinical PCa tissues. PCa cell line LNCAP and DU-145 was employed and transfected with miR-144 mimics or inhibitors. The correlation between miR-144 and EZH2 was verified by luciferase reporter assay. Cell viability, apoptosis and migratory capacity were detected by CCK-8, flow cytometry assay and wound healing assay. The protein level of EZH2, E-Cadherin, N-Cadherin and vimentin were analyzed by western blotting. Results: miR-144 was found to be negatively correlated to the expression of EZH2 in PCa tissues. Further studies identified EZH2 as a direct target of miR-144. Moreover, overexpression of miR-144 downregulated expression of EZH2, reduced cell viability and promoted cell apoptosis, while knockdown of miR-144 led to an inverse result. miR-144 also suppressed epithelial-mesenchymal transition level of PCa cells. Conclusion: Our study indicated that miR-144 negatively regulate the expression of EZH2 in clinical specimens and in vitro. miR-144 can inhibit cell proliferation and induce cell apoptosis in PCa cells. Therefore, miR-144 has the potential to be used as a biomarker for predicting the progression of PCa.

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Prolonged atrazine exposure beginning in utero and adult uterine morphology in mice

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174421000106 ◽

2021 ◽

pp. 1-10

Author(s):

Meaghan J. Griffiths ◽

Amy L. Winship ◽

Jessica M. Stringer ◽

Elyse O. Swindells ◽

Alesia P. Harper ◽

...

Keyword(s):

Drinking Water ◽

Oestrogen Receptor ◽

Endometrial Hyperplasia ◽

Epithelial To Mesenchymal Transition ◽

Cell Metabolism ◽

In Utero ◽

Receptor Expression ◽

Mesenchymal Transition ◽

Pregnant Mice ◽

Emt Markers

Abstract Through drinking water, humans are commonly exposed to atrazine, a herbicide that acts as an endocrine and metabolic disruptor. It interferes with steroidogenesis, including promoting oestrogen production and altering cell metabolism. However, its precise impact on uterine development remains unknown. This study aimed to determine the effect of prolonged atrazine exposure on the uterus. Pregnant mice (n = 5/group) received 5 mg/kg body weight/day atrazine or DMSO in drinking water from gestational day 9.5 until weaning. Offspring continued to be exposed until 3 or 6 months of age (n = 5–9/group), when uteri were collected for morphological and molecular analyses and steroid quantification. Endometrial hyperplasia and leiomyoma were evident in the uteri of atrazine-exposed mice. Uterine oestrogen concentration, oestrogen receptor expression, and localisation were similar between groups, at both ages (P > 0.1). The expression and localisation of key epithelial-to-mesenchymal transition (EMT) genes and proteins, critical for tumourigenesis, remained unchanged between treatments, at both ages (P > 0.1). Hence, oestrogen-mediated changes to established EMT markers do not appear to underlie abnormal uterine morphology evident in atrazine exposure mice. This is the first report of abnormal uterine morphology following prolonged atrazine exposure starting in utero, it is likely that the abnormalities identified would negatively affect female fertility, although mechanisms remain unknown and require further study.

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PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽

10.1038/s41388-021-01707-7 ◽

2021 ◽

Vol 40 (13) ◽

pp. 2355-2366

Author(s):

Laura C. A. Galbraith ◽

Ernest Mui ◽

Colin Nixon ◽

Ann Hedley ◽

David Strachan ◽

...

Keyword(s):

Prostate Cancer ◽

Mitochondrial Biogenesis ◽

Nuclear Export ◽

Epithelial To Mesenchymal Transition ◽

Ppar Gamma ◽

Peroxisome Proliferator ◽

Serine Threonine Kinase ◽

Peroxisome Proliferator Activated Receptor ◽

Mesenchymal Transition ◽

And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61

Cellular Physiology and Biochemistry ◽

10.1159/000495396 ◽

2018 ◽

Vol 51 (2) ◽

pp. 938-948 ◽

Cited By ~ 5

Author(s):

Yazeng Huang ◽

Jun Zhang ◽

Haiyu Shao ◽

Jianwen Liu ◽

Mengran Jin ◽

...

Keyword(s):

Protein Expression ◽

Cell Invasion ◽

Epithelial To Mesenchymal Transition ◽

Regulatory Element ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Osteosarcoma Cell ◽

Reporter Assay ◽

Related Protein ◽

Mesenchymal Transition

Background/Aims: Preventing cell metastasis is an effective therapeutic strategy to treat osteosarcoma and improve prognosis. Statins have been found to have anticancer effects in addition to their cholesterol-lowering action. As a new target of statins, cysteine-rich 61 (CYR61) was recently identified to promote cell migration and metastasis in osteosarcoma. However, the underlying mechanisms mediating the regulation of CYR61 expression by statins remain unknown. Methods: Human osteosarcoma cell lines MG63 and SaOS2 were used to clarify the effect of lovastatin on CYR61 expression. Real-time PCR was performed to detect mRNA or microRNA (miRNA) levels and western blot was performed to detect protein levels. Cell invasive ability was determined using Transwell assays. Lentivirus encoding CYR61 cDNA or sterol regulatory element-binding protein 2 (SREBP-2) shRNA was used to upregulate CYR61 expression or downregulate SREBP-2 expression. Binding of the CYR61 3’ untranslated region (UTR) and miR-33a was analyzed by luciferase reporter assay. Results: We found that lovastatin treatment decreased CYR61 expression, inhibited cell invasion and altered epithelial-to-mesenchymal-transition (EMT)-related protein expression, while CYR61 overexpression abolished the effect of lovastatin. Moreover, lovastatin increased the expression of SREBP-2 and miR-33a, which were then downregulated by SREBP-2 silencing. Bioinformatics analysis indicated that the CYR61 3′UTR harbored a potential miR-33a binding site and luciferase reporter assay demonstrated that CYR61 was a target of miR-33a in osteosarcoma cells. Furthermore, miR-33a could inhibit cell invasion and alter EMT-related protein expression. SREBP-2 silencing or miR-33a inhibitor upregulated CYR61 expression and reversed the effects of lovastatin on cell invasion and EMT-related proteins. Conclusion: Our findings suggest lovastatin suppresses osteosarcoma cell invasion through the SREBP-2/miR-33a/CYR61 pathway.

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