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      SOX2 Enhances the Migration and Invasion of Ovarian Cancer Cells via Src Kinase

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          Abstract

          Ovarian cancer is the leading cause of death among gynecologic cancers and is the fifth leading cause of all cancer-related deaths among women. The development of novel molecular targets is therefore important to many patients. Recently, the SRY-related transcription factor SOX2 has been widely reported to be involved in multiple pathophysiological diseases, including maintenance of stem cell characteristics and carcinogenesis. Up to now, SOX2 has been mainly shown to promote the development of cancer, although its inhibitory roles in cancer have also been reported. However, the role of SOX2 in ovarian cancer is largely unknown. In the present study, we detected the expression of SOX2 in 64 human serous ovarian carcinoma (SOC) tissues and paired corresponding metastatic specimens using immunohistochemistry. The results showed that the expression of SOX2 in primary tumors is much lower than that in the corresponding metastatic lesions. We further found that SOX2 overexpression promotes proliferation, migration and invasion, while inhibiting adhesion abilities of SOC cells. Finally, we found that SOX2 targets Src kinase, a non-receptor tyrosine kinase that regulates cell migration, invasion and adhesion in SOC cells. Together, these results suggested that Src kinase is a key molecule in SOX2-mediated migration and invasion of SOC cells.

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          Most cited references27

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          A protein interaction network for pluripotency of embryonic stem cells.

          Embryonic stem (ES) cells are pluripotent and of therapeutic potential in regenerative medicine. Understanding pluripotency at the molecular level should illuminate fundamental properties of stem cells and the process of cellular reprogramming. Through cell fusion the embryonic cell phenotype can be imposed on somatic cells, a process promoted by the homeodomain protein Nanog, which is central to the maintenance of ES cell pluripotency. Nanog is thought to function in concert with other factors such as Oct4 (ref. 8) and Sox2 (ref. 9) to establish ES cell identity. Here we explore the protein network in which Nanog operates in mouse ES cells. Using affinity purification of Nanog under native conditions followed by mass spectrometry, we have identified physically associated proteins. In an iterative fashion we also identified partners of several Nanog-associated proteins (including Oct4), validated the functional relevance of selected newly identified components and constructed a protein interaction network. The network is highly enriched for nuclear factors that are individually critical for maintenance of the ES cell state and co-regulated on differentiation. The network is linked to multiple co-repressor pathways and is composed of numerous proteins whose encoding genes are putative direct transcriptional targets of its members. This tight protein network seems to function as a cellular module dedicated to pluripotency.
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            Src kinases as therapeutic targets for cancer.

            Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.
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              The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer.

              SOX genes encode a family of high-mobility group transcription factors that play critical roles in organogenesis. The functional specificity of different SOX proteins and the tissue specificity of a particular SOX factor are largely determined by the differential partnership of SOX transcription factors with other transcription regulators, many of which have not yet been discovered. Virtually all members of the SOX family have been found to be deregulated in a wide variety of tumors. However, little is known about the cellular and molecular behaviors involved in the oncogenic potential of SOX proteins. Using cell culture experiments, tissue analysis, molecular profiling, and animal studies, we report here that SOX2 promotes cell proliferation and tumorigenesis by facilitating the G(1)/S transition and through its transcription regulation of the CCND1 gene in breast cancer cells. In addition, we identified beta-catenin as the transcription partner for SOX2 and demonstrated that SOX2 and beta-catenin act in synergy in the transcription regulation of CCND1 in breast cancer cells. Our experiments not only determined a role for SOX2 in mammary tumorigenesis but also revealed another activity of the multifunctional protein, beta-catenin.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                17 June 2014
                : 9
                : 6
                : e99594
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, China
                [2 ]Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
                Thomas Jefferson University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YF XX. Performed the experiments: XW XJ. Analyzed the data: XW JC DY QW. Contributed reagents/materials/analysis tools: ZZ. Wrote the paper: XW.

                Article
                PONE-D-14-02700
                10.1371/journal.pone.0099594
                4061006
                24937695
                a5817a0b-6bd8-4703-9894-62eafdf97cd9
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 February 2014
                : 15 May 2014
                Page count
                Pages: 10
                Funding
                The study was supported by grants from the National Natural Science Foundation of China (NSFC No. 81272883, No. 81020108027 and No. 81172478). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Women's Health
                Obstetrics and Gynecology
                Gynecologic Cancers

                Uncategorized
                Uncategorized

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