The Role of MUC1 in the Pathogenesis of Pancreatic Cancer

MUC1在胰腺癌发病机制中的作用

• 批准号: 7684816
• 负责人: ASHOK K SALUJA
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684816
• 关键词: Apoptosis; Apoptotic; Basic Science; Biological; C-Peptide; Cancer Etiology; Cancer cell line; Cathepsins; Cell Death; Cells; Cessation of life; Cytosol; Development; Diagnostic Neoplasm Staging; Disease; Down-Regulation; Enzymes; Heat shock proteins; Heat-Shock Proteins 70; Human; In Vitro; Laboratories; Lead; Lesion; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane; Mitochondria; Molecular; Molecular Chaperones; Mucin-1 Staining Method; Mucins; Neoplasm Metastasis; Outcome; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pathogenesis; Patients; Peptides; Permeability; Physiological; Play; Process; Property; Regulation; Role; Severities; Specimen; Staging; TNM; Testing; Therapeutic; Tumor stage; United States; base; cancer cell; cancer therapy; chemotherapeutic agent; cytochrome c; design; effective therapy; in vivo; mouse model; novel; overexpression; pancreatic neoplasm; prevent; public health relevance

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Strong basic research efforts are urgently needed to understand the molecular mechanisms responsible for its aggressiveness and to design novel anti-cancer therapies. Recent studies suggest that, besides their physiological role, mucins play a part in the pathogenesis of cancer: mucin1 (MUC1) overexpression has been observed in various cancers, including pancreatic cancer. It is believed that the carboxy terminal peptide of MUC1 is targeted to the mitochondria and inhibits apoptosis by preventing the release of cytochrome c (Cyt C). However, the mechanism by which MUC1 translocates to the mitochondria is unclear, since MUC1 lacks any mitochondrial localization sequence. It has been suggested that Heat Shock Proteins (HSPs) may participate in the mitochondrial translocation of MUC1, and studies in our laboratory have demonstrated that HSP70 is overexpressed in pancreatic cancer cells, and that the downregulation of HSPs leads to apoptosis. We have also demonstrated that one of the mechanisms by which HSP70 inhibits apoptosis in pancreatic cancer cells is by inhibiting Cyt c release from the mitochondria. However, the mechanism by which HSP70 inhibits Cyt c release from mitochondria remains unclear. We have observed that MUC1 is overexpressed in pancreatic cancer cells, where it also interacts with HSP70. We therefore hypothesize that HSP70 inhibits apoptosis in pancreatic cancer cells by transporting MUC1 to the mitochondria, where MUC1 stabilizes mitochondria, and subsequently prevents Cyt c release. Our preliminary studies indicate that downregulating HSP70 in pancreatic cancer cells leads to lysosomal membrane permeabilization and releases lysosomal enzymes into the cytosol, which then activate the apoptotic cascade. However, the mechanism by which HSP70 stabilizes the lysosomes remains unclear. Our preliminary studies suggest that MUC1 co-localizes to lysosomes. Thus, we hypothesize that HSP70 transports MUC1 to lysosomes, as well, and thereby stabilizes them. This novel hypothesis can explain the mechanism by which both HSP70 and MUC1 inhibit apoptosis in pancreatic cancer cells. The proposed studies have been divided into 4 specific aims: The 1st and 2nd specific aims will evaluate the role of MUC1 in the pathogenesis and aggressiveness of pancreatic cancer and will examine inhibiting MUC1 expression as a potential therapeutic strategy in pancreatic cancer; The 3rd and 4th aims will examine the mechanism by which MUC1 stabilizes lysosomes and mitochondria, and will investigate the role played by HSP70 in such processes. Once completed, these studies will greatly increase our understanding of the mechanisms by which cancer cells evade cell death, and will eventually lead us to design novel treatments. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer-related death in the USA. The severity of this cancer can be appreciated by the fact that in 2006 alone, 33,730 new cases were expected, and almost the same number died of the disease. Thus, efforts to gain information on the pathobiology of pancreatic cancer and on the molecular mechanisms related to the invasion and metastasis of tumor cells are urgently needed in order to develop effective treatments.

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因。迫切需要强有力的基础研究工作来了解其侵袭性的分子机制并设计新型抗癌疗法。最近的研究表明，除了其生理作用外，粘蛋白还在癌症的发病机制中发挥作用：在包括胰腺癌在内的各种癌症中都观察到粘蛋白1（MUC1）过度表达。据信MUC1的羧基末端肽靶向线粒体并通过阻止细胞色素c (Cyt C)的释放来抑制细胞凋亡。然而，MUC1 易位到线粒体的机制尚不清楚，因为 MUC1 缺乏任何线粒体定位序列。有研究表明热休克蛋白（HSP）可能参与MUC1的线粒体易位，本实验室的研究表明HSP70在胰腺癌细胞中过度表达，HSP的下调导致细胞凋亡。我们还证明，HSP70 抑制胰腺癌细胞凋亡的机制之一是抑制线粒体中 Cyt c 的释放。然而，HSP70 抑制线粒体 Cyt c 释放的机制仍不清楚。我们观察到 MUC1 在胰腺癌细胞中过度表达，并与 HSP70 相互作用。因此，我们假设 HSP70 通过将 MUC1 转运至线粒体来抑制胰腺癌细胞的凋亡，其中 MUC1 稳定线粒体，并随后阻止 Cyt c 释放。我们的初步研究表明，下调胰腺癌细胞中的 HSP70 会导致溶酶体膜通透，并将溶酶体酶释放到细胞质中，然后激活细胞凋亡级联。然而，HSP70 稳定溶酶体的机制仍不清楚。我们的初步研究表明 MUC1 共定位于溶酶体。因此，我们假设 HSP70 也将 MUC1 转运到溶酶体，从而稳定它们。这一新假设可以解释 HSP70 和 MUC1 抑制胰腺癌细胞凋亡的机制。拟议的研究分为4个具体目标：第一个和第二个具体目标将评估MUC1在胰腺癌发病机制和侵袭性中的作用，并将检查抑制MUC1表达作为胰腺癌的潜在治疗策略；第三个和第四个目标将研究MUC1稳定溶酶体和线粒体的机制，并将研究HSP70在这一过程中所发挥的作用。一旦完成，这些研究将大大增加我们对癌细胞逃避细胞死亡的机制的理解，并最终引导我们设计新的治疗方法。公共卫生相关性：胰腺癌是美国癌症相关死亡的第四大原因。仅 2006 年一年，预计就会有 33,730 例新病例，而几乎同样数量的人死于该疾病，这一事实足以说明这种癌症的严重性。因此，迫切需要获得有关胰腺癌病理学以及与肿瘤细胞侵袭和转移相关的分​​子机制的信息，以开发有效的治疗方法。