REGULATION OF GAP JUNCTION IN CANCER CELLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 根据美国癌症协会的数据，在美国，大约有两分之一的男性和三分之一的女性会在其一生中的某个时候患上癌症。癌细胞在细胞内和细胞间通讯中表现出许多缺陷，这些缺陷导致组织稳态的丧失（过度细胞增殖、侵袭和转移）。 许多器官中的细胞间通讯是通过细胞间间隙连接通道（GJIC）来维持的，该通道允许小分子的转移，其可以调节细胞的生长、分化和功能。 缝隙连接是所有物种动物组织中发现的唯一通讯连接，负责分子量小于1，200道尔顿的离子和分子的直接运输。 这些交通方式是由相对细胞表面上的两个半通道之间的相互作用形成的。 这些半通道是由六种蛋白质连接蛋白（connexins）联合形成的。 由于细胞间连接在维持细胞内环境稳定中的重要性，细胞间连接和连接蛋白表达的调节似乎参与了癌的发生。 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间隙连接功能的上调有关。 由于缝隙连接存在于多细胞生物体的所有器官中，具有细胞类型/组织/器官特异性的各种有毒化学物质对这些缝隙连接的功能障碍可导致非常明显的临床后果，如胚胎致死或致畸、性腺生殖功能障碍、中枢神经系统神经毒性、皮肤增生和起始组织的肿瘤促进。 最近的调查显示，我们的环境受到许多内分泌干扰物的污染，这些干扰物会干扰内分泌系统，对激素平衡产生不利影响或扰乱正常功能，最终导致生殖和发育过程的不利影响。 许多碳氢化合物和有机氯化合物是环境污染物，已被证明可以下调缝隙连接。 这些碳氢化合物如2，3，7，8-四氯二苯并-对-二恶英（TCDD）及其衍生物对缝隙连接的调节在癌症形成中的作用尚不清楚。 因此，了解TCDD如何影响间隙连接细胞间通讯，并随后干扰细胞内稳态将提供有价值的证据的生化机制的行动。 我们推测TCDD通过PKC信号通路调节上皮性乳腺癌细胞的间隙连接活性，并随后抑制间隙连接活性。

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.