肿瘤微环境信号分子PGRN调控宫颈癌肿瘤生长与代谢的研究

宫颈癌女性生殖系统最常见的恶性肿瘤之一，高危型人乳头瘤病毒（human papillomavirus, HPVs）是宫颈癌的首要致病因素。肿瘤微环境是癌症发生的细胞外因素,深入了解肿瘤微环境的功能将促进人类对癌症发生和发展机制的全面认识，并有助于抗癌药物的优化和创新。生长因子Progranulin（PGRN）是一种多功能细胞因子，在乳腺癌、卵巢癌和肝癌等多种癌症中具有致瘤功能，但PGRN在宫颈癌中的表达及功能目前未见报道。本项目拟检测宫颈细胞和临床样本中PGRN表达变化，从细胞和动物水平阐明PGRN对宫颈癌细胞增殖与肿瘤形成的影响，以IL-6/PGRN/AKT/FoxO1和PGRN/PKM2/HIF-1α等信号途径为切入点，深入分析PGRN调控癌细胞增殖与代谢的分子机制，明确肿瘤微环境信号分子PGRN在宫颈癌发生与发展中的重要调控功能，为宫颈癌等肿瘤的防治策略提供新的治疗靶点。

Cervical cancer is one of the most common neoplastic diseases among women, with a combined worldwide incidence of approximately one-half million new cases annually and rates of morbidity and fatality second only to breast cancer. In addition, in recent years the average cervical cancer patient has become progressively younger. Over 99% of cervical carcinomas are positive for human papillomavirus (HPV) DNA, indicating that HPV infection is the most important cause for cervical cancer. The tumour microenvironment, the local conditions experienced by cells in a tumour, including the levels of nutrients, oxygen and signalling molecules such as growth factors and cytokines, is known to play an important role in determining the sequence of acquired phenotypic traits that characterise cancer evolution. A more precise understanding of this role could have a major influence in the understanding of cancer growth and development, and potentially in the optimisation of innovative anti-cancer treatments delivery. Progranulin (PGRN) is a secreted glycoprotein growth factor with tumorigenic roles in a variety of tumors including, among others, breast, ovarian, prostate, bladder, and liver cancer. Expression and function of PGRN in cervical cancer remain unclear. In this project, the following studies will be carried out：.(1) Detection of the expression level of PGRN in cervical epithelial cells and cervical cancer samples, to determine the abnormal PGRN level in cervical cancer; .(2) We will establish whether PGRN respond to IL-6, a cytokine exclusively expressed in cervical cancer microenvironment, and PGRN contribute to the proliferation of cervical cancer via inactivation of transcriptional factor FoxO1 in a PI3K/AKT dependent manner; .(3) Pyruvate kinase isoenzyme type M2 (PKM2), a ubiquitous prototype enzyme present in all tissues during the embryonic stage and cancer, is the final enzyme in glycolysis, which is reported to regulate the activity of hypoxia inducible factor-1α (HIF-1α) as a coactivator. We will collect evidences that PGRN stimulates PKM2 expression in cervical cells in normal and hypoxia condition and in turn regulates tumor cell metabolism regulated by HIF-1α;.(4) Finally, we will confirm the role of PGRN in cervical cancer progression via cervical cancer cells or TC-1 cells transplanted tumor formation assay on null mice or PGRN knockout mice..In conclusion, this project will establish the expression and function in cervical cancer, and analyze the regulatory mechanism of IL-6/PGRN/AKT/FoxO1 and PGRN/PKM2/HIF-1α pathway in cervical cell growth and metabolism. Our studies will provide the first evidence linking PGRN and cervical cancer, give an idea that PGRN, as a signaling molecule in tumor microenvironment of cervical cancer, plays critical role in cervical carcinogenesis, and both in vitro and in vivo studies will contribute to the PGRN targeting therapeutic strategy to cancer, including cervical cancer.