International Journal of Molecular Sciences

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19 pages, 3202 KiB

Open AccessArticle

Identification of Proteins Associated with Ovarian Cancer Chemotherapy Resistance Using MALDI-MSI

by Tannith M. Noye, Parul Mittal, Zoe K. Price, Annie Fewster, Georgia Williams, Tara L. Pukala, Manuela Klingler-Hoffmann, Peter Hoffmann, Martin K. Oehler, Noor A. Lokman and Carmela Ricciardelli

Int. J. Mol. Sci. 2025, 26(12), 5893; https://doi.org/10.3390/ijms26125893 - 19 Jun 2025

Viewed by 54

Abstract

Ovarian cancer is the most lethal gynecological cancer. Up to 75% of cases are high-grade serous ovarian cancer (HGSOC) that have high chemosensitivity to first-line platinum-based therapies. However, 75% of patients will become chemoresistant following relapse. The underlying mechanism for developing resistance to [...] Read more.

Ovarian cancer is the most lethal gynecological cancer. Up to 75% of cases are high-grade serous ovarian cancer (HGSOC) that have high chemosensitivity to first-line platinum-based therapies. However, 75% of patients will become chemoresistant following relapse. The underlying mechanism for developing resistance to chemotherapy in HGSOC is poorly understood. In this study, we employed Matrix-Assisted Laser Desorption/Ionization–Mass Spectrometry Imaging (MALDI-MSI) on matching formalin-fixed paraffin-embedded (FFPE) HGSOC tissues at the time of diagnosis and following relapse with chemotherapy-resistant disease (n = 4). We identified m/z values that were differentially abundant in the matching diagnosis and relapse HGSOC tissues. These were matched to proteins using nano-liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified upregulated proteins in the HGSOC relapse tissues, including COL12A1, FUBP1, PLEC, SLC4A1, and TKT. These proteins were validated by immunohistochemistry (IHC) and gene expression using online databases. IHC showed COL12A1, FUBP1, PLEC, SLC4A1, and TKT protein abundance were significantly elevated in HGSOC relapse tissues compared to matching tissues at diagnosis. COL12A1, FUBP1, PLEC, and TKT mRNA expression levels were significantly increased in HGSOC compared to normal ovary and associated with poor prognosis in HGSOC. We confirmed that higher protein abundance of both COL12A1 and PLEC correlated with reduced progression-free survival in HGSOC patients. Furthermore, both COL12A1 and PLEC mRNA and protein levels were significantly associated with chemotherapy resistance. In summary, using MALDI-MSI, we have identified proteins, including COL12A1 and PLEC, associated with chemotherapy resistance to be further evaluated as HGSOC biomarkers and/or therapeutic targets. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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17 pages, 5189 KiB

Open AccessArticle

Establishment of Novel High-Grade Serous Ovarian Carcinoma Cell Line OVAR79

by Polina V. Shnaider, Irina K. Malyants, Olga M. Ivanova, Veronika D. Gordeeva, Ekaterina A. Svirina, Natalya B. Zakharzhevskaya, Olga Y. Shagaleeva, Oksana V. Selezneva, Alexandra N. Bogomazova, Maria M. Lukina, Olga I. Aleshikova, Nataliya A. Babaeva, Andrey V. Slonov and Victoria O. Shender

Int. J. Mol. Sci. 2024, 25(24), 13236; https://doi.org/10.3390/ijms252413236 - 10 Dec 2024

Viewed by 1575

Abstract

High-grade serous ovarian carcinoma (HGSOC) remains the most common and deadly form of ovarian cancer. However, available cell lines usually fail to appropriately represent its complex molecular and histological features. To overcome this drawback, we established OVAR79, a new cell line derived from [...] Read more.

High-grade serous ovarian carcinoma (HGSOC) remains the most common and deadly form of ovarian cancer. However, available cell lines usually fail to appropriately represent its complex molecular and histological features. To overcome this drawback, we established OVAR79, a new cell line derived from the ascitic fluid of a patient with a diagnosis of HGSOC, which adds a unique set of properties to the study of ovarian cancer. In contrast to the common models, OVAR79 expresses TP53 without the common hotspot mutations and harbors the rare combination of mutations in both PIK3CA and PTEN genes, together with high-grade chromosomal instability with multiple gains and losses. These features, together with the high proliferation rate, ease of cultivation, and exceptional transfection efficiency of OVAR79, make it a readily available and versatile tool for various studies in the laboratory. We extensively characterized its growth, migration, and sensitivity to platinum- and taxane-based treatments in comparison with the commonly used SKOV3 and OVCAR3 ovarian cell lines. In summary, OVAR79 is an excellent addition for basic and translational ovarian cancer research and offers new insights into the biology of HGSOC. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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20 pages, 12906 KiB

Open AccessArticle

Comprehensive Analysis of MICALL2 Reveals Its Potential Roles in EGFR Stabilization and Ovarian Cancer Cell Invasion

by Tianxiang Xia, Fengwen Ye, Weizhen Zhao, Pengxiang Min, Chenxiang Qi, Qianwen Wang, Mingyu Zhao, Yujie Zhang and Jun Du

Int. J. Mol. Sci. 2024, 25(1), 518; https://doi.org/10.3390/ijms25010518 - 30 Dec 2023

Cited by 10 | Viewed by 1754

Abstract

Molecules interacting with CasL (MICALs) are critical mediators of cell motility that act by cytoskeleton rearrangement. However, the molecular mechanisms underlying the regulation of cancer cell invasion remain elusive. The aim of this study was to investigate the potential role of one member [...] Read more.

Molecules interacting with CasL (MICALs) are critical mediators of cell motility that act by cytoskeleton rearrangement. However, the molecular mechanisms underlying the regulation of cancer cell invasion remain elusive. The aim of this study was to investigate the potential role of one member of MICALs, i.e., MICALL2, in the invasion and function of ovarian cancer cells. We showed by bioinformatics analysis that MICALL2 expression was significantly higher in tissues of advanced-stage ovarian cancer and associated with poor overall survival of patients. MICALL2 was strongly correlated with the infiltration of multiple types of immune cells and T-cell exhaustion markers. Moreover, enrichment analyses showed that MICALL2 was involved in the tumor-related matrix degradation pathway. Mechanistically, MMP9 was identified as the target gene of MICALL2 for the regulation of invadopodium formation and SKOV3, HO-8910PM cell invasion. In addition, EGFR–AKT–mTOR signaling was identified as the downstream pathway of MICALL2 in the regulation of MMP9 expression. Furthermore, MICALL2 silencing promoted EGFR degradation; however, this effect was abrogated by treatment with the autophagy inhibitors acadesine and chloroquine diphosphate. Silencing of MICALL2 resulted in a suppressive activity of Rac1 while suppressing Rac1 activation attenuated the pro-EGFR, pro-MMP9, and proinvasive effects induced by the overexpression of MICALL2. Collectively, our results indicated that MICALL2 participated in the process of immune infiltration and invasion by ovarian cancer cells. Moreover, MICALL2 prevented EGFR degradation in a Rac1-dependent manner, consequently leading to EGFR–AKT–mTOR–MMP9 signaling activation and invadopodia-mediated matrix degradation. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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12 pages, 3127 KiB

Open AccessArticle

Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents

by Yurika Nakagawa-Saito, Yuta Mitobe, Shuhei Suzuki, Keita Togashi, Asuka Sugai, Chifumi Kitanaka and Masashi Okada

Int. J. Mol. Sci. 2023, 24(13), 10817; https://doi.org/10.3390/ijms241310817 - 28 Jun 2023

Cited by 2 | Viewed by 1697

Abstract

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of [...] Read more.

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1–survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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16 pages, 2923 KiB

Open AccessArticle

Advanced Glycation End Products as a Potential Target for Restructuring the Ovarian Cancer Microenvironment: A Pilot Study

by Elizabeth I. Harper, Michael D. Siroky, Tyvette S. Hilliard, Gena M. Dominique, Catherine Hammond, Yueying Liu, Jing Yang, Veronica B. Hubble, Danica J. Walsh, Roberta J. Melander, Christian Melander, Matthew J. Ravosa and M. Sharon Stack

Int. J. Mol. Sci. 2023, 24(12), 9804; https://doi.org/10.3390/ijms24129804 - 6 Jun 2023

Cited by 4 | Viewed by 2618

Abstract

Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in the ovarian cancer microenvironment that have been shown to create a [...] Read more.

Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in the ovarian cancer microenvironment that have been shown to create a permissive metastatic niche, including the formation of advanced glycation end products, or AGEs, that form crosslinks between collagen molecules. Small molecules that disrupt AGEs, known as AGE breakers, have been examined in other diseases, but their efficacy in ovarian cancer has not been evaluated. The goal of this pilot study is to target age-related changes in the tumor microenvironment with the long-term aim of improving response to therapy in older patients. Here, we show that AGE breakers have the potential to change the omental collagen structure and modulate the peritoneal immune landscape, suggesting a potential use for AGE breakers in the treatment of ovarian cancer. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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Review

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16 pages, 641 KiB

Open AccessReview

The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis

by Long Xu, Xiaoyu Yan, Jian Wang, Yuanxin Zhao, Qingqing Liu, Jiaying Fu, Xinyi Shi and Jing Su

Int. J. Mol. Sci. 2023, 24(20), 15066; https://doi.org/10.3390/ijms242015066 - 11 Oct 2023

Cited by 4 | Viewed by 2168

Abstract

Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation [...] Read more.

Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation of histone and some non-histone proteins and that are involved in the regulation of a variety of biological processes via the regulation of gene transcription and the functions of non-histone proteins such as transcription factors and enzymes. Aberrant expressions of HDACs are common in ovarian cancer. Many studies have found that HDACs are involved in regulating a variety of events associated with ovarian cancer metastasis, including cell migration, invasion, and the epithelial–mesenchymal transformation. Herein, we provide a brief overview of ovarian cancer metastasis and the dysregulated expression of HDACs in ovarian cancer. In addition, we discuss the roles of HDACs in the regulation of ovarian cancer metastasis. Finally, we discuss the development of compounds that target HDACs and highlight their importance in the future of ovarian cancer therapy. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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14 pages, 1913 KiB

Open AccessReview

Estrogens, Estrogen Receptors and Tumor Microenvironment in Ovarian Cancer

by Marta Justyna Kozieł and Agnieszka Wanda Piastowska-Ciesielska

Int. J. Mol. Sci. 2023, 24(19), 14673; https://doi.org/10.3390/ijms241914673 - 28 Sep 2023

Cited by 30 | Viewed by 5350

Abstract

Ovarian cancer is one of the most common cancers in women and the most concerning issues in gynecological oncology in recent years. It is postulated that many factors may contribute to the development of ovarian cancer, including hormonal imbalance. Estrogens are a group [...] Read more.

Ovarian cancer is one of the most common cancers in women and the most concerning issues in gynecological oncology in recent years. It is postulated that many factors may contribute to the development of ovarian cancer, including hormonal imbalance. Estrogens are a group of hormones that have an important role both in physiological and pathological processes. In ovarian cancer, they may regulate proliferation, invasiveness and epithelial to mesenchymal transition. Estrogen signaling also takes part in the regulation of the biology of the tumor microenvironment. This review summarizes the information connected with estrogen receptors, estrogens and their association with a tumor microenvironment. Moreover, this review also includes information about the changes in estrogen receptor expression upon exposition to various environmental chemicals. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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24 pages, 1005 KiB

Open AccessReview

An Overview of PARP Resistance in Ovarian Cancer from a Molecular and Clinical Perspective

by Nicoletta Cordani, Tommaso Bianchi, Luca Carlofrancesco Ammoni, Diego Luigi Cortinovis, Marina Elena Cazzaniga, Andrea Alberto Lissoni, Fabio Landoni and Stefania Canova

Int. J. Mol. Sci. 2023, 24(15), 11890; https://doi.org/10.3390/ijms241511890 - 25 Jul 2023

Cited by 13 | Viewed by 3892

Abstract

Epithelial ovarian cancer (EOC), a primarily high-grade serous carcinoma (HGSOC), is one of the major causes of high death-to-incidence ratios of all gynecological cancers. Cytoreductive surgery and platinum-based chemotherapy represent the main treatments for this aggressive disease. Molecular characterization of HGSOC has revealed [...] Read more.

Epithelial ovarian cancer (EOC), a primarily high-grade serous carcinoma (HGSOC), is one of the major causes of high death-to-incidence ratios of all gynecological cancers. Cytoreductive surgery and platinum-based chemotherapy represent the main treatments for this aggressive disease. Molecular characterization of HGSOC has revealed that up to 50% of cases have a deficiency in the homologous recombination repair (HRR) system, which makes these tumors sensitive to poly ADP-ribose inhibitors (PARP-is). However, drug resistance often occurs and overcoming it represents a big challenge. A number of strategies are under investigation, with the most promising being combinations of PARP-is with antiangiogenetic agents and immune checkpoint inhibitors. Moreover, new drugs targeting different pathways, including the ATR-CHK1-WEE1, the PI3K-AKT and the RAS/RAF/MEK, are under development both in phase I and II–III clinical trials. Nevertheless, there is still a long way to go, and the next few years promise to be exciting. Full article

(This article belongs to the Special Issue Current Research for Ovarian Cancer Biology and Therapeutics)

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