The Role of Carboxypeptidase E in Cancer

羧肽酶 E 在癌症中的作用

• 批准号: 8351197
• 负责人: Yoke p Loh
• 金额: $ 78.39万
• 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/8351197
• 关键词: Benign; Biological Markers; Breast; Cell Nucleus; Cellular Neurobiology; Clinical Research; Colon; Complex; Diagnosis; Diagnostic Neoplasm Staging; Disseminated Malignant Neoplasm; Enzymes; Epigenetic Process; Future; Genes; Growth; Head and Neck Squamous Cell Carcinoma; Human; Malignant Epithelial Cell; Malignant Neoplasms; Messenger RNA; Methods; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Paraganglioma; Patients; Pheochromocytoma; Primary Neoplasm; Primary carcinoma of the liver cells; Process; Prognostic Marker; Protein Isoforms; RNA Splicing; Rectal Cancer; Reporting; Resected; Role; Secretory Vesicles; Sensitivity and Specificity; Time; Tumor Cell Line; cancer cell; cancer therapy; carboxypeptidase H; improved; metastatic process; migration; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; 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, 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 mRNA quantification in primary HCC from patients established a cut off level, above which predicted future metastasis within 2 years with high sensitivity and specificity and independent of cancer stage. Furthermore, in a prospective clinical study on patients with pheochromocytoma/paragangliomas, we were able to predict with high accuracy from the mRNA copy numbers of CPE-deltaN in the resected tumors, those patients who would develop future metastasis, although they were diagnosed with benign tumors at the time of surgery. Additionally, we showed that CPE-delta N is also an excellent biomarker for diagnosis of metastatic colon rectal cancer. Thus, CPE-deltaN is a novel tumor inducer and a powerful prognostic marker for predicting future metastasis in different cancers, superior to histopathological diagnosis.

尽管报道了许多生物标志物，但很少有可用于预测转移。在我们最近的研究中，我们发现了激素原加工酶羧肽酶 E (CPE-deltaN) 的一种新型剪接亚型，该剪接亚型在转移性肝细胞癌、结肠癌、乳腺癌、头颈癌细胞中升高。 CPE-deltaN 缺乏分泌颗粒野生型 CPE 中通常存在的 N 末端，并且定位于转移性癌细胞的细胞核。肝细胞癌 (HCC) 细胞中 CPE-deltaN 的过度表达可通过表观遗传机制上调转移基因的表达，从而促进其增殖和迁移。 siRNA敲低高度转移性HCC细胞中的CPE-deltaN表达可抑制其在裸鼠中的生长和转移。在回顾性临床研究中，对原发性 HCC 患者的 CPE-deltaN mRNA 定量建立了一个截止水平，高于该水平可预测未来 2 年内的转移，具有高敏感性和特异性，并且与癌症分期无关。此外，在一项针对嗜铬细胞瘤/副神经节瘤患者的前瞻性临床研究中，我们能够根据切除的肿瘤中 CPE-deltaN 的 mRNA 拷贝数高精度预测那些被诊断为良性肿瘤的患者未来会发生转移。手术时的肿瘤。此外，我们还发现 CPE-delta N 也是诊断转移性结肠直肠癌的极佳生物标志物。因此，CPE-deltaN是一种新型肿瘤诱导剂，也是预测不同癌症未来转移的强大预后标志物，优于组织病理学诊断。