The Role of Carboxypeptidase E in Cancer

羧肽酶 E 在癌症中的作用

• 批准号: 7968715
• 负责人: Yoke p Loh
• 金额: $ 43.96万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7968715
• 关键词: Benign; Biological Markers; Breast; Cell Nucleus; Cellular Neurobiology; Clinical Research; Colonic Neoplasms; Complex; Development; Diagnosis; Disseminated Malignant Neoplasm; Enzymes; Epigenetic Process; Future; Genes; Genus Cola; Growth; Head and Neck Squamous Cell Carcinoma; Human; Malignant Epithelial Cell; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Methods; Neoplasm Metastasis; Nude Mice; Paraganglioma; Patients; Primary Neoplasm; Primary carcinoma of the liver cells; Process; Prognostic Marker; Prostate; Protein Isoforms; RNA; RNA Splicing; Reporting; Resected; Role; Secretory Vesicles; Tumor Cell Line; cancer cell; cancer therapy; carboxypeptidase H; follow-up; improved; metastatic process; migration; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; prognostic; prohormone; prospective; therapeutic target; treatment strategy; tumor; tumor growth

Despite the numerous biomarkers reported, few are useful for predicting metastasis. In our recent studies, we have uncovered a novel splice isoform of the prohormone processing enzyme, carboxypeptidase E (CPE-deltaN) that is elevated in metastatic hepatocellular, colon, breast, prostate, head and neck carcinoma cells. CPE-deltaN lacks the N-terminus that is normally present in secretory granule wild-type CPE, and is localized to the nucleus of metastatic cancer cells. Overexpression of CPE-deltaN in hepatocellular carcinoma (HCC) cells promoted their proliferation and migration by up-regulating expression of a metastasis gene via epigenetic mechanisms. SiRNA knockdown of CPE-deltaN expression in highly metastatic HCC cells inhibited their growth and metastasis in nude mice. In retrospective clinical studies, CPE-deltaN RNA quantification in primary HCC and colon tumors from patients established a level, above which predicted metastasis with high prognostic significance (p<0.0001). Furthermore, in a prospective clinical study on patients with paragangliomas, we were able to successfully predict from the mRNA copy numbers of CPE-deltaN of the resected tumors of several patients who were initially diagnosed as having benign tumors, that they would develop metastasis in the future. Indeed subsequent follow-up of these patients revealed development of metastasis over several years. Thus, CPE-deltaN is a new mediator of tumor metastasis and a powerful prognostic marker.

尽管报道了许多生物标志物，但很少有对预测转移有用。在最近的研究中，我们发现了激素加工酶，羧肽酶E（CPE-deltan）的新型剪接同工型，该酶在转移性肝细胞，结肠，乳腺，前列腺，头部和颈部癌细胞中升高。 CPE-Deltan缺少通常在分泌颗粒野生型CPE中存在的N末端，并且位于转移性癌细胞的核。 CPE-DELTAN在肝细胞癌（HCC）细胞中的过表达通过表观遗传机制上调转移基因的表达来促进其增殖和迁移。高度转移性HCC细胞中CPE-DELTAN表达的siRNA敲低抑制了其裸鼠的生长和转移。在回顾性的临床研究中，来自患者的原发性HCC和结肠肿瘤中的CPE-DELTAN RNA定量建立了一个水平，高于该水平，预测的转移具有很高的预后意义（p <0.0001）。此外，在一项针对帕拉瓜瘤患者的前瞻性临床研究中，我们能够从几名最初被诊断为良性肿瘤的几名患者的CPE-deltan的mRNA拷贝数中成功预测，以便他们将来会发展转移。实际上，随后对这些患者的随访显示了几年来转移的发展。因此，CPE-Deltan是肿瘤转移和强大预后标记的新介质。