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

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.

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。

宫颈癌是世界范围内女性生殖系统最常见的恶性肿瘤之一，高危型HPV感染是宫颈癌的首要病因，但仅有少数HPV感染的女性发展为宫颈癌，提示其他因素也参与了宫颈癌的进展。炎症在肿瘤形成中发挥重要作用的观点已经被广泛接受,肿瘤微环境中免疫细胞及其分泌的生长因子和细胞因子具有关键功能。PGRN作为肿瘤微环境中的生长因子之一，与多种肿瘤的发生发展密切相关，可促进多种癌细胞的转化、增殖、生存、迁移与侵袭等，然而PGRN与宫颈癌的相关性及其在宫颈癌中的功能仍未见报道。本项目通过临床组织、细胞水平和荷瘤鼠动物模型研究，以及信号途径分析，证明了PGRN在宫颈癌组织中高表达，PGRN促进宫颈细胞恶性转化、增殖与葡萄糖代谢，增强宫颈细胞成瘤及肿瘤生长能力；发现PGRN与mTOR磷酸化水平在宫颈癌组织中呈正相关，明确PGRN激活宫颈癌细胞中Akt/FoxO1、Erk、mTOR等信号途径，进而在PGRN介导的宫颈癌细胞行为中发挥关键作用；并获得了PGRN通过调节糖酵解和磷酸戊糖途径等参与葡萄糖代谢的提示性信息。本项目首次明确了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，为宫颈癌防治策略提供新的治疗靶点，并深入阐述了PGRN执行其生物学功能的分子机制。此外，在本项目资助下，项目组在肝细胞癌中验证了PGRN对mTOR信号途径的激活作用，证明PGRN/mTOR信号途径对肝细胞癌细胞增殖、迁移与侵袭的影响，以及炎性细胞因子IL-6对肝细胞癌细胞中PGRN表达的调控机制。