scholarly journals Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Guo-Qing Chen ◽  
Ping Ye ◽  
Rong-Song Ling ◽  
Fa Zeng ◽  
Xiong-Shan Zhu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Histone Demethylase ◽  
Potential Therapeutic Target ◽  
Stem Cell Maintenance ◽  
Platinum Based Chemotherapy ◽  
Current Therapies ◽  
Sphere Formation

Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum-based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remains sparse. In the current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cell (CSC) maintenance. Depletion of KDM4C significantly reduced the CSC population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSC maintenance and underscore its importance as a potential therapeutic target.

scholarly journals Histone demethylase KDM4C is required for ovarian cancer stem cell maintenance

2019 ◽  
Author(s):  
Guoqing Chen ◽  
Ping Ye ◽  
Fa Zeng ◽  
Xiongshan Zhu ◽  
Lu Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Histone Demethylase ◽  
Ovarian Cancer Stem Cells ◽  
Stem Cell Maintenance ◽  
Platinum Based Chemotherapy ◽  
Current Therapies

Abstract Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remain sparse. In current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cells (CSCs) maintenance. Depletion of KDM4C significantly reduced the CSCs population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSCs maintenance and underscore its importance as a potential therapeutic target.

scholarly journals OTUB2 Facilitates Tumorigenesis of Gastric Cancer Through Promoting KDM1A-Mediated Stem Cell-Like Properties

2021 ◽  
Vol 11 ◽  
Author(s):  
Guangming Liu ◽  
Wei Guo ◽  
Junjie Qin ◽  
Zhiliang Lin
Keyword(s):  
Gastric Cancer ◽  
Stem Cell ◽  
Survival Rates ◽  
Histone Demethylase ◽  
Deubiquitinating Enzyme ◽  
Stem Cell Markers ◽  
Loss Of Function ◽  
Sphere Formation

Otubain 2 (OTUB2), a deubiquitinating enzyme, overexpression is considered to predict poor outcome in various cancers. However, the function and potential regulatory mechanisms of OTUB2 in gastric cancer (GC) progression remains unclear. To determine how OTUB2 participate in GC progression, the gain and loss of-function experiments were conducted in vivo and in vitro. We found that OTUB2 was upregulated in GC samples (n=140) and cells. Moreover, the overall, first progression and post progression survival rates of GC patients with high OTUB2 expression showed a poorer prognosis than that in those patients with low OTUB2 expression. Down-regulation of OTUB2 suppressed sphere formation and reduced expression of stem cell markers in GC cells. Furthermore, OTUB2-silenced GC cells also showed a decreased proliferation, invasion, migration, and in vivo tumorigenic ability. However, OTUB2 overexpression showed the opposite effects. Notably, we demonstrated that OTUB2 increased lysine-specific histone demethylase 1A (KDM1A) expression through deubiquitination. KDM1A, a demethylase known to promote demethylation of downstream genes, was identified to promote the maintenance of cancer stem cell characteristics. Moreover, the alterations caused by OTUB2 overexpression were partly inversed by KDM1A knockdown and in turn KDM1A overexpression reversed the changes induced by OTUB2 shRNA. Taken together, we demonstrate that OTUB2 may serve as a vital driver in GC tumorigenesis by enhancing KDM1A-mediated stem cell-like properties.

scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

2019 ◽  
Author(s):  
Carlos J. Díaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G. Kleinschmidt ◽  
Kristin N. Taylor ◽  
Allison M. Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gene Copy ◽  
Platinum Resistance ◽  
List Type ◽  
High Grade ◽  
Cancer Resistance ◽  
Platinum Chemotherapy

AbstractGene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-β-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encodingKRAS,MYCandFAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosisin vitroandin vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/β-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.Graphical SummaryKey PointsHigh grade serous ovarian carcinoma tumors containPTK2(FAK) 8q24.3 gains associated with prognostic differences.KMF, a new murine ovarian cancer model withK-Ras,Myc, andFAK gene gains and intrinsic platinum resistance.FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.FAK facilitates a β-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.

scholarly journals Abstract 1985: Upregulation of miR-328 contributes to ovarian cancer stem cell maintenance by downregulating DDB2

2018 ◽  
Author(s):  
Amit K. Srivastava ◽  
Tiantian Cui ◽  
Chunhua Han ◽  
Ananya Banerjee ◽  
Shuri Cai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

scholarly journals The IL-17A/IL-17RA Axis Is Not Related to Overall Survival and Cancer Stem Cell Modulation in Pancreatic Cancer

2020 ◽  
Vol 21 (6) ◽  
pp. 2215
Author(s):  
Jiahui Li ◽  
Christopher Betzler ◽  
Philipp Lohneis ◽  
Marie Christine Popp ◽  
Jiwei Qin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Stem Cell Markers ◽  
Sphere Formation

(1) Background: IL-17A accelerates pancreatic intraepithelial neoplasia (PanIN) progression. In this study, we examined whether IL-17A/IL-17RA promotes pancreatic ductal adenocarcinoma (PDAC) aggressiveness in terms of survival and cancer stem cell modulation. (2) Methods: In vitro, the wound-healing assay, the sphere formation assay, and flow cytometry were applied to assess cancer stem cell features. In vivo, pancreatic tumors were induced in C57BL/6 mice using electroporation with oncogenic plasmids (P53-/- R172H; KrasG12V). Anti-IL-17 antibodies were administered as immunotherapy. We analyzed IL-17A/IL-17RA related survival using publicly available transcriptomic data (n = 903). (3) Results: IL-17A/IL-17RA expression was not related to survival in PDAC patients. IL-17A neither induces stem cell markers nor increases sphere formation and cell motility in vitro. Blocking the IL-17A/IL-17RA axis in a murine pancreatic cancer model did not improve the survival of mice, but reduced the tumor burden slightly. (4) Conclusions: IL-17A does not promote stem cell expansion in PDAC cell lines. Blocking IL-17A/IL-17RA signaling does not interfere with pancreatic cancer development and progression and may not be considered as a promising monotherapy for PDAC.

New Markers For Human Ovarian Cancer That Link Platinum Resistance To The Cancer Stem Cell Phenotype And Define New Therapeutic Combinations And Diagnostic Tools

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S119-S119
Author(s):  
Y S Kamel
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Bioinformatics Analysis ◽  
Genetic Alterations ◽  
Ovarian Tumors ◽  
Cell Phenotype ◽  
Platinum Resistance

Abstract Introduction/Objective Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed. Methods We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres. Results Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer. Conclusion The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer.

Ovarian cancer stem cell: A potential therapeutic target for overcoming multidrug resistance

2018 ◽  
Vol 234 (4) ◽  
pp. 3238-3253 ◽  
Author(s):  
Aynaz Mihanfar ◽  
Javad Aghazadeh Attari ◽  
Iraj Mohebbi ◽  
Maryam Majidinia ◽  
Mojtaba Kaviani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Multidrug Resistance ◽  
Cancer Stem Cell ◽  
Therapeutic Target ◽  
Potential Therapeutic Target

scholarly journals NF-κB Signaling in Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1182 ◽  
Author(s):  
Brittney S. Harrington ◽  
Christina M. Annunziata
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Stem Cell Maintenance ◽  
Promote Cell Survival ◽  
Canonical Pathways ◽  
Cancer Cell Population ◽  
Cell Maintenance

The NF-κB signaling pathway is a master and commander in ovarian cancer (OC) that promotes chemoresistance, cancer stem cell maintenance, metastasis and immune evasion. Many signaling pathways are dysregulated in OC and can activate NF-κB signaling through canonical or non-canonical pathways which have both overlapping and distinct roles in tumor progression. The activation of canonical NF-κB signaling has been well established for anti-apoptotic and immunomodulatory functions in response to the tumor microenvironment and the non-canonical pathway in cancer stem cell maintenance and tumor re-initiation. NF-κB activity in OC cells helps to create an immune-evasive environment and to attract infiltrating immune cells with tumor-promoting phenotypes, which in turn, drive constitutive NF-κB activation in OC cells to promote cell survival and metastasis. For these reasons, NF-κB is an attractive target in OC, but current strategies are limited and broad inhibition of this major signaling pathway in normal physiological and immunological functions may produce unwanted side effects. There are some promising pre-clinical outcomes from developing research to target and inhibit NF-κB only in the tumor-reinitiating cancer cell population of OC and concurrently activate canonical NF-κB signaling in immune cells to promote anti-tumor immunity.

scholarly journals ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3692
Author(s):  
Qipeng Fan ◽  
Wen Zhang ◽  
Robert E. Emerson ◽  
Yan Xu
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Stem Cell Marker ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Upstream Regulator ◽  
Genetic Compensation

High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 as a novel CSC marker in HGSOC. Fluorescence-activated cell sorter (FACS)-sorted ZIP4+, but not ZIP4− cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4+, but not ZIP4− cells, formed tumors/ascites in vivo. We conducted limiting dilution experiments and showed that 100–200 ZIP4+ cells from both PE04 and PEA2 cells formed larger tumors than those from 100–200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Genetic compensation studies showed that NOTCH3, but not NOTCH1, was a critical downstream mediator of ZIP4. Furthermore, NOTCH3, but not NOTCH1, physically bound to ZIP4. Collectively, our data suggest that ZIP4 is a novel CSC marker and the new ZIP4-NOTCH3 axis represents important therapeutic targets in HGSOC.

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