REGULATION OF GAP JUNCTION IN COLON CANCER CELLS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。根据美国癌症协会的数据，在美国，大约有二分之一的男性和三分之一的女性会在一生中的某个时候患上癌症。癌细胞在细胞内和细胞间的交流中表现出许多缺陷，这些缺陷会导致组织稳态的丧失（细胞过度增殖、侵袭和转移）。许多器官的细胞间通讯是通过细胞间隙连接通道（GJIC）维持的，它允许小分子的转移，这些小分子可以调节细胞的生长、分化和功能。间隙连接是在所有物种的动物组织中发现的唯一的通信连接，它负责直接传输分子量小于1200道尔顿的离子和分子。这些交通方式是由对立细胞表面的两个半通道相互作用形成的。这些半通道是由六种蛋白质（连接蛋白）结合形成的。由于细胞间连接在维持细胞稳态中的重要性，细胞间连接的调节和连接蛋白的表达似乎参与了癌变。间隙连接功能的稳定异常调节与几种癌基因的激活有关。一些肿瘤抑制基因也与缝隙连接功能的上调有关。由于间隙连接存在于多细胞生物的所有器官中，各种具有细胞类型/组织/器官特异性的有毒化学物质对这些间隙连接的功能障碍可能会带来非常不同的临床后果，如胚胎致死或致畸、性腺生殖功能障碍、中枢神经系统的神经毒性、皮肤增生和初始组织的肿瘤促进。最近的研究表明，我们的环境受到许多内分泌干扰物的污染，这些干扰物可以干扰内分泌系统，对激素平衡产生不利影响或破坏正常功能，最终导致生殖和发育过程中的有害影响。许多碳氢化合物和有机氯化合物是环境污染物，已被证明可以下调间隙连接。这些碳氢化合物如2,3,7,8-四氯二苯并-对二恶英（TCDD）及其衍生物在癌症形成中的调控作用尚不清楚。因此，了解TCDD如何影响间隙连接细胞间通讯并随后干扰细胞稳态将为其作用的生化机制提供有价值的证据。我们假设TCDD通过PKC信号通路调节间隙连接活性，从而抑制上皮性乳腺癌细胞的间隙连接活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. According to the American Cancer Society, approximately one out of two among men and one out of three among women will develop cancer at some point during the course of their lifetime in the U.S. Cancer cells exhibit many defects in intracellular and intercellular communication that contribute to the loss of tissue homeostasis (excess cell proliferation, invasion, and metastasis). Intercellular communication in many organs is maintained via intercellular gap junction channels (GJIC) allow the transfer of small molecules which may regulate cell growth, differentiation, and function. Gap junctions are the only communicating junctions found in animal tissues, in all species, which are responsible for the direct traffic of ions and molecules with molecular weights less than 1,200 Daltons. These traffic ways are formed by the interaction between two hemichannels on the surface of opposing cells. These hemichannels are formed by the association of six proteins, the connexins. Because of the importance of intercellular junctions in the maintenance of the cellular homeostasis, the modulation of intercellular junctions and expression of connexin seems to be involved in carcinogenesis. Stable abnormal regulation of gap junction function has been associated with the activation of several oncogenes. Several tumor suppressor genes have also been associated with the up-regulation of gap junction function. Since gap junctions exist in all organs of multi-cellular organisms, the dysfunction of these gap junctions by various toxic chemicals which have cell type/tissue/organ specificity could bring about very distinct clinical consequences, such as embryo lethality or teratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the central nervous system, hyperplasia of the skin, and tumor promotion of initiated tissue. Recent investigations demonstrate that our environment is contaminated with many endocrine disruptors, which can interfere with the endocrine systems and adversely effect hormone balance or disrupt normal function, eventually leading to detrimental effects in the reproductive and developmental processes. Many hydrocarbons and organochlorine compounds are environmental pollutants that have been shown to downregulate gap junctions. The regulation of gap junction by these hydrocarbon compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its derivatives are unclear in cancer formation. Thus, understanding how TCDD affects gap junctional intercellular communication and subsequently interfere with cell homeostasis will provide valuable evidence of biochemical mechanisms of action. We hypothesize that TCDD regulates gap junction activity via PKC signal pathway and subsequently inhibits gap junction activity in epithelial breast cancer cells.