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，结肠癌，乳腺癌，头颈癌细胞中升高。 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，患者初级HCC中的CPE-DELTAN mRNA定量确定了一个切断的水平，高于该水平，这在2年内预测了未来的转移，具有高灵敏度和特异性，并且独立于癌症阶段。此外，在一项针对嗜铬细胞瘤/paragliomas患者的前瞻性临床研究中，我们能够从切除的肿瘤中CPE-DELTAN的mRNA拷贝数量高度准确地预测，尽管他们在手术时诊断为良性肿瘤，但会发展为未来转移的患者。此外，我们表明CPE-DELTA N也是诊断转移性结肠直肠癌的出色生物标志物。因此，CPE-DELTAN是一种新型肿瘤诱导剂，也是一种强大的预后标记，用于预测不同癌症未来转移，优于组织病理学诊断。