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Ravindranath KJ, Srinivasan H. Regulating the expression of matrix metalloproteinases to inhibit ovarian carcinoma using isoquinoline alkaloid from Allium ascalonicum. Sci Rep 2025; 15:9228. [PMID: 40097575 PMCID: PMC11914158 DOI: 10.1038/s41598-025-94111-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/11/2025] [Indexed: 03/19/2025] Open
Abstract
Ovarian carcinoma is one of the fatal gynecological cancers due to the lack of clinical symptoms at earlier stages of disease leading to metastasis and lower survival rates. Hence, an in-depth exploration of the mechanisms of metastasis facilitates the development of novel-targeted therapeutic strategies to treat the disease. Research studies have reported that three predominant Matrix metalloproteinases (MMPs), namely, MMP14, MMP2 and MMP9 can induce the migration of ovarian cancer cells, Epithelial-Mesenchymal transition, breakdown of extracellular matrix, upregulation of expression of transcription factors etc. in the microenvironment of ovarian tumors. In our current research, these predominant MMPs were used as target proteins and docked with potential anti-cancerous phyto-nutraceuticals present in Allium ascalonicum species. Allium ascalonicum, commonly referred to as Shallots is being used in various cuisines worldwide and is still largely unexploited for its anti-cancer properties. Docking results, revealed three potential phyto-nutraceuticals, of which, 1-[[3,5-bis(phenylmethoxy)phenyl]methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline, an isoquinoline alkaloid was considered the best, since it exhibits significant binding affinity when compared to that of the standard drug, Melphalan. Molecular dynamic simulation studies exhibited that MMP2 is highly flexible and can form more stable interactions. Furthermore, simulation studies of finest interaction pose of the target MMPs with the best phyto-nutraceutical, revealed stable interactions and occurrence of conformational changes. The results, also suggested that, the best phyto-nutraceutical of Allium ascalonicum is a novel isoquinoline alkaloid, with favorable bioavailability scores that interact with target MMPs to control the progression and metastasis of ovarian cancer, proposing the prospect of formulating it into sustainable medications for treating metastasized Ovarian Cancer.
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Affiliation(s)
- Karunya Jenin Ravindranath
- School of Life Sciences, B. S. Abdur Rahman Crescent Institute of Science & Technology, Vandalur, Chennai, 600048, India
| | - Hemalatha Srinivasan
- School of Life Sciences, B. S. Abdur Rahman Crescent Institute of Science & Technology, Vandalur, Chennai, 600048, India.
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Braccini S, Pecorini G, Biagini S, Tacchini C, Battisti A, Puppi D. Chitosan/alginate polyelectrolyte complex hydrogels by additive manufacturing for in vitro 3D ovarian cancer modeling. Int J Biol Macromol 2025; 296:139795. [PMID: 39805455 DOI: 10.1016/j.ijbiomac.2025.139795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 01/04/2025] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Polyelectrolyte complexes (PECs) are self-assembled systems formed from oppositely charged polymers, used to create hydrogels for cell culture. This work was aimed at additive manufacturing 3D hydrogels made of a PEC between chitosan (Cs) and alginate, as well as their investigation for in vitro 3D ovarian cancer modeling. PEC hydrogels stability in cell culture medium demonstrated their suitability for long-term cell culture applications. Higher in vitro viability of two human ovarian cancer cell lines was detected at different time points on PEC hydrogels than on Cs hydrogels, used as a control. In addition, during the 63-day culture experiment, cells effectively colonized the scaffolds while retaining their aggressive tumor characteristics. A significantly lower sensitivity to cisplatin and eugenol, also when combined, was observed in the developed 3D ovarian cancer models, in comparison to what was achieved in relevant 2D cell cultures. The obtained results demonstrated therefore the suitability of the developed scaffolds for in vitro investigation of tumor modeling.
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Affiliation(s)
- Simona Braccini
- BIOLab Research Group, Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM - Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
| | - Gianni Pecorini
- BIOLab Research Group, Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM - Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
| | - Serena Biagini
- BIOLab Research Group, Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM - Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
| | - Chiara Tacchini
- BIOLab Research Group, Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM - Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
| | - Antonella Battisti
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, p.zza San Silvestro 12, 56127 Pisa, Italy
| | - Dario Puppi
- BIOLab Research Group, Department of Chemistry and Industrial Chemistry, University of Pisa, UdR INSTM - Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy.
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Rho SB, Kim BR, Lee SH, Lee CH. Translationally Controlled Tumor Protein Enhances Angiogenesis in Ovarian Tumors by Activating Vascular Endothelial Growth Factor Receptor 2 Signaling. Biomol Ther (Seoul) 2025; 33:193-202. [PMID: 39664017 PMCID: PMC11704413 DOI: 10.4062/biomolther.2024.206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024] Open
Abstract
Translationally controlled tumor protein (TCTP) is a regulatory protein that plays pivotal roles in cellular processes including the cell cycle, apoptosis, microtubule stabilization, embryo development, stress responses, and cancer. However, the molecular mechanism by which it promotes tumor angiogenesis is still unclear. In this study, we explored the mechanisms underlying stimulation of angiogenesis by a novel TCTP. Recombinant TCTP enhanced vascular endothelial growth factor (VEGF)-induced endothelial cell migration, capillary-like tubular structure formation, and cell proliferation by interacting with VEGF receptor 2 (VEGFR-2) in vitro. In contrast, we showed that TCTP knockdown (using short interfering [si]TCTP) led to a decrease in ovarian tumor cells. We also examined the expression of VEGF and hypoxia inducible factor 1 (HIF-1α), an important angiogenic factor. The expression of VEGF as well as HIF-1α was dramatically decreased by siTCTP. Mechanistically, siTCTP inhibited VEGFR-2 tyrosine phosphorylation and phosphorylation of its downstream targets PI3K, Akt, and mTOR. Collectively, these findings indicate that TCTP can promote proliferation and angiogenesis via the VEGFR-2/PI3K and mTOR signaling pathways in ovarian tumor cells, providing new insight into the mechanism behind the involvement of TCTP in tumor angiogenesis.
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Affiliation(s)
- Seung Bae Rho
- Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Boh-Ram Kim
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
| | - Seung-Hoon Lee
- Department of Life Science, Yong In University, Yongin 17092, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
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Kicman A, Gacuta E, Marecki R, Kicman MS, Kulesza M, Klank-Sokołowska E, Knapp P, Niczyporuk M, Szmitkowski M, Ławicki S. Diagnostic Utility of Metalloproteinases from Collagenase Group (MMP-1, MMP-8 and MMP-13) in Biochemical Diagnosis of Ovarian Carcinoma. Cancers (Basel) 2024; 16:3969. [PMID: 39682156 DOI: 10.3390/cancers16233969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/19/2024] [Accepted: 11/24/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Ovarian carcinoma (OC) has an unfavorable prognosis due to lack of screening and an asymptomatic course. New diagnostic methods are being sought to enable earlier diagnosis of this condition. The purpose of this study was to determine the diagnostic utility of collagenases (MMP-1, MMP-8 and MMP-13) in the diagnosis of OC compared to HE4 and CA125 and the ROMA. METHODS The study group consisted of 120 patients with OC, the control group: 70 patients with benign ovarian lesions (BLs) and 50 healthy women (HS). MMP-1, MMP-8 and MMP-13 were determined by ELISA and HE4 and CA125 by CMIA. RESULTS OC patients had higher levels of MMP-1 and MMP-13 compared to the BL and HS groups. MMP-1 (SE: 81.66%; SP: 94%; PPV: 97.02%; NPV: 68.11%; AUC: 0.9625) and MMP-13 (SE: 77.50%; SP: 94%; PPV: 96.875%; NPV: 63.51%; AUC: 0.917) showed similar or higher diagnostic values to routine markers (HE4: SE:85%; SP: 92%; PPV: 96.22%; NPV: 71.875%; AUC: 0.943; CA125: SE: 80%; SP: 98%; PPV: 98.96%; NPV: 67.12%; AUC: 0.909) and the ROMA (SE: 90.83%; SP: 94%; PPV: 97.32%; NPV: 81.03%; AUC: 0.955). Performing combined analyses of individual MMPs and MMPs with ROMA was associated with further increases in diagnostic parameters. CONCLUSIONS MMP-1 and MMP-13 have shown preliminary potential as diagnostic markers and auxiliary markers to ROMA in biochemical diagnosis of OC.
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Affiliation(s)
- Aleksandra Kicman
- Department of Aesthetic Medicine, The Faculty of Pharmacy, Medical University of Białystok, 15-267 Białystok, Poland
| | - Ewa Gacuta
- Department of Perinatology, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland
| | - Rafał Marecki
- Department of Psychiatry, The Faculty of Medicine, Medical University of Białystok, 15-272 Białystok, Poland
| | | | - Monika Kulesza
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland
| | - Ewa Klank-Sokołowska
- University Cancer Center, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland
| | - Paweł Knapp
- University Cancer Center, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland
| | - Marek Niczyporuk
- Department of Aesthetic Medicine, The Faculty of Pharmacy, Medical University of Białystok, 15-267 Białystok, Poland
| | - Maciej Szmitkowski
- Department of Biochemical Diagnostics, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland
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Akhlaghipour I, Moghbeli M. Matrix metalloproteinases as the critical regulators of cisplatin response and tumor cell invasion. Eur J Pharmacol 2024; 982:176966. [PMID: 39216742 DOI: 10.1016/j.ejphar.2024.176966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/10/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Cisplatin (CDDP) as one of the most common first-line chemotherapy drugs plays a vital role in the treatment of a wide range of malignant tumors. Nevertheless, CDDP resistance is observed as a therapeutic challenge in a large number of cancer patients. Considering the CDDP side effects in normal tissues, predicting the CDDP response of cancer patients can significantly help to choose the appropriate therapeutic strategy. In this regard, investigating the molecular mechanisms involved in CDDP resistance can lead to the introduction of prognostic markers in cancer patients. Matrix metalloproteinases (MMPs) have critical roles in tissue remodeling and cell migration through extracellular matrix degradation. Therefore, defects in MMPs functions can be associated with tumor metastasis and chemo resistance. In the present review, we discussed the role of MMPs in CDDP response and tumor cell invasion. PubMed, Scopus, Google Scholar, and Web of Science were searched using "MMP", "cisplatin", and "cancer" keywords for data retrieval that was limited to Apr 20, 2024. It has been reported that MMPs can increase CDDP resistance in tumor cells as the effectors of PI3K/AKT, MAPK, and NF-κB signaling pathways or independently through the regulation of structural proteins, autophagy, and epithelial-to-mesenchymal transition (EMT) process. This review has an effective role in introducing MMPs as the prognostic markers and therapeutic targets in CDDP-resistant cancer patients.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Axemaker H, Plesselova S, Calar K, Jorgensen M, Wollman J, de la Puente P. Reprogramming of normal fibroblasts into ovarian cancer-associated fibroblasts via non-vesicular paracrine signaling induces an activated fibroblast phenotype. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119801. [PMID: 39038611 PMCID: PMC11365755 DOI: 10.1016/j.bbamcr.2024.119801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/24/2024]
Abstract
Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present that conditioned media from ovarian cancer lines leads to an increase in the activated state of fibroblasts demonstrated by functional assays and up-regulation of known CAF-related genes and ECM pathways. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression. Critically, the conditioned CAFs resemble a transcriptional signature with involvement of ECM remodeling. The present study provides mechanistic and functional insights about the activation and reprogramming of CAFs in the ovarian tumor microenvironment mediated by non-vesicular paracrine signaling. Moreover, it provides a translational based approach to reprogram normal fibroblasts from both uterine and ovarian origin into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF/ECM-mediated chemoresistance in OC are further warranted.
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Affiliation(s)
- Hailey Axemaker
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Simona Plesselova
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Kristin Calar
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Megan Jorgensen
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Jared Wollman
- Flow Cytometry Core, Sanford Research, Sioux Falls, SD 57104, USA
| | - Pilar de la Puente
- Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA; Flow Cytometry Core, Sanford Research, Sioux Falls, SD 57104, USA; Department of Obstetrics and Gynecology, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA; Department of Surgery, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA.
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7
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Fujimoto H, Yoshihara M, Rodgers R, Iyoshi S, Mogi K, Miyamoto E, Hayakawa S, Hayashi M, Nomura S, Kitami K, Uno K, Sugiyama M, Koya Y, Yamakita Y, Nawa A, Enomoto A, Ricciardelli C, Kajiyama H. Tumor-associated fibrosis: a unique mechanism promoting ovarian cancer metastasis and peritoneal dissemination. Cancer Metastasis Rev 2024; 43:1037-1053. [PMID: 38546906 PMCID: PMC11300578 DOI: 10.1007/s10555-024-10169-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 01/11/2024] [Indexed: 08/06/2024]
Abstract
Epithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.
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Affiliation(s)
- Hiroki Fujimoto
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, Australia
| | - Masato Yoshihara
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Raymond Rodgers
- School of Biomedicine, Robinson Research Institute, The University of Adelaide, Adelaide, Australia
| | - Shohei Iyoshi
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Kazumasa Mogi
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Emiri Miyamoto
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sae Hayakawa
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Maia Hayashi
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Nomura
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhisa Kitami
- Department of Obstetrics and Gynaecology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kaname Uno
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University Graduate School of Medicine, Lund, Sweden
| | - Mai Sugiyama
- Bell Research Center-Department of Obstetrics and Gynaecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Koya
- Bell Research Center-Department of Obstetrics and Gynaecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiko Yamakita
- Bell Research Center-Department of Obstetrics and Gynaecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akihiro Nawa
- Bell Research Center-Department of Obstetrics and Gynaecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynaecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kicman A, Gacuta E, Kulesza M, Będkowska EG, Marecki R, Klank-Sokołowska E, Knapp P, Niczyporuk M, Ławicki S. Diagnostic Utility of Selected Matrix Metalloproteinases (MMP-2, MMP-3, MMP-11, MMP-26), HE4, CA125 and ROMA Algorithm in Diagnosis of Ovarian Cancer. Int J Mol Sci 2024; 25:6265. [PMID: 38892452 PMCID: PMC11173327 DOI: 10.3390/ijms25116265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.
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Affiliation(s)
- Aleksandra Kicman
- Department of Aesthetic Medicine, The Faculty of Pharmacy, Medical University of Białystok, 15-267 Białystok, Poland; (A.K.); (M.N.)
| | - Ewa Gacuta
- Department of Perinatology, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland;
| | - Monika Kulesza
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland;
| | - Ewa Grażyna Będkowska
- Department of Haematological Diagnostics, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland;
| | - Rafał Marecki
- Department of Psychiatry, The Faculty of Medicine, Medical University of Białystok, 15-272 Białystok, Poland;
| | - Ewa Klank-Sokołowska
- University Cancer Center, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland; (E.K.-S.); (P.K.)
| | - Paweł Knapp
- University Cancer Center, University Clinical Hospital of Bialystok, 15-276 Białystok, Poland; (E.K.-S.); (P.K.)
| | - Marek Niczyporuk
- Department of Aesthetic Medicine, The Faculty of Pharmacy, Medical University of Białystok, 15-267 Białystok, Poland; (A.K.); (M.N.)
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, The Faculty of Medicine, Medical University of Białystok, 15-269 Białystok, Poland;
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Lee M, Kim S, Lee SY, Son JG, Park J, Park S, Yeun J, Lee TG, Im SG, Jeon JS. Hydrophobic surface induced pro-metastatic cancer cells for in vitro extravasation models. Bioact Mater 2024; 34:401-413. [PMID: 38282966 PMCID: PMC10819557 DOI: 10.1016/j.bioactmat.2023.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 12/08/2023] [Accepted: 12/23/2023] [Indexed: 01/30/2024] Open
Abstract
In vitro vascularized cancer models utilizing microfluidics have emerged as a promising tool for mechanism study and drug screening. However, the lack of consideration and preparation methods for cancer cellular sources that are capable of adequately replicating the metastatic features of circulating tumor cells contributed to low relevancy with in vivo experimental results. Here, we show that the properties of cancer cellular sources have a considerable impact on the validity of the in vitro metastasis model. Notably, with a hydrophobic surface, we can create highly metastatic spheroids equipped with aggressive invasion, endothelium adhesion capabilities, and activated metabolic features. Combining these metastatic spheroids with the well-constructed microfluidic-based extravasation model, we validate that these metastatic spheroids exhibited a distinct extravasation response to epidermal growth factor (EGF) and normal human lung fibroblasts compared to the 2D cultured cancer cells, which is consistent with the previously reported results of in vivo experiments. Furthermore, the applicability of the developed model as a therapeutic screening platform for cancer extravasation is validated through profiling and inhibition of cytokines. We believe this model incorporating hydrophobic surface-cultured 3D cancer cells provides reliable experimental data in a clear and concise manner, bridging the gap between the conventional in vitro models and in vivo experiments.
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Affiliation(s)
- Minseok Lee
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Seunggyu Kim
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sun Young Lee
- Bioimaging Team, Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), Gajeong-ro 267, Yuseong-gu, Daejeon, 34113, Republic of Korea
| | - Jin Gyeong Son
- Bioimaging Team, Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), Gajeong-ro 267, Yuseong-gu, Daejeon, 34113, Republic of Korea
| | - Joonha Park
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Seonghyeon Park
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jemin Yeun
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Tae Geol Lee
- Bioimaging Team, Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), Gajeong-ro 267, Yuseong-gu, Daejeon, 34113, Republic of Korea
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
- KAIST Institute for the NanoCentury (KINC), Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jessie S. Jeon
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daehak-ro 291, Yuseong-gu, Daejeon, 34141, Republic of Korea
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10
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Costa D, Scalise E, Ielapi N, Bracale UM, Andreucci M, Serra R. Metalloproteinases as Biomarkers and Sociomarkers in Human Health and Disease. Biomolecules 2024; 14:96. [PMID: 38254696 PMCID: PMC10813678 DOI: 10.3390/biom14010096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/05/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Metalloproteinases (MPs) are zinc-dependent enzymes with proteolytic activity and a variety of functions in the pathophysiology of human diseases. The main objectives of this review are to analyze a specific family of MPs, the matrix metalloproteinases (MMPs), in the most common chronic and complex diseases that affect patients' social lives and to better understand the nature of the associations between MMPs and the psychosocial environment. In accordance with the PRISMA extension for a scoping review, an examination was carried out. A collection of 24 studies was analyzed, focusing on the molecular mechanisms of MMP and their connection to the manifestation of social aspects in human disease. The complexity of the relationship between MMP and social problems is presented via an interdisciplinary approach based on complexity paradigm as a new approach for conceptualizing knowledge in health research. Finally, two implications emerge from the study: first, the psychosocial states of individuals have a profound impact on their overall health and disease conditions, which implies the importance of adopting a holistic perspective on human well-being, encompassing both physical and psychosocial aspects. Second, the use of MPs as biomarkers may provide physicians with valuable tools for a better understanding of disease when used in conjunction with "sociomarkers" to develop mathematical predictive models.
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Affiliation(s)
- Davide Costa
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (D.C.); (E.S.)
- Interuniversity Center of Phlebolymphology (CIFL), Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Enrica Scalise
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (D.C.); (E.S.)
- Interuniversity Center of Phlebolymphology (CIFL), Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Nicola Ielapi
- Department of Public Health and Infectious Disease, “Sapienza” University of Rome, 00185 Rome, Italy;
| | | | - Michele Andreucci
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (D.C.); (E.S.)
- Interuniversity Center of Phlebolymphology (CIFL), Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
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11
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Pawar NR, Buzza MS, Duru N, Strong AA, Antalis TM. Matriptase drives dissemination of ovarian cancer spheroids by a PAR-2/PI3K/Akt/MMP9 signaling axis. J Cell Biol 2023; 222:e202209114. [PMID: 37737895 PMCID: PMC10515437 DOI: 10.1083/jcb.202209114] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 07/06/2023] [Accepted: 08/14/2023] [Indexed: 09/23/2023] Open
Abstract
The transmembrane serine protease matriptase is a key regulator of both barrier-disruptive and protective epithelial cell-cell interactions. Elevated matriptase is a consistent feature of epithelial ovarian cancers (OvCa), where multicellular spheroids shed from the primary tumor into the peritoneal cavity are critical drivers of metastasis. Dynamic cell-to-cell adhesive contacts are required for spheroid formation and maintenance. Here, we show that overactive matriptase, reflected in an increased ratio of matriptase to its inhibitor hepatocyte growth factor activator inhibitor 1 (HAI-1), disrupts cell-cell contacts to produce loose prometastatic spheroids that display increased mesothelial cell adhesion and submesothelial invasion. We show that these activities are dependent on the matriptase activation of a protease-activated receptor-2 (PAR-2) signaling pathway involving PI3K/Akt and MMP9-induced disruption of cell-cell adhesion by the release of the soluble E-cadherin ectodomain. These data reveal a novel pathological connection between matriptase activation of PAR-2 and disruption of cell-cell adhesion, and support the clinical investigation of this signaling axis as a therapeutic strategy for aggressive metastatic OvCa.
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Affiliation(s)
- Nisha R. Pawar
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Marguerite S. Buzza
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
- Research and Development Service, VA Maryland Health Care System, Baltimore, MD, USA
| | - Nadire Duru
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Amando A. Strong
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Toni M. Antalis
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
- Research and Development Service, VA Maryland Health Care System, Baltimore, MD, USA
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12
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Wang F, Jin F, Peng S, Li C, Wang L, Wang S. Adipocyte-derived CCDC3 promotes tumorigenesis in epithelial ovarian cancer through the Wnt/ß-catenin signalling pathway. Biochem Biophys Rep 2023; 35:101507. [PMID: 37601453 PMCID: PMC10439399 DOI: 10.1016/j.bbrep.2023.101507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 03/22/2023] [Accepted: 06/28/2023] [Indexed: 08/22/2023] Open
Abstract
Introduction Epithelial ovarian cancer (EOC) is a highly aggressive disease whose unique metastatic site is the omentum. Coiled-coil domain containing 3 (CCDC3) is an adipocyte-derived secreted protein that is specifically elevated in omental adipose tissue. However, its function is still unknown. Material and methods Initially, a Kaplan-Meier plot was applied to evaluate the prognostic value of CCDC3 expression in patients with EOC. A bioinformatics analysis was next used to explore the biological function of CCDC3 in EOC. Western blot, quantitative real-time polymerase chain reaction, and in vitro invasion and migration assays were performed using SKOV3 cells and CCDC3 secreted by rat adipocytes to analyzes the impact of CCDC3 on EOC and the underlying mechanism. Results Overexpression of CCDC3 was associated with poor prognosis of EOC. CCDC3 interacted with multiple key signalling pathways, including the Wnt/β-catenin pathway. EOC cellular proliferation, migration, and invasion were promoted in vitro when co-cultured with CCDC3 enriched conditioned medium, and this tumour-promoting effect was induced by activating the Wnt/β-catenin pathway. Furthermore, the epithelial-mesenchymal transition of EOC cells was reversed after CCDC3 silencing. Conclusions Our results support that CCDC3 promotes EOC tumorigenesis through the Wnt/β-catenin pathway and that CCDC3 may serve as a novel prognostic biomarker and therapeutic target for metastatic EOC.
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Affiliation(s)
- Fen Wang
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China
| | - Feng Jin
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China
| | - Shanshan Peng
- Department of Gynecology, Shenzhen Baoan Maternal and Child Healthcare Hospital, Shenzhen 518000, China
| | - Chen Li
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China
| | - Li Wang
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China
| | - Shubin Wang
- Department of Medical Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Shenzhen 518036, China
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13
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Almutairi S, Kalloush HM, Manoon NA, Bardaweel SK. Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023). Molecules 2023; 28:5567. [PMID: 37513440 PMCID: PMC10384300 DOI: 10.3390/molecules28145567] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/09/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.
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Affiliation(s)
- Shriefa Almutairi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Hanin Moh'd Kalloush
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
- Department of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
| | - Nour A Manoon
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
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14
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Choi JY, Jeong M, Lee K, Kim JO, Lee WH, Park I, Kwon HC, Choi JH. Sedum middendorffianum Maxim Induces Apoptosis and Inhibits the Invasion of Human Ovarian Cancer Cells via Oxidative Stress Regulation. Antioxidants (Basel) 2023; 12:1386. [PMID: 37507925 PMCID: PMC10376315 DOI: 10.3390/antiox12071386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Sedum middendorffianum Maxim (SMM) is a Korean endemic plant belonging to the Crassulaceae family. This study aimed to investigate the antitumor effects of the SMM extract on human ovarian cancer cells. Among five endemic plants grown in Korea, the SMM extract showed the most potent cytotoxicity in ovarian cancer cells and had little effect on normal ovarian surface epithelial cells. Furthermore, we revealed that the SMM extract dose-dependently induced apoptosis in human ovarian cancer A2780 and SKOV3 cells. The SMM extract markedly stimulated the activation of caspase-3/8, while the broad-spectrum caspase inhibitor and caspase-8 selective inhibitor significantly reversed SMM extract-induced apoptosis. In addition, the SMM extract significantly inhibited cell invasion and the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 in ovarian cancer cells. Notably, the SMM extract increased the generation of intracellular ROS, and pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed SMM-induced cytotoxicity and anti-invasive activity. Moreover, NAC treatment reversed the SMM-induced inhibition of MMP-2/9 expression. Taken together, these data suggest that the SMM extract induces caspase-dependent apoptotic cell death and inhibits MMP-dependent invasion via ROS regulation.
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Affiliation(s)
- Ju-Yeon Choi
- Department of Biomedical and Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Miran Jeong
- Department of Biomedical and Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kijun Lee
- Department of Biomedical and Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jin-Ok Kim
- Department of Biomedical and Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wan Hee Lee
- Hantaek Botanical Garden, Yongin 17183, Republic of Korea
| | - InWha Park
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung 25451, Republic of Korea
| | - Hak Cheol Kwon
- Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung 25451, Republic of Korea
| | - Jung-Hye Choi
- Department of Biomedical and Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea
- Hantaek Botanical Garden, Yongin 17183, Republic of Korea
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15
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Kelly R, Aviles D, Krisulevicz C, Hunter K, Krill L, Warshal D, Ostrovsky O. The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome. Biomolecules 2023; 13:1066. [PMID: 37509102 PMCID: PMC10377145 DOI: 10.3390/biom13071066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes.
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Affiliation(s)
- Rebeca Kelly
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - Diego Aviles
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | | | - Krystal Hunter
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Cooper Research Institute, Cooper University Healthcare, Camden, NJ 08103, USA
| | - Lauren Krill
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - David Warshal
- Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper University Hospital, Camden, NJ 08103, USA
| | - Olga Ostrovsky
- Cooper Medical School of Rowan University, Camden, NJ 08103, USA
- Cooper Research Institute, Cooper University Healthcare, Camden, NJ 08103, USA
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16
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Cai J, Hu Q, He Z, Chen X, Wang J, Yin X, Ma X, Zeng J. Scutellaria baicalensis Georgi and Their Natural Flavonoid Compounds in the Treatment of Ovarian Cancer: A Review. Molecules 2023; 28:5082. [PMID: 37446743 DOI: 10.3390/molecules28135082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Ovarian cancer (OC) is one of the most common types of cancer in women with a high mortality rate, and the treatment of OC is prone to high recurrence rates and side effects. Scutellaria baicalensis (SB) is a herbal medicine with good anti-cancer activity, and several studies have shown that SB and its flavonoids have some anti-OC properties. This paper elucidated the common pathogenesis of OC, including cell proliferation and cell cycle regulation, cell invasion and metastasis, apoptosis and autophagy, drug resistance and angiogenesis. The mechanisms of SB and its flavonoids, wogonin, baicalein, baicalin, Oroxylin A, and scutellarein, in the treatment of OC, are revealed, such as wogonin inhibits proliferation, induces apoptosis, inhibits invasion and metastasis, and increases the cytotoxicity of the drug. Baicalein also inhibits vascular endothelial growth factor (VEGF) expression etc. Analyzing their advantages and disadvantages in treating OC provides a new perspective on the role of SB and its flavonoids in OC treatment. It serves as a resource for future OC research and development.
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Affiliation(s)
- Jiaying Cai
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zhelin He
- Endoscopy Center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiaoyan Chen
- Endoscopy Center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Jian Wang
- Endoscopy Center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiang Yin
- Endoscopy Center, Guang'an Hospital of Traditional Chinese Medicine, Guang'an 638000, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
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17
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Workman S, Wilson MJ. RNA sequencing and expression analysis reveal a role for Lhx9 in the haploinsufficient adult mouse ovary. Mol Reprod Dev 2023; 90:295-309. [PMID: 37084273 DOI: 10.1002/mrd.23686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 02/26/2023] [Accepted: 04/05/2023] [Indexed: 04/23/2023]
Abstract
Understanding the molecular pathways that underpin ovarian development and function is vital for improving the research approaches to investigating fertility. Despite a significant improvement in our knowledge of molecular activity in the ovary, many questions remain unanswered in the quest to understand factors influencing fertility and ovarian pathologies such as cancer. Here, we present an investigation into the expression and function of the developmental transcription factor LIM Homeobox 9 (LHX9) in the adult mouse ovary. We have characterized Lhx9 expression in several cell types of the mature ovary across follicle stages. To evaluate possible LHX9 function in the adult ovary, we investigated ovarian anatomy and transcription in an Lhx9+/- knockout mouse model displaying subfertility. Despite a lack of gross anatomical differences between genotypes, RNA-sequencing found that 90 differentially expressed genes between Lhx9+/ - and Lhx9+/+ mice. Gene ontology analyses revealed a reduced expression of genes with major roles in ovarian steroidogenesis and an increased expression of genes associated with ovarian cancer. Analysis of the ovarian epithelium revealed Lhx9+/ - mice have a disorganized epithelial phenotype, corresponding to a significant increase in epithelial marker gene expression. These results provide an analysis of Lhx9 in the adult mouse ovary, suggesting a role in fertility and ovarian epithelial cancer.
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Affiliation(s)
- Stephanie Workman
- Developmental Genomics Laboratory, Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Megan J Wilson
- Developmental Genomics Laboratory, Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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18
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Islam MR, Rahman MM, Dhar PS, Nowrin FT, Sultana N, Akter M, Rauf A, Khalil AA, Gianoncelli A, Ribaudo G. The Role of Natural and Semi-Synthetic Compounds in Ovarian Cancer: Updates on Mechanisms of Action, Current Trends and Perspectives. Molecules 2023; 28:2070. [PMID: 36903316 PMCID: PMC10004182 DOI: 10.3390/molecules28052070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Ovarian cancer represents a major health concern for the female population: there is no obvious cause, it is frequently misdiagnosed, and it is characterized by a poor prognosis. Additionally, patients are inclined to recurrences because of metastasis and poor treatment tolerance. Combining innovative therapeutic techniques with established approaches can aid in improving treatment outcomes. Because of their multi-target actions, long application history, and widespread availability, natural compounds have particular advantages in this connection. Thus, effective therapeutic alternatives with improved patient tolerance hopefully can be identified within the world of natural and nature-derived products. Moreover, natural compounds are generally perceived to have more limited adverse effects on healthy cells or tissues, suggesting their potential role as valid treatment alternatives. In general, the anticancer mechanisms of such molecules are connected to the reduction of cell proliferation and metastasis, autophagy stimulation and improved response to chemotherapeutics. This review aims at discussing the mechanistic insights and possible targets of natural compounds against ovarian cancer, from the perspective of medicinal chemists. In addition, an overview of the pharmacology of natural products studied to date for their potential application towards ovarian cancer models is presented. The chemical aspects as well as available bioactivity data are discussed and commented on, with particular attention to the underlying molecular mechanism(s).
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Affiliation(s)
- Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Puja Sutro Dhar
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Feana Tasmim Nowrin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Nasrin Sultana
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Muniya Akter
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar 23430, Pakistan
| | - Anees Ahmed Khalil
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore 54000, Pakistan
| | - Alessandra Gianoncelli
- Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123 Brescia, Italy
| | - Giovanni Ribaudo
- Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Viale Europa 11, 25123 Brescia, Italy
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19
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Kicman A, Niczyporuk M, Kulesza M, Motyka J, Ławicki S. Utility of Matrix Metalloproteinases in the Diagnosis, Monitoring and Prognosis of Ovarian Cancer Patients. Cancer Manag Res 2022; 14:3359-3382. [PMID: 36474934 PMCID: PMC9719685 DOI: 10.2147/cmar.s385658] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/08/2022] [Indexed: 01/14/2024] Open
Abstract
Ovarian cancer is one of the most common gynecologic malignancies. It is characterized by a high mortality rate, which is mainly due to the asymptomatic course of the disease. In light of the high mortality rate and increasing morbidity, new diagnostic methods are being explored to enable earlier detection, better monitoring, and improved prognosis. Such diagnostic methods include the assessment of tumor markers in various biological samples. Among the markers currently being investigated, extracellular matrix metalloproteinases (MMPs) are of particular interest. The objective of this article was to compile the existing knowledge of MMPs in ovarian cancer patients and to describe their potential diagnostic utility. Additionally, this article provides an overview of the symptoms, complications, and risk factors associated with ovarian cancer and the role of MMPs in physiology and pathology. Preliminary results indicate that tissue expression and blood and body fluid levels of MMPs may be different in ovarian cancer patients than in healthy women. The expression and concentration of individual MMPs have been shown to be correlated with cancer stage and disease severity. In addition, the preliminary value of some of these enzymes in predicting prognosis is discussed. However, as the amount of data is limited, more studies are needed to fully evaluate the potential function of individual MMPs in ovarian cancer patients. Based on the knowledge gathered for this article, it seems that MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, are tentatively the most useful. A thorough evaluation of their utility as modern biomarkers in ovarian cancer requires further investigation.
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Affiliation(s)
- Aleksandra Kicman
- Department of Aesthetic Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Marek Niczyporuk
- Department of Aesthetic Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Monika Kulesza
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Motyka
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
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20
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Zuo C, Zhang Y, Cao C, Feng J, Jiao M, Chen L. Elucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning. Nat Commun 2022; 13:5962. [PMID: 36216831 PMCID: PMC9551038 DOI: 10.1038/s41467-022-33619-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 09/26/2022] [Indexed: 12/02/2022] Open
Abstract
Spatially resolved transcriptomics (SRT) technology enables us to gain novel insights into tissue architecture and cell development, especially in tumors. However, lacking computational exploitation of biological contexts and multi-view features severely hinders the elucidation of tissue heterogeneity. Here, we propose stMVC, a multi-view graph collaborative-learning model that integrates histology, gene expression, spatial location, and biological contexts in analyzing SRT data by attention. Specifically, stMVC adopting semi-supervised graph attention autoencoder separately learns view-specific representations of histological-similarity-graph or spatial-location-graph, and then simultaneously integrates two-view graphs for robust representations through attention under semi-supervision of biological contexts. stMVC outperforms other tools in detecting tissue structure, inferring trajectory relationships, and denoising on benchmark slices of human cortex. Particularly, stMVC identifies disease-related cell-states and their transition cell-states in breast cancer study, which are further validated by the functional and survival analysis of independent clinical data. Those results demonstrate clinical and prognostic applications from SRT data.
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Affiliation(s)
- Chunman Zuo
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China.
- Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Chen Cao
- School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211166, China
| | - Jinwang Feng
- Key Laboratory of Information Fusion Technology of Ministry of Education, School of Automation, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Mingqi Jiao
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China.
- Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong, 519031, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
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21
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Chen CJ, Shang HS, Huang YL, Tien N, Chen YL, Hsu SY, Wu RSC, Tang CL, Lien JC, Lee MH, Lu HF, Hsia TC. Bisdemethoxycurcumin suppresses human brain glioblastoma multiforme GBM 8401 cell migration and invasion via affecting NF-κB and MMP-2 and MMP-9 signaling pathway in vitro. ENVIRONMENTAL TOXICOLOGY 2022; 37:2388-2397. [PMID: 35735092 DOI: 10.1002/tox.23604] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 06/15/2023]
Abstract
Human glioblastoma (GBM) is one of the common cancer death in adults worldwide, and its metastasis will lead to difficult treatment. Finding compounds for future to develop treatment is urgent. Bisdemethoxycurcumin (BDMC), a natural product, was isolated from the rhizome of turmeric (Curcuma longa), which has been shown to against many human cancer cells. In the present study, we evaluated the antimetastasis activity of BDMC in human GBM cells. Cell proliferation, cell viability, cellular uptake, wound healing, migration and invasion, and western blotting were analyzed. Results indicated that BDMC at 1.5-3 μM significantly decreased the cell proliferation by MTT assay. BDMC showed the highest uptake by cells at 3 h. After treatment of BDMC at 12-48 h significantly inhibited cell motility in GBM 8401 cells by wound healing assay. BDMC suppressed cell migration and invasion at 24 and 48 h treatment by transwell chamber assay. BDMC significantly decreased the levels of proteins associated with PI3K/Akt, Ras/MEK/ERK pathways and resulted in the decrease in the expressions of NF-κB, MMP-2, MMP-9, and N-cadherin, leading to the inhibition of cell migration and invasion. These findings suggest that BDMC may be a potential candidate for the antimetastasis of human GBM cells in the future.
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Affiliation(s)
- Chiung-Ju Chen
- Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Hung-Sheng Shang
- Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Clinical of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yuan-Li Huang
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung City, Taiwan
| | - Ni Tien
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yung-Liang Chen
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan
| | - Sheng-Yao Hsu
- Department of Ophthalmology, An Nan Hospital, China Medical University, Tainan, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Rick Sai-Chuen Wu
- Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Lun Tang
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jin-Cherng Lien
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Mei-Hui Lee
- Department of Genetic Counseling Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsu-Feng Lu
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung City, Taiwan
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Te-Chun Hsia
- Department of Respiratory Therapy, China Medical University, Taichung, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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22
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Borzdziłowska P, Bednarek I. Alpha Mangostin and Cisplatin as Modulators of Exosomal Interaction of Ovarian Cancer Cell with Fibroblasts. Int J Mol Sci 2022; 23:8913. [PMID: 36012171 PMCID: PMC9408324 DOI: 10.3390/ijms23168913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 12/02/2022] Open
Abstract
The diversity of exosomes and their role in the microenvironment make them an important point of interest in the development of cancer. In our study, we evaluated the effect of exosomes derived from ovarian cancer cells on gene expression in fibroblasts, including genes involved in metastasis. We also attempted to evaluate the indirect effect of cisplatin and/or α-mangostin on metastasis. In this aspect, we verified the changes induced by the drugs we tested on vesicular transfer associated with the release of exosomes by cells. We isolated exosomes from ovarian cancer cells treated and untreated with drugs, and then normal human fibroblasts were treated with the isolated exosomes. Changes in the expression of genes involved in the metastasis process were then examined. In our study, we observed altered expression of genes involved in various steps of the metastasis process (including genes related to cell adhesion, genes related to the interaction with the extracellular matrix, the cell cycle, cell growth and proliferation, and apoptosis). We have shown that α-mangostin and/or cisplatin, as chemotherapeutic agents, not only directly affect tumor cells but may also indirectly (via exosomes) contribute to delaying metastasis development.
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Affiliation(s)
- Paulina Borzdziłowska
- Department of Biotechnology and Genetic Engineering, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
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23
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Circulating and non-circulating proteins and nucleic acids as biomarkers and therapeutic molecules in ovarian cancer. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Synthesis, Characterization, Molecular Docking and Molecular Dynamics Simulations of Benzamide Derivatives as Potential Anti-Ovarian Cancer Agents. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133785] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Huang X, Jiang L, Lu S, Yuan M, Lin H, Li B, Wen Z, Zhong Y. Overexpression of ERCC6L correlates with poor prognosis and confers malignant phenotypes of lung adenocarcinoma. Oncol Rep 2022; 48:131. [PMID: 35656882 PMCID: PMC9204608 DOI: 10.3892/or.2022.8342] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 05/09/2022] [Indexed: 11/05/2022] Open
Abstract
Excision repair cross‑complementation group 6 like (ERCC6L) has been reported to be upregulated in a variety of malignant tumors and plays a critical oncogenic role. However, the role and molecular mechanism of ERCC6L in lung adenocarcinoma (LUAD) remain unclear, and were therefore investigated in the present study. Clinical data of patients with LUAD were obtained and bioinformatics analysis was performed to investigate the expression characteristics, prognostic value, and biological function of ERCC6L. In addition, cell function experiments were performed to detect the effect of ERCC6L silencing on the biological behavior of LUAD cells. The results revealed that ERCC6L expression was significantly higher in LUAD tissues vs. normal lung tissues and closely associated with nodal invasion, advanced clinical stage and survival in LUAD. Overexpression of ERCC6L was an independent prognostic biomarker of overall survival, progression‑free interval, and disease‑specific survival in patients with LUAD. DNA amplification and low methylation levels of ERCC6L suggested regulation at both the genetic and epigenetic levels. The most significant positive genes co‑expressed with ERCC6L were mainly enriched in the cell cycle signaling pathway. The major functions of ERCC6L in LUAD cells were positively correlated with the cell cycle, DNA damage, DNA repair, proliferation, invasion and epithelial‑mesenchymal transition (EMT). Knockdown of ERCC6L inhibited the proliferative, migratory and invasive abilities of A549 and PC9 cells. It also promoted cell apoptosis, and led to cell cycle arrest in the S phase. ERCC6L may regulate the EMT process through the Wnt/β‑catenin and Wnt/Notch 3 signaling pathways, thus regulating the tumorigenesis and progression of LUAD. The overexpression of ERCC6L may be a biological indicator for the diagnosis and prognosis of LUAD. ERCC6L may be a novel molecular target for the treatment of lung cancer.
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Affiliation(s)
- Xiaoyue Huang
- Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region 530004, P.R. China
| | - Lingyu Jiang
- Intensive Care Unit, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Sufang Lu
- Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region 530004, P.R. China
| | - Mingqing Yuan
- Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region 530004, P.R. China
| | - Hui Lin
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Baijun Li
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhaoke Wen
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yonglong Zhong
- Department of Thoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Silibinin exerts anti-cancer activity on human ovarian cancer cells by increasing apoptosis and inhibiting epithelial-mesenchymal transition (EMT). Gene 2022; 823:146275. [PMID: 35189245 DOI: 10.1016/j.gene.2022.146275] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 01/13/2022] [Accepted: 02/03/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND Silibinin, the principal flavonoid derived from milk thistle seeds, has been demonstrated to have strong inhibitory effects against human malignancies. The inhibitory function of silibinin on ovarian cancer, however, is not fully identified. In this essay, both in vivo and in vitro investigations were conducted to survey the silibinin's blocking effects on ovarian cancer. METHODS The impacts of silibinin on two ovarian cancer cell lines, SKOV-3 and A2870, were determined by evaluating cell viability, migration, invasion, and apoptosis. Q-RT-PCR and western blotting techniques were carried out to explore the protein levels of signaling pathway markers. A mouse xenograft model was utilized to determine the silibinin efficacy in inhibiting tumor growth. RESULTS After cell treatment with silibinin, cell viability, migration, and invasion were appreciably inhibited in cancer cell lines, but cell apoptosis was promoted. Also, silibinin reversed the epithelial-mesenchymal transition (EMT) mechanism by inducing E-cadherin expression and reducing N-cadherin and vimentin expression, suppressing the levels of regulators related to EMT such as Snail, Slug, and ZEB1 transcription factors, and also decreasing PI3K/AKT, Smad2/3, and β-catenin intermediate molecules in vitro. Silibinin effectively ameliorated tumor growth in vivo. CONCLUSION silibinin could be considered a potent agent against ovarian cancer based on the results.
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Tune BXJ, Sim MS, Poh CL, Guad RM, Woon CK, Hazarika I, Das A, Gopinath SCB, Rajan M, Sekar M, Subramaniyan V, Fuloria NK, Fuloria S, Batumalaie K, Wu YS. Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors. JOURNAL OF ONCOLOGY 2022; 2022:3249766. [PMID: 35586209 PMCID: PMC9110224 DOI: 10.1155/2022/3249766] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 04/11/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.
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Affiliation(s)
- Bernadette Xin Jie Tune
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, 88400 Sabah, Malaysia
| | - Choy Ker Woon
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, 47000 Selangor, Malaysia
| | - Iswar Hazarika
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Guwahati 781017, India
| | - Anju Das
- Department of Pharmacology, Royal School of Pharmacy, Royal Global University, Guwahati 781035, India
| | - Subash C. B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, 02600 Perlis, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, 01000 Perlis, Malaysia
| | - Mariappan Rajan
- Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Perak, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor 42610, Malaysia
| | | | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Semeling, Bedong, Kedah 08100, Malaysia
| | - Kalaivani Batumalaie
- Department of Biomedical Sciences, Faculty of Health Sciences, Asia Metropolitan University, 81750 Johor Bahru, Malaysia
| | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
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28
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Escalona RM, Kannourakis G, Findlay JK, Ahmed N. Expression of TIMPs and MMPs in Ovarian Tumors, Ascites, Ascites-Derived Cells, and Cancer Cell Lines: Characteristic Modulatory Response Before and After Chemotherapy Treatment. Front Oncol 2022; 11:796588. [PMID: 35047406 PMCID: PMC8762252 DOI: 10.3389/fonc.2021.796588] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/07/2021] [Indexed: 12/27/2022] Open
Abstract
Background The tissue inhibitors of metalloproteinase (TIMPs) and their associated metalloproteinase (MMPs) are essential regulators of tissue homeostasis and are essential for cancer progression. This study analyzed the expression of TIMP-1,-2,-3 and the associated MMPs (MMP-2,-9,-11,-14) in different Stages, Grades and World Health Organization (WHO) classifications of serous ovarian tumors, ascites, ascites-derived cells from chemo-naïve (CN) and relapsed (CR) patients, and in ovarian cancer cell lines. The status of TIMPs and associated MMPs in response to chemotherapy treatment was assessed in cancer cell lines; TCGA data was interrogated to gauge TIMPs and associated MMPs as prognostic and platinum-response indicators. Methods The levels of TIMP-1, -2 and -3 were assessed by immunohistochemistry. The mRNA expression of TIMPs and MMPs was quantified by real time PCR (qRT-PCR). The chemosensitivity (IC50 values) to Cisplatin or Paclitaxel in cell lines was evaluated by MTT assay. The levels of TIMPs in ascites and cell lysates were analyzed by an ELISA assay. Results The expression of TIMP-2 was significantly upregulated in Type 2 compared to Type 1 tumors and normal/benign ovarian tissues. TIMP-3 expression was significantly enhanced in Stage III, Grade 3 and Type 2 tumors compared to normal/benign ovarian tissues. The mRNA expression of MMP-9,-11 and -14 was significantly upregulated in Stage IV compared to normal/benign ovarian tissues. The expression of TIMP-1 was highest, followed by TIMP-2 and then TIMP-3 in CN ascites. At the cellular level, TIMP-2 mRNA expression was significantly higher in CN compared to CR epithelial cells in patients. The expression of TIMP-1 and -2, MMPs and cancer stem cells (CSCs) were upregulated in response to chemotherapy treatments in cancer cell lines. Interrogation of the TCGA dataset suggests shifts in platinum responses in patients consistent with genetic alterations in TIMP-2, -3 and MMP-2, -11 genes in tumors; and decreased overall survival (OS) and progression-free survival (PFS) in patients with altered MMP-14 genes. Conclusions TIMPs and related MMPs are differentially expressed in serous ovarian tumors, ascites, ascites-derived cells and ovarian cancer cell lines. Chemotherapy treatment modulates expression of TIMPs and MMPs in association with increased expression of genes related to cancer stem cells.
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Affiliation(s)
- Ruth M Escalona
- Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia.,Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Translational Medicine, Monash University, Melbourne, VIC, Australia
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia.,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, Australia
| | - Jock K Findlay
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia.,Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Translational Medicine, Monash University, Melbourne, VIC, Australia
| | - Nuzhat Ahmed
- Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia.,Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Translational Medicine, Monash University, Melbourne, VIC, Australia.,School of Science, Psychology and Sport, Federation University Australia, Ballarat, VIC, Australia
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Begum Y, Pandit A, Swarnakar S. Insights Into the Regulation of Gynecological Inflammation-Mediated Malignancy by Metalloproteinases. Front Cell Dev Biol 2021; 9:780510. [PMID: 34912809 PMCID: PMC8667270 DOI: 10.3389/fcell.2021.780510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/12/2021] [Indexed: 12/09/2022] Open
Abstract
Gynecological illness accounts for around 4.5% of the global disease burden, which is higher than other key global health concerns such as malaria (1.04%), TB (1.9%), ischemic heart disease (2.2%), and maternal disorders (3.5%). Gynecological conditions in women of reproductive age are linked to both in terms of diagnosis and treatment, especially in low-income economies, which poses a serious social problem. A greater understanding of health promotion and illness management can help to prevent diseases in gynecology. Due to the lack of established biomarkers, the identification of gynecological diseases, including malignancies, has proven to be challenging in most situations, and histological exams remain the gold standard. Metalloproteinases (MMPs, ADAMs, ADAMTSs) and their endogenous inhibitors (TIMPs) modulate the protease-dependent bioavailability of local niche components (e.g., growth factors), matrix turnover, and cellular interactions to govern specific physical and biochemical characteristics of the environment. Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM), and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that contribute significantly to the disintegration of extracellular matrix proteins and shedding of membrane-bound receptor molecules in several diseases, including arthritis. MMPs are noteworthy genes associated with cancer development, functional angiogenesis, invasion, metastasis, and immune surveillance evasion. These genes are often elevated in cancer and multiple benign gynecological disorders like endometriosis, according to research. Migration through the extracellular matrix, which involves proteolytic activity, is an essential step in tumor cell extravasation and metastasis. However, none of the MMPs’ expression patterns, as well as their diagnostic and prognostic potential, have been studied in a pan-cancer context. The latter plays a very important role in cell signaling and might be used as a cancer treatment target. ADAMs are implicated in tumor cell proliferation, angiogenesis, and metastasis. This review will focus on the contribution of the aforementioned metalloproteinases in regulating gynecological disorders and their subsequent manipulation for therapeutic intervention.
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Affiliation(s)
- Yasmin Begum
- Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Anuradha Pandit
- Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Snehasikta Swarnakar
- Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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Xu XL, Deng SL, Lian ZX, Yu K. Resveratrol Targets a Variety of Oncogenic and Oncosuppressive Signaling for Ovarian Cancer Prevention and Treatment. Antioxidants (Basel) 2021; 10:antiox10111718. [PMID: 34829589 PMCID: PMC8614917 DOI: 10.3390/antiox10111718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer is a heterogeneous disease and is also the major cause of death among women from gynecologic malignancies. A combination of surgery and chemotherapy is the major therapy for ovarian cancer. Unfortunately, despite good response rates to initial surgery and chemotherapy, most patients relapse and have a generally poor survival rate. The present research sheds light on the therapeutic effects of multiple natural products in patients with ovarian cancer. Notably, these natural ingredients do not have adverse effects on healthy cells and tissues, indicating that natural products can serve as a safe alternative therapy for ovarian cancer. Trans-3,4,5′-Trihydroxystibene (resveratrol) is a natural product that is commonly found in the human diet and that has been shown to have anticancer effects on various human cancer cells. This review summarizes current knowledge regarding the progress of resveratrol against tumor cell proliferation, metastasis, apoptosis induction, autophagy, sensitization, and antioxidation as well as anti-inflammation. It also provides information regarding the role of resveratrol analogues in ovarian cancer. A better understanding of the role of resveratrol in ovarian cancer may provide a new array for the prevention and therapy of ovarian cancer.
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Affiliation(s)
- Xue-Ling Xu
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Shou-Long Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China; or
| | - Zheng-Xing Lian
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
| | - Kun Yu
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
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Insights into the Role of Oxidative Stress in Ovarian Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8388258. [PMID: 34659640 PMCID: PMC8516553 DOI: 10.1155/2021/8388258] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022]
Abstract
Oxidative stress (OS) arises when the body is subjected to harmful endogenous or exogenous factors that overwhelm the antioxidant system. There is increasing evidence that OS is involved in a number of diseases, including ovarian cancer (OC). OC is the most lethal gynecological malignancy, and risk factors include genetic factors, age, infertility, nulliparity, microbial infections, obesity, smoking, etc. OS can promote the proliferation, metastasis, and therapy resistance of OC, while high levels of OS have cytotoxic effects and induce apoptosis in OC cells. This review focuses on the relationship between OS and the development of OC from four aspects: genetic alterations, signaling pathways, transcription factors, and the tumor microenvironment. Furthermore, strategies to target aberrant OS in OC are summarized and discussed, with a view to providing new ideas for clinical treatment.
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Reijonen P, Peltonen R, Tervahartiala T, Sorsa T, Isoniemi H. Serum Matrix Metalloproteinase-8 and Myeloperoxidase Predict Survival after Resection of Colorectal Liver Metastases. Oncology 2021; 99:766-779. [PMID: 34571507 DOI: 10.1159/000518955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 08/07/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Matrix metalloproteinases (MMPs) have been extensively studied in several malignancies, and myeloperoxidase (MPO) is a promising new prognostic biomarker. We investigated the prognostic value of MMP-8, MMP-9, and MPO, as well as carcinoembryonic antigen (CEA), CA19-9, and C-reactive protein (CRP) in colorectal cancer with operable liver metastases. METHODS This study included 419 patients who underwent liver resection for colorectal metastases at the Helsinki University Hospital between 2000 and 2013. Serum samples were drawn before and 3 months after liver resection. We evaluated associations of MMP-8, MMP-9, MPO, CRP, CEA, and CA19-9 concentrations to disease-free survival (DFS) and overall survival (OS) using the Cox proportional hazards model and Kaplan-Meier log-rank method. RESULTS In univariate Cox regression analyses, pre- and postoperatively high MMP-8 (HR 1.53, 95% CI: 1.07-2.19, p = 0.021 and HR 1.45, 95% CI: 1.01-2.09, p = 0.044, respectively) associated with worse 10-year OS. Postoperatively high MPO indicated better 5-year DFS (HR 0.70, 95% CI: 0.54-0.90, p = 0.007). Elevated pre- and postoperative CEA and CA19-9 as well as postoperative CRP indicated impaired survival. CONCLUSIONS Pre- and postoperatively high MMP-8 associates with worse 10-year OS, and postoperatively high MPO associates with better 5-year DFS. CEA, CA19-9, and CRP are also prognostic.
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Affiliation(s)
- Pauliina Reijonen
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Reetta Peltonen
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Taina Tervahartiala
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Helena Isoniemi
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,Research Programs Unit, Translational Cancer Medicine Program, University of Helsinki, Helsinki, Finland
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Vos MC, van der Wurff AAM, van Kuppevelt TH, Massuger LFAG. The role of MMP-14 in ovarian cancer: a systematic review. J Ovarian Res 2021; 14:101. [PMID: 34344453 PMCID: PMC8336022 DOI: 10.1186/s13048-021-00852-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 07/23/2021] [Indexed: 12/18/2022] Open
Abstract
AIM In order to evaluate the role of MMP-14 in ovarian cancer, a systematic review was conducted. METHODS In March 2020, a search in Pubmed was performed with MMP-14 and ovarian cancer as search terms. After exclusion of the references not on MMP-14 or ovarian cancer or not in English, the studies found were classified into two categories: basic research and clinicopathological research. RESULTS In total, 94 references were found of which 33 were excluded. Two additional articles were found in the reference lists of the included studies. Based on the full texts, another 4 were excluded. Eventually, 59 studies were included in the review, 32 on basic research and 19 on clinicopathological research. 8 studies fell in both categories. The basic research studies show that MMP-14 plays an important role in ovarian cancer in the processes of proliferation, invasion, angiogenesis and metastasis. In clinocopathological research, MMP-14 expression is found in most tumours with characteristics of poor prognosis but this immunohistochemical MMP-14 determination does not seem to be an independent predictor of prognosis. CONCLUSIONS From this systematic review of the literature concerning MMP-14 in ovarian cancer it becomes clear that MMP-14 plays various important roles in the pathophysiology of ovarian cancer. The exact translation of these roles in the pathophysiology to the importance of MMP-14 in clinicopathological research in ovarian cancer and possible therapeutic role of anti-MMP-14 agents needs further elucidation.
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Affiliation(s)
- M. Caroline Vos
- Department of Obstetrics and Gynaecology, Elisabeth-Tweesteden Hospital, PO Box 90151, 5000 LC Tilburg, the Netherlands
| | | | - Toin H. van Kuppevelt
- Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands
| | - Leon F. A. G. Massuger
- Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands
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Aligned Collagen-CNT Nanofibrils and the Modulation Effect on Ovarian Cancer Cells. JOURNAL OF COMPOSITES SCIENCE 2021; 5. [PMID: 35664989 PMCID: PMC9164112 DOI: 10.3390/jcs5060148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Fibrillar collagen is a one-dimensional biopolymer and is the most abundant structural protein in the extracellular matrix (ECM) of connective tissues. Due to the unique properties of carbon nanotubes (CNTs), considerable attention has been given to the application of CNTs in developing biocomposite materials for tissue engineering and drug delivery. When introduced to tissues, CNTs inevitably interact and integrate with collagen and impose a discernible effect on cells in the vicinity. The positive effect of the collagen-CNT (COL-CNT) matrix in tissue regeneration and the cytotoxicity of free CNTs have been investigated extensively. In this study, we aimed to examine the effect of COL-CNT on mediating the interaction between the matrix and SKOV3 ovarian cancer cells. We generated unidirectionally aligned collagen and COL-CNT nanofibrils, mimicking the structure and dimension of collagen fibrils in native tissues. AFM analysis revealed that the one-dimensional structure, high stiffness, and low adhesion of COL-CNT greatly facilitated the polarization of SKOV3 cells by regulating the β−1 integrin-mediated cell–matrix interaction, cytoskeleton rearrangement, and cell migration. Protein and gene level analyses implied that both collagen and COL-CNT matrices induced the epithelial–mesenchymal transition (EMT), and the COL-CNT matrix prompted a higher level of cell transformation. However, the induced cells expressed CD44 at a reduced level and MMP2 at an increased level, and they were responsive to the chemotherapy drug gemcitabine. The results suggested that the COL-CNT matrix induced the transdifferentiation of the epithelial cancer cells to mature, less aggressive, and less potent cells, which are inapt for tumor metastasis and chemoresistance. Thus, the presence of CNT in a collagen matrix is unlikely to cause an adverse effect on cancer patients if a controlled dose of CNT is used for drug delivery or tissue regeneration.
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Rowswell-Turner RB, Singh RK, Urh A, Yano N, Kim KK, Khazan N, Pandita R, Sivagnanalingam U, Hovanesian V, James NE, Ribeiro JR, Kadambi S, Linehan DC, Moore RG. HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression. THE JOURNAL OF IMMUNOLOGY 2021; 206:2478-2488. [PMID: 33903172 DOI: 10.4049/jimmunol.2000281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 03/08/2021] [Indexed: 01/18/2023]
Abstract
Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high- and low-expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.
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Affiliation(s)
- Rachael B Rowswell-Turner
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY .,Division of Hematology and Oncology, Department of Internal Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Rakesh K Singh
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Anze Urh
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, East Garden City, NY
| | - Naohiro Yano
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
| | - Kyu Kwang Kim
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Negar Khazan
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Ravina Pandita
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Umayal Sivagnanalingam
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | | | - Nicole E James
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
| | - Jennifer R Ribeiro
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI
| | - Sindhuja Kadambi
- Division of Hematology and Oncology, Department of Internal Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - David C Linehan
- Division of Surgical Oncology, Department of Surgery, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Richard G Moore
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
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Tofani LB, Sousa LO, Luiz MT, Abriata JP, Marchetti JM, Leopoldino AM, Swiech K. Generation of a Three-Dimensional in Vitro Ovarian Cancer Co-Culture Model for Drug Screening Assays. J Pharm Sci 2021; 110:2629-2636. [PMID: 33848527 DOI: 10.1016/j.xphs.2021.04.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 02/07/2023]
Abstract
In vitro 3D culture models have emerged in the cancer field due to their ability to recapitulate characteristics of the in vivo tumor. Herein, we described the establishment and characterization of 3D multicellular spheroids using ovarian cancer cells (SKOV-3) in co-culture with mesenchymal cells (MUC-9) or fibroblasts (CCD27-Sk). We demonstrated that SKOV-3 cells in co-culture were able to form regular and compact spheroids with diameters ranging from 300 to 400 µm and with a roundness close to 1.0 regardless of the type of stromal cell used. In the 3D culture an increase was not observed in spheroid diameter nor was there significant cell growth. What is more, the 3D co-cultures presented an up regulation of genes related to tumorigenesis, angiogenesis and metastases (MMP2, VEGFA, SNAI1, ZEB1 and VIM) when compared with 2D and 3D monoculture. As expected, both 3D cultures (mono and co-cultures) exhibited a higher Paclitaxel chemoresistance when compared to 2D condition. Although we did not observe differences in the Paclitaxel resistance between the 3D mono and co-cultures, the gene expression results indicate that the presence of mesenchymal cells and fibroblasts better recapitulate the in vivo tumor microenvironment, being able, therefore, to more accurately evaluate drug efficacy for ovarian cancer therapy.
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Affiliation(s)
- Larissa Bueno Tofani
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Lucas Oliveira Sousa
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Marcela Tavares Luiz
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Juliana Palma Abriata
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Juliana Maldonado Marchetti
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Andréia Machado Leopoldino
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil
| | - Kamilla Swiech
- School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café w/n, Ribeirão Preto, Sao Paulo, Brazil.
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Carey P, Low E, Harper E, Stack MS. Metalloproteinases in Ovarian Cancer. Int J Mol Sci 2021; 22:3403. [PMID: 33810259 PMCID: PMC8036623 DOI: 10.3390/ijms22073403] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 01/25/2023] Open
Abstract
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor-microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.
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Affiliation(s)
- Preston Carey
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Preprofessional Studies, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Ethan Low
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Elizabeth Harper
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - M. Sharon Stack
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
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Sawyer TW, Koevary JW, Howard CC, Austin OJ, Rice PS, Hutchens GV, Chambers SK, Connolly DC, Barton JK. Fluorescence and Multiphoton Imaging for Tissue Characterization of a Model of Postmenopausal Ovarian Cancer. Lasers Surg Med 2020; 52:993-1009. [PMID: 32311117 PMCID: PMC7572562 DOI: 10.1002/lsm.23251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND OBJECTIVES To determine the efficacy of targeted fluorescent biomarkers and multiphoton imaging to characterize early changes in ovarian tissue with the onset of cancer. STUDY DESIGN/MATERIALS AND METHODS A transgenic TgMISIIR-TAg mouse was used as an animal model for ovarian cancer. Mice were injected with fluorescent dyes to bind to the folate receptor α, matrix metalloproteinases, and integrins. Half of the mice were treated with 4-vinylcyclohexene diepoxide (VCD) to simulate menopause. Widefield fluorescence imaging (WFI) and multiphoton imaging of the ovaries and oviducts were conducted at 4 and 8 weeks of age. The fluorescence signal magnitude was quantified, and texture features were derived from multiphoton imaging. Linear discriminant analysis was then used to classify mouse groups. RESULTS Imaging features from both fluorescence imaging and multiphoton imaging show significant changes (P < 0.01) with age, VCD treatment, and genotype. The classification model is able to classify different groups to accuracies of 75.53%, 69.53%, and 86.76%, for age, VCD treatment, and genotype, respectively. Building a classification model using features from multiple modalities shows marked improvement over individual modalities. CONCLUSIONS This study demonstrates that using WFI with targeted biomarkers, and multiphoton imaging with endogenous contrast shows promise for detecting early changes in ovarian tissue with the onset of cancer. The results indicate that multimodal imaging can provide higher sensitivity for classifying tissue types than using single modalities alone. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.
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Affiliation(s)
- T. W. Sawyer
- James C Wyant College of Optical Sciences, University of Arizona, Tucson, AZ, USA
| | - J. W. Koevary
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
| | - C. C. Howard
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
| | - O. J. Austin
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
| | - P. S. Rice
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
| | - G. V. Hutchens
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
| | - S. K. Chambers
- College of Medicine, University of Arizona, Tucson, AZ, USA
| | | | - J. K. Barton
- James C Wyant College of Optical Sciences, University of Arizona, Tucson, AZ, USA
- Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA
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Hamutoğlu R, Bulut HE, Kaloğlu C, Önder O, Dağdeviren T, Aydemir MN, Korkmaz EM. The regulation of trophoblast invasion and decidual reaction by matrix metalloproteinase-2, metalloproteinase-7, and metalloproteinase-9 expressions in the rat endometrium. Reprod Med Biol 2020; 19:385-397. [PMID: 33071641 PMCID: PMC7542015 DOI: 10.1002/rmb2.12342] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/07/2020] [Accepted: 07/13/2020] [Indexed: 01/02/2023] Open
Abstract
PURPOSE We aimed to evaluate how matrix metalloproteinases (MMPs) regulate the trophoblast invasion and placentation. METHODS Female rats were divided into the estrous cycle and early pregnancy day groups. Obtained uterine tissues and implantation sites were processed for immunofluorescence and real-time PCR examinations. RESULTS The mRNA expression of MMP-7 was higher than MMP-2 and MMP-9. Immunofluorescence findings confirmed that MMP-2, MMP-7, and MMP-9 were localized in the endometrial stroma, while MMP-7 was high in glandular and lining epithelial cells throughout the entire estrous cycle. However, their immunolocalizations and mRNA expressions were dramatically changed with the early pregnancy days. The MMP-7 reached very strong immunostaining in the giant trophoblast cells (GTCs), and the cytoplasm of mature and differentiating decidual cells, whereas MMP-2 and MMP-9 were mostly seen in the primary decidual zone (PDZ), GTCs, and the endothelium of blood vessels. CONCLUSIONS All three MMPs seemed likely to be a key mediator of trophoblast invasion into the decidual region as well as angiogenesis during the placentation process. Due to the strong and wide expression of MMP-7 in the mature decidua, it could be suggested that MMP-7 is important for decidual ECM remodeling and it might be used as a new marker of decidual reaction.
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Affiliation(s)
- Rasim Hamutoğlu
- Department of Histology and EmbryologyFaculty of MedicineCumhuriyet UniversitySivasTurkey
| | - Hüseyin Eray Bulut
- Department of Histology and EmbryologyFaculty of MedicineCumhuriyet UniversitySivasTurkey
| | - Celal Kaloğlu
- Department of Histology and EmbryologyFaculty of MedicineCumhuriyet UniversitySivasTurkey
- Cumhuriyet University Assisted Reproduction Technology (ART) CenterSivasTurkey
| | - Ozan Önder
- Department of Histology and EmbryologyFaculty of MedicineCumhuriyet UniversitySivasTurkey
| | - Tuğba Dağdeviren
- Department of Histology and EmbryologyFaculty of MedicineCumhuriyet UniversitySivasTurkey
| | - Merve Nur Aydemir
- Department of Molecular Biology and GeneticsFaculty of ScienceCumhuriyet UniversitySivasTurkey
| | - Ertan Mahir Korkmaz
- Department of Molecular Biology and GeneticsFaculty of ScienceCumhuriyet UniversitySivasTurkey
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Lin L, Chou H, Chang S, Liao E, Tsai Y, Wei Y, Chen H, Lin M, Wang Y, Chien Y, Yu X, Chan H. Targeting UDP-glucose dehydrogenase inhibits ovarian cancer growth and metastasis. J Cell Mol Med 2020; 24:11883-11902. [PMID: 32893977 PMCID: PMC7578908 DOI: 10.1111/jcmm.15808] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
More than 70% of patients with ovarian cancer are diagnosed in advanced stages. Therefore, it is urgent to identify a promising prognostic marker and understand the mechanism of ovarian cancer metastasis development. By using proteomics approaches, we found that UDP-glucose dehydrogenase (UGDH) was up-regulated in highly metastatic ovarian cancer TOV21G cells, characterized by high invasiveness (TOV21GHI ), in comparison to its parental control. Previous reports demonstrated that UGDH is involved in cell migration, but its specific role in cancer metastasis remains unclear. By performing immunohistochemical staining with tissue microarray, we found overexpression of UGDH in ovarian cancer tissue, but not in normal adjacent tissue. Silencing using RNA interference (RNAi) was utilized to knockdown UGDH, which resulted in a significant decrease in metastatic ability in transwell migration, transwell invasion and wound healing assays. The knockdown of UGDH caused cell cycle arrest in the G0 /G1 phase and induced a massive decrease of tumour formation rate in vivo. Our data showed that UGDH-depletion led to the down-regulation of epithelial-mesenchymal transition (EMT)-related markers as well as MMP2, and inactivation of the ERK/MAPK pathway. In conclusion, we found that the up-regulation of UGDH is related to ovarian cancer metastasis and the deficiency of UGDH leads to the decrease of cell migration, cell invasion, wound healing and cell proliferation ability. Our findings reveal that UGDH can serve as a prognostic marker and that the inhibition of UGDH is a promising strategy for ovarian cancer treatment.
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Affiliation(s)
- Li‐Hsun Lin
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Hsiu‐Chuan Chou
- Institute of Analytical and Environmental SciencesNational Tsing Hua UniversityHsinchuTaiwan
| | - Shing‐Jyh Chang
- Department of Obstetrics and GynecologyHsinchu MacKay Memorial HospitalHsinchuTaiwan
| | - En‐Chi Liao
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Yi‐Ting Tsai
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Yu‐Shan Wei
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Hsin‐Yi Chen
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Meng‐Wei Lin
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Yi‐Shiuan Wang
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Yu‐An Chien
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
| | - Xin‐Ru Yu
- Institute of Analytical and Environmental SciencesNational Tsing Hua UniversityHsinchuTaiwan
| | - Hong‐Lin Chan
- Institute of Bioinformatics and Structural BiologyNational Tsing Hua UniversityHsinchuTaiwan
- Department of Medical SciencesNational Tsing Hua UniversityHsinchuTaiwan
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Zeng Y, Sun J, Bao J, Zhu T. BK polyomavirus infection promotes growth and aggressiveness in bladder cancer. Virol J 2020; 17:139. [PMID: 32928222 PMCID: PMC7488779 DOI: 10.1186/s12985-020-01399-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023] Open
Abstract
Background Recent studies have confirmed the integration of the BK polyomavirus (BKPyV) gene into the cellular genome of urothelial carcinomas in transplant recipients, further confirming the correlation between BKPyV and urothelial carcinomas after transplantation. However, the role BKPyV infections play in the biological function of bladder cancer remains unclear. Methods We developed a BKPyV-infected bladder cancer cell model and a mice tumor model to discuss the role of BKPyV infections. Results Our research proves that BKPyV infections promote the proliferation, invasion and migration of bladder cancer cells, while the activation of β-catenin signaling pathway is one of its mediation mechanisms. Conclusions We first described BKPyV infection promotes the proliferation, invasion and migration of bladder cancer. We verified the role of β-catenin signaling pathway and Epithelial-Mesenchymal Transition effect in BKPyV-infected bladder cancer. These results provide meaningful information towards the diagnosis and treatment of clinical bladder cancer.
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Affiliation(s)
- Yigang Zeng
- Department of Urology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Jiajia Sun
- Department of Urology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Juan Bao
- Department of Urology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Tongyu Zhu
- Department of Urology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China. .,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
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D’Oronzo S, Silvestris E, Lovero D, Cafforio P, Duda L, Cormio G, Paradiso A, Palmirotta R, Silvestris F. DEAD-Box Helicase 4 (Ddx4) + Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers. Int J Mol Sci 2020; 21:6096. [PMID: 32847044 PMCID: PMC7503840 DOI: 10.3390/ijms21176096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/14/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022] Open
Abstract
DEAD-Box Helicase 4 (Ddx4)+ ovarian stem cells are able to differentiate into several cell types under appropriate stimuli. Ddx4 expression has been correlated with poor prognosis of serous ovarian cancer (OC), while the potential role of Ddx4+ cells in non-serous epithelial OC (NS-EOC) is almost unexplored. The aim of this study was to demonstrate the presence of Ddx4+ cells in NS-EOC and investigate the effect of follicle-stimulating hormone (FSH) on this population. Increased Ddx4 expression was demonstrated in samples from patients with advanced NS-EOC, compared to those with early-stage disease. Under FSH stimulation, OC-derived Ddx4+ cells differentiated into mesenchymal-like (ML) cells, able to deregulate genes involved in cell migration, invasiveness, stemness and chemoresistance in A2780 OC cells. This effect was primarily induced by ML-cells deriving from advanced NS-EOC, suggesting that a tumor-conditioned germ cell niche inhabits its microenvironment and is able to modulate, in a paracrine manner, tumor cell behavior through transcriptome modulation.
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Affiliation(s)
- Stella D’Oronzo
- Department of Biomedical Sciences and Human Oncology–Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; (D.L.); (P.C.); (R.P.)
- I.R.C.C.S-Giovanni Paolo II Cancer Institute, 70124 Bari, Italy; (E.S.); (G.C.); (A.P.)
| | - Erica Silvestris
- I.R.C.C.S-Giovanni Paolo II Cancer Institute, 70124 Bari, Italy; (E.S.); (G.C.); (A.P.)
| | - Domenica Lovero
- Department of Biomedical Sciences and Human Oncology–Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; (D.L.); (P.C.); (R.P.)
| | - Paola Cafforio
- Department of Biomedical Sciences and Human Oncology–Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; (D.L.); (P.C.); (R.P.)
| | - Loren Duda
- Department of Pathology, University of Foggia, 71122 Foggia, Italy;
| | - Gennaro Cormio
- I.R.C.C.S-Giovanni Paolo II Cancer Institute, 70124 Bari, Italy; (E.S.); (G.C.); (A.P.)
- Department of Biomedical Sciences and Human Oncology–Section of 2nd Unit of Obstetrics and Gynecology, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Angelo Paradiso
- I.R.C.C.S-Giovanni Paolo II Cancer Institute, 70124 Bari, Italy; (E.S.); (G.C.); (A.P.)
| | - Raffaele Palmirotta
- Department of Biomedical Sciences and Human Oncology–Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; (D.L.); (P.C.); (R.P.)
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology–Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, 70121 Bari, Italy; (D.L.); (P.C.); (R.P.)
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Yan YB, Tian Q, Zhang JF, Xiang Y. Antitumor effects and molecular mechanisms of action of natural products in ovarian cancer. Oncol Lett 2020; 20:141. [PMID: 32934709 PMCID: PMC7471673 DOI: 10.3892/ol.2020.12001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 08/03/2020] [Indexed: 02/07/2023] Open
Abstract
Ovarian cancer is a common malignancy and the second leading cause of mortality among females with genital tract cancer. At present, postoperative platinum drugs and paclitaxel-based chemotherapy is the gold standard treatment for ovarian cancer. However, patients who receive this chemotherapy often develop cumulative toxic effects and are prone to chemotherapy resistance. Therefore, it is necessary to determine more effective treatment options that would be better tolerated by patients. Recent studies have reported the therapeutic effects of numerous natural products in patients with ovarian cancer. Notably, these natural ingredients do not induce adverse effects in healthy cells and tissues, suggesting that natural products may serve as a safe alternative treatment for ovarian cancer. The antitumor effects of natural products are attributed to suppression of cell proliferation and metastasis, stimulation of autophagy, improved chemotherapy sensitivity, and induction of apoptosis. The present review focused on the antitumor effects of several natural products, including curcumin, resveratrol, ginsenosides, (-)-epigallocatechin-3-gallate and quercetin, which are increasingly being investigated as therapeutic options in ovarian cancer, and discussed the molecular mechanisms involved in cell proliferation, apoptosis, autophagy, metastasis and sensitization.
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Affiliation(s)
- Yun-Bo Yan
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Qing Tian
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China.,Department of Cell Biology and Genetics, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Ji-Fang Zhang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China.,Department of Cell Biology and Genetics, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
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Batool A, Liu H, Liu YX, Chen SR. CD83, a Novel MAPK Signaling Pathway Interactor, Determines Ovarian Cancer Cell Fate. Cancers (Basel) 2020; 12:cancers12082269. [PMID: 32823589 PMCID: PMC7465057 DOI: 10.3390/cancers12082269] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/07/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
Ovarian cancer is a leading cause of death from gynecologic malignancies worldwide. Although CD83 is widely described as a solid marker for mature dendritic cells, emerging pieces of evidence indicate the expression of membrane protein CD83 by various tumor cells, including ovarian cancer cells. However, the potential role of CD83 in ovarian cancer cell properties and development remains absolutely unknown. By using human CD83 stable overexpression and knockdown sublines of several ovarian cancer cells, we observed that CD83 advanced the growth proliferation, colony formation ability, spheroid formation, and in vivo tumorigenicity of ovarian cancer cells; surprisingly, CD83 limited their migration and invasion potentials. Positive regulation of proliferation/stemness factors (e.g., cyclin-CDKs and KIT/CD44) but negative regulation of matrix metallopeptidases (e.g., MMP1 and 7) by CD83 were revealed by the integrated analysis of transcriptome and proteome. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) first identified the association of CD83 with MAP3K7 (also known as TAK1) and MAP3K7-binding protein TAB1 on the cell membrane. Moreover, CD83 functions through the activation of MAP3K7-MEK1/2-ERK1/2 cascades to further regulate downstream FOXO1/p21/CDK2/CCNB1 and STAT3/DKK1 signaling pathways, thus activating proliferation and spheroid formation of ovarian cancer cells, respectively. Collectively, our findings define a CD83-MAPK pathway in the regulation of proliferation and stemness in ovarian cancer cells, with potential therapeutic applications in blocking their progression.
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Affiliation(s)
- Aalia Batool
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
- Laboratory of Reproductive Neuroendocrinology, Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
| | - Hao Liu
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
| | - Yi-Xun Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
| | - Su-Ren Chen
- Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (A.B.); (H.L.)
- Correspondence:
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Luddi A, Marrocco C, Governini L, Semplici B, Pavone V, Luisi S, Petraglia F, Piomboni P. Expression of Matrix Metalloproteinases and Their Inhibitors in Endometrium: High Levels in Endometriotic Lesions. Int J Mol Sci 2020; 21:ijms21082840. [PMID: 32325785 PMCID: PMC7215833 DOI: 10.3390/ijms21082840] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 12/21/2022] Open
Abstract
Endometriosis is a condition defined as presence of endometrium outside of the uterine cavity. These endometrial cells are able to attach and invade the peritoneum or ovary, thus forming respectively the deep infiltrating endometriosis (DIE) and the ovarian endometrioma (OMA), the ectopic lesions feature of this pathology. Endometriotic cells display high invasiveness and share some features of malignancy with cancer cells. Indeed, the tissue remodeling underlining lesion formation is achieved by matrix metalloproteinases (MMPs) and their inhibitors. Therefore, these molecules are believed to play a key role in development and pathogenesis of endometriosis. This study investigated the molecular profile of metalloproteinases and their inhibitors in healthy (n = 15) and eutopic endometrium (n = 19) in OMA (n = 10) and DIE (n = 9); moreover, we firstly validated the most reliable housekeeping genes allowing accurate gene expression analysis in these tissues. Gene expression, Western blot, and immunofluorescence analysis of MMP2, MMP3, and MMP10 and their tissue inhibitors TIMP1 and TIMP2 demonstrated that these enzymes are finely tuned in these tissues. In OMA lesions, all the investigated MMPs and their inhibitors were significantly increased, while DIE expressed high levels of MMP3. Finally, in vitro TNFα treatment induced a significant upregulation of MMP3, MMP10, and TIMP2 in both healthy and eutopic endometrial stromal cells. This study, shedding light on MMP and TIMP expression in endometriosis, confirms that these molecules are altered both in eutopic endometrium and endometriotic lesions. Although further studies are needed, these data may help in understanding the molecular mechanisms involved in the extracellular matrix remodeling, a crucial process for the endometrial physiology.
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Affiliation(s)
- Alice Luddi
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Camilla Marrocco
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Laura Governini
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Bianca Semplici
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Valentina Pavone
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Stefano Luisi
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
| | - Felice Petraglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy;
| | - Paola Piomboni
- Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy; (A.L.); (C.M.); (L.G.); (B.S.); (V.P.); (S.L.)
- Correspondence: ; Tel.: +39-0577-586632
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The Accuracy of Single MicroRNAs in Peripheral Blood to Diagnose Ovarian Cancer: An Updated Meta-Analysis. DISEASE MARKERS 2020; 2020:1075942. [PMID: 32025275 PMCID: PMC6983285 DOI: 10.1155/2020/1075942] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 12/09/2019] [Accepted: 12/23/2019] [Indexed: 12/26/2022]
Abstract
Background Ovarian cancer is the 5th leading cause of death of women due to cancer in the United States. Although carbohydrate antigen 125 has a moderate diagnostic utility, the phenomenon of false-positive exists. As novel effective biomarkers, some single microRNAs (miRNAs) have diagnostic values for ovarian cancer, but the results lack consistency. In order to precisely and comprehensively assess the diagnostic value of single miRNAs for ovarian cancer, a meta-analysis is performed. Methods Articles concerning the diagnostic value of single miRNAs for ovarian cancer were searched from databases. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with the corresponding 95% confidence interval (CI) were calculated. Area under curve (AUC) of the summary receiver-operating characteristic (SROC) curve was also calculated. Results In total, 22 studies including 8 kinds of single miRNAs were enrolled in this paper (6 studies for miR-200c, 3 studies for miR-200a and miR-200b, and 2 studies for miR-205, miR-145, miR-141, miR-429, and miR-125b). For miR-200c, the pooled SEN and SPE were, respectively, 0.768 (95% CI: 0.722-0.811) and 0.680 (95% CI: 0.624-0.732); the pooled PLR and NLR were, respectively, 2.897 (95% CI: 1.787-4.698) and 0.340 (95% CI: 0.276-0.417); the pooled DOR was 8.917 (95% CI: 4.521-17.587); and AUC of SROC curve was 0.815. For miR-200a, the pooled SEN and SPE were, respectively, 0.759 (95% CI: 0.670-0.833) and 0.717 (95% CI: 0.627-0.795); the pooled PLR and NLR were, respectively, 3.129 (95% CI: 0.997-9.816) and 0.301 (95% CI: 0.207-0.437); the pooled DOR was 11.323 (95% CI: 3.493-36.711); and AUC of SROC curve was 0.857. For miR-200b, the pooled SEN and SPE were, respectively, 0.853 (95% CI: 0.776-0.912) and 0.775 (95% CI: 0.690-0.846); the pooled PLR and NLR were, respectively, 4.327 (95% CI: 0.683-27.415) and 0.225 (95% CI: 0.081-0.625); the pooled DOR was 19.678 (95% CI: 2.812-137.72); and AUC of SROC curve was 0.90. For miR-205, miR-145, miR-141, miR-429, and miR-125b, each diagnostic value should be interpreted cautiously because only two studies were included. Conclusions miR-200c, miR-200a, and miR-200b can be useful diagnostic biomarkers for ovarian cancer. More related studies are needed for miR-205, miR-145, miR-141, miR-429, and miR-125b.
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Kim MS, Kim JH, Ahn E, Cho Y, Han S, Lee C, Bae G, Oh JS, Kim K, Seo D. Novel functions for 2-phenylbenzimidazole-5-sulphonic acid: Inhibition of ovarian cancer cell responses and tumour angiogenesis. J Cell Mol Med 2020; 24:2688-2700. [PMID: 31958895 PMCID: PMC7028853 DOI: 10.1111/jcmm.14989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/19/2019] [Accepted: 12/21/2019] [Indexed: 01/02/2023] Open
Abstract
In this study, we investigated the effects and molecular mechanisms of 2-phenylbenzimidazole-5-sulphonic acid (PBSA), an ultraviolet B protecting agent used in sunscreen lotions and moisturizers, on ovarian cancer cell responses and tumour angiogenesis. PBSA treatment markedly blocked mitogen-induced invasion through down-regulation of matrix metalloproteinase (MMP) expression and activity in ovarian cancer SKOV-3 cells. In addition, PBSA inhibited mitogen-induced cell proliferation by suppression of cyclin-dependent kinases (Cdks), but not cyclins, leading to pRb hypophosphorylation and G1 phase cell cycle arrest. These anti-cancer activities of PBSA in ovarian cancer cell invasion and proliferation were mediated by the inhibition of mitogen-activated protein kinase kinase 3/6-p38 mitogen-activated protein kinase (MKK3/6-p38MAPK ) activity and subsequent down-regulation of MMP-2, MMP-9, Cdk4, Cdk2 and integrin β1, as evidenced by treatment with p38MAPK inhibitor SB203580. Furthermore, PBSA suppressed the expression and secretion of vascular endothelial growth factor in SKOV-3 cells, leading to inhibition of capillary-like tubular structures in vitro and angiogenic sprouting ex vivo. Taken together, our results demonstrate the pharmacological effects and molecular targets of PBSA on modulating ovarian cancer cell responses and tumour angiogenesis, and suggest further evaluation and development of PBSA as a promising chemotherapeutic agent for the treatment of ovarian cancer.
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Affiliation(s)
- Min Su Kim
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
| | - Jae Hyeon Kim
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
| | - Eun‐Kyung Ahn
- BiocenterGyeonggi Business & Science AcceleratorSuwonKorea
| | - Young‐Rak Cho
- BiocenterGyeonggi Business & Science AcceleratorSuwonKorea
| | - Surim Han
- Department of ChemistryCollege of Natural ScienceDankook UniversityCheonanKorea
| | - Choong‐Hyun Lee
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
| | - Gyu‐Un Bae
- Department of PharmacyCollege of PharmacySookmyung Women’s UniversitySeoulKorea
| | - Joa Sub Oh
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
| | - Kyu‐Bong Kim
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
| | - Dong‐Wan Seo
- Department of PharmacyCollege of PharmacyDankook UniversityCheonanKorea
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48
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Nguyen VHL, Hough R, Bernaudo S, Peng C. Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis. J Ovarian Res 2019; 12:122. [PMID: 31829231 PMCID: PMC6905042 DOI: 10.1186/s13048-019-0596-z] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations of CTNNB1, AXIN, or APC, have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the β-catenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies.
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Affiliation(s)
| | - Rebecca Hough
- Department of Biology, York University, Toronto, Ontario, Canada
| | | | - Chun Peng
- Department of Biology, York University, Toronto, Ontario, Canada. .,Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada.
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Sawyer TW, Koevary JW, Rice FPS, Howard CC, Austin OJ, Connolly DC, Cai KQ, Barton JK. Quantification of multiphoton and fluorescence images of reproductive tissues from a mouse ovarian cancer model shows promise for early disease detection. JOURNAL OF BIOMEDICAL OPTICS 2019; 24:1-16. [PMID: 31571434 PMCID: PMC6768507 DOI: 10.1117/1.jbo.24.9.096010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 09/13/2019] [Indexed: 05/12/2023]
Abstract
Ovarian cancer is the deadliest gynecologic cancer due predominantly to late diagnosis. Early detection of ovarian cancer can increase 5-year survival rates from 40% up to 92%, yet no reliable early detection techniques exist. Multiphoton microscopy (MPM) is a relatively new imaging technique sensitive to endogenous fluorophores, which has tremendous potential for clinical diagnosis, though it is limited in its application to the ovaries. Wide-field fluorescence imaging (WFI) has been proposed as a complementary technique to MPM, as it offers high-resolution imagery of the entire organ and can be tailored to target specific biomarkers that are not captured by MPM imaging. We applied texture analysis to MPM images of a mouse model of ovarian cancer. We also conducted WFI targeting the folate receptor and matrix metalloproteinases. We find that texture analysis of MPM images of the ovary can differentiate between genotypes, which is a proxy for disease, with high statistical significance (p < 0.001). The wide-field fluorescence signal also changes significantly between genotypes (p < 0.01). We use the features to classify multiple tissue groups to over 80% accuracy. These results suggest that MPM and WFI are promising techniques for the early detection of ovarian cancer.
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Affiliation(s)
- Travis W. Sawyer
- University of Arizona, College of Optical Sciences, Tucson, Arizona, United States
| | - Jennifer W. Koevary
- University of Arizona, Department of Biomedical Engineering, Tucson, Arizona, United States
| | - Faith P. S. Rice
- University of Arizona, Department of Biomedical Engineering, Tucson, Arizona, United States
| | - Caitlin C. Howard
- University of Arizona, Department of Biomedical Engineering, Tucson, Arizona, United States
| | - Olivia J. Austin
- University of Arizona, Department of Biomedical Engineering, Tucson, Arizona, United States
| | | | - Kathy Q. Cai
- Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States
| | - Jennifer K. Barton
- University of Arizona, College of Optical Sciences, Tucson, Arizona, United States
- University of Arizona, Department of Biomedical Engineering, Tucson, Arizona, United States
- Address all correspondence to Jennifer K. Barton, E-mail:
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Matrix Metalloproteinase Expressions Play Important role in Prediction of Ovarian Cancer Outcome. Sci Rep 2019; 9:11677. [PMID: 31406154 PMCID: PMC6691000 DOI: 10.1038/s41598-019-47871-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 06/12/2019] [Indexed: 11/11/2022] Open
Abstract
Ovarian cancer has a high death rate and is often not detected until late stages. While some studies found high expressions of MMPs correlated with cancer invasion, metastasis, and poor prognosis, however, several other studies indicated MMPs might inhibit cancer rather than promote cancer in certain situations. Thus, the role of different MMPs in different cancer types needs a systematic re-evaluation. In this study, we used RNA-Seq and corresponding clinical data downloaded from TCGA and analyzed the correlations between MMP expressions and the clinicopathologic characteristics and outcome in ovarian serous cystadenocarcinoma (OSC) patients. Among the MMPs investigated, MMP-3 was significantly increased in high-grade and high-stage tumors compared with low-grade and low-stage ones. Using univariate analysis and multivariate Cox model, high expressions of MMP-19 and -20 were found to associate with poor overall survival independent of clinicopathologic characteristics. Moreover, using in vitro studies, we found ovarian cancer cell lines with higher MMP-19 and -20 protein expressing levels were associated with anti-cancer drugs resistance, while knockdown of MMP-19 or -20 increased ovarian cancer cell sensitivities to several clinical using chemotherapy agents. Finally, knockdown of MMP-19 or -20 also decreased the invasion abilities of several ovarian cancer cell lines. These in vitro studies provided potential mechanisms of high MMP-19 and -20 expressions in the poor prognosis of ovarian cancer.
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