scholarly journals C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jiahong Tan ◽  
Xu Zheng ◽  
Mengchen Li ◽  
Fei Ye ◽  
Chunyan Song ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitors ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Enhancer Binding Protein ◽  
Recombination Repair ◽  
Inhibitor Resistance

AbstractPARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.

scholarly journals Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 966 ◽  
Author(s):  
Marianna Buttarelli ◽  
Marta De Donato ◽  
Giuseppina Raspaglio ◽  
Gabriele Babini ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Biology ◽  
Tissue Level ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Clinical Value ◽  
Pre Treatment ◽  
Phosphatase And Tensin Homologue

Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC.

scholarly journals A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 662 ◽  
Author(s):  
Martyna Pakuła ◽  
Paweł Uruski ◽  
Arkadiusz Niklas ◽  
Aldona Woźniak ◽  
Dariusz Szpurek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Specific Pattern ◽  
Laboratory Animals ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mesenchymal Transition

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

scholarly journals Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

2021 ◽  
Vol 14 (11) ◽  
pp. 101203
Author(s):  
Mark W Nachtigal ◽  
Paris Musaphir ◽  
Shiv Dhiman ◽  
Alon D Altman ◽  
Frank Schweizer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ether Lipid ◽  
High Grade ◽  
Serous Ovarian Cancer

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.

scholarly journals A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3821
Author(s):  
Qipeng Fan ◽  
Lihong Li ◽  
Tian-Li Wang ◽  
Robert E. Emerson ◽  
Yan Xu
Keyword(s):  
Ovarian Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Hypoxia Inducible Factor ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Highly Effective ◽  
Endothelial Growth Factor ◽  
Targeting Strategy

We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC.

scholarly journals TP53mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer

2015 ◽  
Vol 43 (14) ◽  
pp. 6945-6958 ◽  
Author(s):  
Jeremy Chien ◽  
Hugues Sicotte ◽  
Jian-Bing Fan ◽  
Sean Humphray ◽  
Julie M. Cunningham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Early Stage ◽  
Homologous Recombination Repair ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Recombination Repair

scholarly journals Platinum resistance induces diverse evolutionary trajectories in high grade serous ovarian cancer

2020 ◽  
Author(s):  
J.I. Hoare ◽  
H. Hockings ◽  
J. Saxena ◽  
V.L. Silva ◽  
E. Maniati ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Dna Recombination ◽  
Unmet Need ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Platinum Resistant ◽  
Recombination Pathway

AbstractResistance to therapy is an enduring challenge in cancer care. Here we interrogate this critical unmet need using high grade serous ovarian cancer (HGSC) as a disease model. We have generated a unique panel of platinum-resistant HGSC models and shown that they share multiple transcriptomic features with relapsed human HGSC. Moreover, they evolve diverse in vivo phenotypes reflecting the human disease. We previously characterised copy number signatures in HGSC that correlate with patient survival and now provide the first evidence that these signatures undergo recurrent alterations during platinum therapy. Furthermore, specific, resistance-associated signature change is associated with functionally relevant gene expression differences. For example, reduced signature 3 (BRCA1/2-related homologous recombination deficiency) is associated with increased expression of homologous recombination repair genes (Rad51C, Rad51D, BRCA1) and DNA recombination pathway enrichment. Our mechanistic examination therefore provides new and clinically relevant insights into the genomic evolution of platinum-resistant cancers.

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