Jayathirtha Madhuri, Neagu Anca-Narcisa, Whitham Danielle, Alwine Shelby, Darie Costel C
Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson University Potsdam, NY 13699-5810, USA.
Laboratory of Animal Histology, Faculty of Biology, "Alexandru Ioan Cuza" University of Iasi Carol I bvd. No. 22, Iasi 700505, Romania.
Am J Cancer Res. 2022 Sep 15;12(9):4373-4398. eCollection 2022.
MCF7 is a commonly used luminal type A non-invasive/poor-invasive human breast cancer cell line that does not usually migrate or invade compared with MDA-MB-231 highly metastatic cells, which emphasize an invasive and migratory behavior. Under special conditions, MCF7 cells might acquire invasive features. The aberration in expression and biological functions of the jumping translocation breackpoint (JTB) protein is associated with malignant transformation of cells, based on mitochondrial dysfunction, inhibition of tumor suppressive function of TGF-β, and involvement in cancer cell cycle. To investigate new putative functions of JTB by cellular proteomics, we analyzed the biological processes and pathways that are associated with the JTB protein downregulation. The results demonstrated that MCF7 cell line developed a more "aggressive" phenotype and behavior. Most of the proteins that were overexpressed in this experiment promoted the actin cytoskeleton reorganization that is involved in growth and metastatic dissemination of cancer cells. Some of these proteins are involved in the epithelial-mesenchymal transition (EMT) process (ACTBL2, TUBA4A, MYH14, CSPG5, PKM, UGDH, HSP90AA2, and MIF), in correlation with the energy metabolism reprogramming (PKM, UGDH), stress-response (HSP10, HSP70A1A, HSP90AA2), and immune and inflammatory response (MIF and ERp57-TAPBP). Almost all upregulated proteins in JTB downregulated condition promote viability, motility, proliferation, invasion, survival into a hostile microenvironment, metabolic reprogramming, and escaping of tumor cells from host immune control, leading to a more invasive phenotype for MCF7 cell line. Due to their downregulated condition, four proteins, such as CREBZF, KMT2B, SELENOS and CACNA1I are also involved in maintenance of the invasive phenotype of cancer cells, promoting cell proliferation, migration, invasion and tumorigenesis. Other downregulated proteins, such as MAZ, PLEKHG2, ENO1, TPI2, TOR2A, and CNNM1, may promote suppression of cancer cell growth, invasion, EMT, tumorigenic abilities, interacting with glucose and lipid metabolism, disrupting nuclear envelope stability, or suppressing apoptosis and developing anti-angiogenetic activities. Therefore, the main biological processes and pathways that may increase the tumorigenic potential of the MCF7 cells in JTB downregulated condition are related to the actin cytoskeleton organization, EMT, mitotic cell cycle, glycolysis and fatty acid metabolism, inflammatory response and macrophage activation, chemotaxis and migration, cellular response to stress condition (oxidative stress and hypoxia), transcription control, histone modification and ion transport.
MCF7是一种常用的腔面A型非侵袭性/低侵袭性人乳腺癌细胞系，与具有高度转移行为的MDA-MB-231细胞相比，通常不会迁移或侵袭。在特殊条件下，MCF7细胞可能获得侵袭性特征。跳跃易位断点（JTB）蛋白的表达和生物学功能异常与细胞的恶性转化有关，其机制基于线粒体功能障碍、TGF-β肿瘤抑制功能的抑制以及参与癌细胞周期。为了通过细胞蛋白质组学研究JTB的新推定功能，我们分析了与JTB蛋白下调相关的生物学过程和途径。结果表明，MCF7细胞系表现出更“侵袭性”的表型和行为。本实验中过表达的大多数蛋白质促进了肌动蛋白细胞骨架重排，这与癌细胞的生长和转移扩散有关。其中一些蛋白质参与上皮-间质转化（EMT）过程（ACTBL2、TUBA4A、MYH14、CSPG5、PKM、UGDH、HSP90AA2和MIF），与能量代谢重编程（PKM、UGDH）、应激反应（HSP10、HSP70A1A、HSP90AA2）以及免疫和炎症反应（MIF和ERp57-TAPBP）相关。在JTB下调条件下，几乎所有上调的蛋白质都促进肿瘤细胞的活力、运动性、增殖、侵袭、在恶劣微环境中的存活、代谢重编程以及逃避宿主免疫控制，导致MCF7细胞系具有更具侵袭性的表型。由于其下调状态，CREBZF、KMT2B、SELENOS和CACNA1I这四种蛋白质也参与维持癌细胞的侵袭性表型，促进细胞增殖、迁移、侵袭和肿瘤发生。其他下调的蛋白质，如MAZ、PLEKHG2、ENO1、TPI2、TOR2A和CNNM1，可能促进癌细胞生长、侵袭、EMT、致瘤能力的抑制，与葡萄糖和脂质代谢相互作用，破坏核膜稳定性，或抑制细胞凋亡并发挥抗血管生成活性。因此，在JTB下调条件下可能增加MCF7细胞致瘤潜力的主要生物学过程和途径与肌动蛋白细胞骨架组织、EMT、有丝分裂细胞周期、糖酵解和脂肪酸代谢、炎症反应和巨噬细胞激活、趋化性和迁移、细胞对应激条件（氧化应激和缺氧）的反应、转录控制、组蛋白修饰和离子转运有关。
