Fascin1 expression in high-grade serous ovarian carcinoma is a prognostic marker and knockdown of fascin1 suppresses the proliferation of ovarian cancer cells

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. However, it is still unclear how genetic dysregulations and biological processes generate the malignant subtype of HGSOC. Here we show that expression levels of microtubule affinity-regulating kinase 3 (MARK3) are downregulated in HGSOC, and that its downregulation significantly correlates with poor prognosis in HGSOC patients. MARK3 overexpression suppresses cell proliferation and angiogenesis of ovarian cancer cells. The LKB1-MARK3 axis is activated by metabolic stress, which leads to the phosphorylation of CDC25B and CDC25C, followed by induction of G2/M phase arrest. RNA-seq and ATAC-seq analyses indicate that MARK3 attenuates cell cycle progression and angiogenesis partly through downregulation of AP-1 and Hippo signaling target genes. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs.

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WTAP is a prognostic marker of high-grade serous ovarian cancer and regulates the progression of ovarian cancer cells

OncoTargets and Therapy ◽

10.2147/ott.s205730 ◽

2019 ◽

Vol Volume 12 ◽

pp. 6191-6201 ◽

Cited By ~ 11

Author(s):

Hai-Lan Yu ◽

Xu-Dong Ma ◽

Jin-Fei Tong ◽

Jian-Qiong Li ◽

Xiao-Jing Guan ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Prognostic Marker ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer

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TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway

Cell Death and Disease ◽

10.1038/s41419-021-04429-6 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Gonghua Qi ◽

Hanlin Ma ◽

Yingwei Li ◽

Jiali Peng ◽

Jingying Chen ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Spindle Assembly Checkpoint ◽

Ovarian Cancer Cells ◽

High Grade ◽

Cisplatin Sensitivity

AbstractHigh-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.

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Extracellular vesicles derived from ascitic fluid enhance growth and migration of ovarian cancer cells

Scientific Reports ◽

10.1038/s41598-021-88163-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aparna Mitra ◽

Kyoko Yoshida-Court ◽

Travis N. Solley ◽

Megan Mikkelson ◽

Chi Lam Au Yeung ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Carcinoma ◽

Advanced Stages ◽

And Migration ◽

Cancer Spheroids ◽

Omental Fat ◽

Low Expression

AbstractOvarian cancer is associated with a high mortality rate due to diagnosis at advanced stages. Dissemination often occurs intraperitoneally within the ascites fluid. The microenvironment can support dissemination through several mechanisms. One potential ascites factor which may mediate dissemination are EVs or extracellular vesicles that can carry information in the form of miRNAs, proteins, lipids, and act as mediators of cellular communication. We present our observations on EVs isolated from ascitic supernatants from patients diagnosed with high grade serous ovarian carcinoma in augmenting motility, growth, and migration towards omental fat. MicroRNA profiling of EVs from malignant ascitic supernatant demonstrates high expression of miR 200c-3p, miR18a-5p, miR1246, and miR1290 and low expression of miR 100- 5p as compared to EVs isolated from benign ascitic supernatant. The migration of ovarian cancer spheroids towards omental fat is enhanced in the presence of malignant ascitic EVs. Gene expression of these cells showed increased expression of ZBED2, ZBTB20, ABCC3, UHMK1, and low expression of Transgelin and MARCKS. We present evidence that ovarian ascitic EVs increase the growth of ovarian cancer spheroids through miRNAs.

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GATA3 and stemness of high-grade serous ovarian carcinoma: novel hope for the deadliest type of ovarian cancer

Human Cell ◽

10.1007/s13577-020-00368-0 ◽

2020 ◽

Vol 33 (3) ◽

pp. 904-906 ◽

Cited By ~ 1

Author(s):

Amr Ahmed El-Arabey ◽

Mohnad Abdalla ◽

Adel Rashad Abd-Allah

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

High Grade ◽

Serous Ovarian Carcinoma

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Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

10.1101/727537 ◽

2019 ◽

Cited By ~ 1

Author(s):

N. Tamura ◽

N. Shaikh ◽

D. Muliaditan ◽

J. McGuinness ◽

D. Moralli ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Single Molecule ◽

Chromosomal Instability ◽

Poor Prognosis ◽

Spindle Assembly Checkpoint ◽

Western World ◽

Cancer Type ◽

High Grade ◽

Serous Ovarian Carcinoma

AbstractChromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

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Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time

Biomolecules ◽

10.3390/biom11111711 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1711

Author(s):

Michelle Bilbao ◽

Chelsea Katz ◽

Stephanie L. Kass ◽

Devon Smith ◽

Krystal Hunter ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

3D Culture ◽

Extended Period ◽

Recurrent Ovarian Cancer ◽

Epigenetic Therapy ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Cancer Spheroids

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.

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