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      Hypoxia-inducible factor-1α induces CX3CR1 expression and promotes the epithelial to mesenchymal transition (EMT) in ovarian cancer cells

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          Abstract

          Background

          Chemokines are involved in the homing of various cancer cells, including those of ovarian cancer (OvCa), to distant organs. They may also promote or inhibit cancer progression and metastasis. Hypoxia, a common phenomenon in malignant tumors, promotes cell proliferation regulated by HIF-1α. Hypoxia-induced genes are involved in metastasis-associated functions and in the epithelial-to-mesenchymal transition (EMT).

          Results

          Tissue microarrays of human OvCa showed elevated expression of CX3CR1 and HIF-1α compared to normal cells, and their levels were higher in adenocarcinoma stages II and III. To substantiate these observations, we performed studies using OvCa cells. Following exposure to hypoxia, OVCAR-3, SW 626, and TOV-112D cells showed high expression of CX3CR1, a transmembrane protein involved in the adhesion and migration of leukocytes, causing an increased chemotactic response to CX3CL1, the ligand for CX3CR1. As determined by flow cytometry, immunofluorescence, RT-PCR, and western blots, there were higher expressions of CX3CR1 and HIF-1α in OvCa cell lines exposed to hypoxia. Further, OvCa cells expressing CX3CR1 were sensitive to the CX3CL1 ligand. Chemotaxis based on chemokine receptors was influential in elevating the expression of EMT markers and matrix metalloproteinases, which are involved in the progression and metastasis of cancer cells.

          Conclusions

          In OvCa cells, CX3CR1 was upregulated in a process involving hypoxia-mediated regulation of HIF-1α. The elevated levels of CX3CR1, which were sensitive to CX3CL1, increased EMT markers that led to the progression and metastasis of OvCa. Thus, CX3CR1 and HIF-1α are suitable targets for treatment of OvCa.

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          Most cited references25

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          Epidemiology of ovarian cancer: a review

          Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.
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            Regulation of the Chemokine Receptor CXCR4 by Hypoxia

            Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 α and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.
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              Worldwide burden of gynaecological cancer: the size of the problem.

              The estimation of cancer burden is valuable to set up priorities for disease control. The comprehensive global cancer statistics from the International Agency for Research on Cancer indicate that gynaecological cancers accounted for 19% of the 5.1 million estimated new cancer cases, 2.9 million cancer deaths and 13 million 5-year prevalent cancer cases among women in the world in 2002. Cervical cancer accounted for 493 000 new cases and 273 000 deaths; uterine body cancer for 199 000 new cases and 50 000 deaths; ovarian cancer for 204 000 new cases and 125 000 deaths; cancers of the vagina, vulva and choriocarcinoma together constituted 45 900 cases. More than 80% of the cervical cancer cases occurred in developing countries and two-thirds of corpus uteri cases occurred in the developed world. Political will and advocacy to invest in healthcare infrastructure and human resources to improve service delivery and accessibility are vital to reduce the current burden in low- and medium-resource countries.
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                Author and article information

                Contributors
                404-756-6661 , rsingh@msm.edu
                Journal
                J Ovarian Res
                J Ovarian Res
                Journal of Ovarian Research
                BioMed Central (London )
                1757-2215
                10 May 2019
                10 May 2019
                2019
                : 12
                : 42
                Affiliations
                [1 ]ISNI 0000 0001 2228 775X, GRID grid.9001.8, Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, ; 720 Westview Drive SW, Atlanta, GA USA
                [2 ]ISNI 0000 0000 9485 5579, GRID grid.251976.e, Department of Biological Sciences, , Alabama State University, ; 915 S Jackson Street, Montgomery, AL USA
                Article
                517
                10.1186/s13048-019-0517-1
                6511167
                31077234
                36e2cea5-3149-4e0a-b520-98c4a0a71ae2
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 March 2019
                : 23 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: SC1CA193758
                Award ID: U54CA118638
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000005, U.S. Department of Defense;
                Award ID: W81XWH1810429
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Obstetrics & Gynecology
                ovarian cancer,hypoxia,chemokines,cx3cr1,emt markers
                Obstetrics & Gynecology
                ovarian cancer, hypoxia, chemokines, cx3cr1, emt markers

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