Expression of TIMPs and MMPs in Ovarian Tumors, Ascites, Ascites-Derived Cells, and Cancer Cell Lines: Characteristic Modulatory Response Before and After Chemotherapy Treatment

BackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionsTIMPs 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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Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines

Journal of Ovarian Research ◽

10.1186/1757-2215-6-75 ◽

2013 ◽

Vol 6 (1) ◽

pp. 75 ◽

Cited By ~ 34

Author(s):

Sergiy Konovalov ◽

Ivan Garcia-Bassets

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Ovarian Tumors ◽

Ovarian Cancer Cell Lines ◽

Lysine Specific Demethylase

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Apoptosis-related mRNA expression profiles of ovarian cancer cell lines following cisplatin treatment

Journal of Gynecologic Oncology ◽

10.3802/jgo.2010.21.4.255 ◽

2010 ◽

Vol 21 (4) ◽

pp. 255 ◽

Cited By ~ 5

Author(s):

JooHee Yoon ◽

Eung-Sam Kim ◽

Sung Jong Lee ◽

Chang-Wook Park ◽

Hyung Jin Cha ◽

...

Keyword(s):

Ovarian Cancer ◽

Mrna Expression ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Expression Profiles ◽

Cancer Cell Lines ◽

Ovarian Cancer Cell Lines

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Expression of Adiponectin and Its Receptors Is Altered in Epithelial Ovarian Tumors and Ascites-Derived Ovarian Cancer Cell Lines

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000369 ◽

2015 ◽

Vol 25 (3) ◽

pp. 399-406 ◽

Cited By ~ 12

Author(s):

Anupama Tiwari ◽

Olga M. Ocon-Grove ◽

Jill A. Hadley ◽

James R. Giles ◽

Patricia A. Johnson ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Ovarian Tumors ◽

Ovarian Cancer Cell Lines

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Expression of Jun and Fos proteins in ovarian tumors of different malignant potential and in ovarian cancer cell lines

Oncology Reports ◽

10.3892/or_00000422 ◽

2009 ◽

Vol 22 (01) ◽

Cited By ~ 4

Author(s):

Milde-Langosch

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Malignant Potential ◽

Ovarian Tumors ◽

Ovarian Cancer Cell Lines

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Epigenetic alteration of BRCA1 in human ovarian tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16532 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16532-e16532

Author(s):

K. Takehara ◽

K. Miyamoto ◽

Y. Kawakami ◽

M. Kumagai ◽

O. Samura ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Clinicopathological Features ◽

Ovarian Tumors ◽

Breast Cancers ◽

Epigenetic Alteration ◽

Ovarian Cancer Cell Lines

e16532 Background: The breast cancer susceptibility gene 1 (BRCA1) is mutated in half of hereditary breast cancers, and in about 80% of hereditary breast and ovarian cancers. Also, BRCA1 expression is decreased in sporadic breast cancers by other mechanisms, such as epigenetic alteration, suggesting its important role in sporadic breast cancers. The epigenetic alteration of BRCA1 and its contribution in sporadic ovarian tumors are not fully understood. Methods: We evaluated the DNA methylation status of the BRCA1 5’ CpG island by methylation-specific PCR in 12 human ovarian cancer cell lines and 39 primary epithelial ovarian tumor specimens. Cases included the following: malignant (n = 16), borderline (n = 8), and benign (n = 16) tumors. The correlation between these results and clinicopathological features was examined. Results: BRCA1 was hypermethylated in one of 12 (8%) ovarian cancer cell lines and 15 of 39 (38%) primary ovarian tumors. Relative to clinicopathological features, BRCA1 methylation was detected in 39% of malignant and borderline tumors and in 38% of benign tumors, suggesting the importance of BRCA1 pathway in both types of tumors. Some adjacent nontumorous tissues also showed aberrant methylation. Conclusions: BRCA1 was found to be frequently hypermethylated both in benign and malignant ovarian tumors. Our results suggest that epigenetic alteration of BRCA1 might play a role in the development of benign and malignant sporadic ovarian tumors. No significant financial relationships to disclose.

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