REGULATION OF GAP JUNCTION IN COLON CANCER CELLS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。根据美国癌症协会的数据，在美国，大约二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的通讯方面存在许多缺陷，导致组织内稳态的丧失(细胞过度增殖、侵袭和转移)。许多器官中的细胞间通讯是通过细胞间缝隙连接通道(GJIC)维持的，允许小分子的转移，这些小分子可能调节细胞的生长、分化和功能。缝隙连接是在所有物种的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的两个半通道相互作用形成的。这些半突是由六种蛋白质--连接蛋白结合而成的。由于细胞间连接在维持细胞内环境平衡中的重要作用，细胞间连接的调节和连接蛋白的表达似乎参与了肿瘤的发生。缝隙连接功能的稳定异常调节与几个癌基因的激活有关。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使这些缝隙连接功能障碍，可能会导致非常不同的临床后果，如胚胎致死或畸形、性腺生殖功能障碍、中枢神经系统的神经毒性、皮肤增生和起始组织的肿瘤促进。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，影响激素平衡或扰乱正常功能，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已被证明下调缝隙连接的环境污染物。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对缝隙连接的调控尚不清楚。因此，了解TCDD如何影响缝隙连接细胞间的通讯，进而干扰细胞内稳态，将为生化作用机制提供有价值的证据。我们假设TCDD通过PKC信号通路调节缝隙连接活性，从而抑制乳腺癌细胞的缝隙连接活性。

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.