27HC在女性非吸烟肺癌发生发展中的作用及分子机制研究

Nonsmoking female lung cancer patients were believed to be a different kind of disease as its specificity in incidence, clinical feature and also the molecular mechanism. 27-hydroxycholesterol as a main product of cholesterol metabolism, was reported to promote breast cancer cell proliferation by ER, to promote cell migration and invasion by LXR. 27HC played key role in relationship between obesity and breast cancer. Our study found that increased serum cholesterol level in non-smoking female lung cancer patients correlated with female estrogen variables. We are planning to use 120 female nonsmoking lung cancer patients’s blood sample testing 27HC, CYP27A1 and CYP7B1 expression and to use patient tissue sample for IHC staining for ER and LXR, after all these test for the correlation between serum expression and IHC stating. Also, we are planning to use patients DNA for genotyping the polymorphisms in CYP27A1 and CYP7B1 investigating the genetic regulation of 27HC. Furthermore, using lung cancer cell line for the in vitro analysis of 27HC functions in lung cancer cell line; using SCID mice model for in vivo analysis 27HC and its functions in tumor exgraft. In conclusion, we are planing to use the genetic background test for the regulation, the patients sample for validation the relationship, in vitro and in vivo analysis for functional study to explore 27HC and its function in non-smoking female lung cancer patients.

女性非吸烟肺癌由于其在发病率、临床特征、分子机制等方面的特殊性，备受研究重视，雌激素在其发病中发挥重要作用。27-羟基胆固醇（27HC）是胆固醇代谢产物，其发挥雌激素样作用促进肿瘤细胞生长，可作为联系肥胖与肿瘤的纽带。27HC与女性非吸烟肺癌这种雌激素依赖肿瘤的关系不明确。本研究拟通过120例女性非吸烟肺癌患者的回顾性研究检测血清27HC及其代谢关键酶CYP27A1和CYP7B1水平，结合组织标本免疫组化，探讨女性非吸烟肺癌中的27HC及其代谢关键酶的表达与雌激素受体、肝X受体的关联；并利用体外细胞学实验和小鼠模型体内实验验证27HC在肺癌发生发展中的机制；结合27HC合成代谢关键酶CYP27A1和CYP7B1基因单核甘酸多态性检测，分析血清27HC水平的调控。从遗传背景调控、病人标本验证、体外细胞水平和小鼠模型体内模型综合揭示27HC在女性非吸烟肺癌的发生发展中的作用及机制。

女性非吸烟肺癌由于其在发病率、临床特征、分子机制等方面的特殊性，备受研究重视， 雌激素在其发病中发挥重要作用。27-羟基胆固醇（27HC）是胆固醇代谢产物，在乳腺癌中发挥雌激素样作用促进肿瘤细胞生长。27HC与女性非吸烟肺癌这种雌激素依赖肿瘤的关系不明确。本研究通过LCMS法检测临床样本血浆27HC表达水平，分析发现27HC在女性非吸烟肺癌患者中含量高于女性肺部良性肿瘤患者。患者随访进行生存分析发现，27HC与女性非吸烟肺腺癌患者的无进展生存相关，血浆27HC含量高的患者更容易出现疾病进展。本研究还对27HC产生和代谢相关基因的基因多态性进行了检测，分析了27HC相关的遗传背景与女性非吸烟肺腺癌发病的易感性的关系，发现27HC相关的受体基因NR1H2的基因多态性与女性非吸烟肺腺癌的易感性相关。体外细胞学实验证实27HC处理高表达ERα的女性肺癌细胞H292，可以促进细胞生长，增殖，迁移。发现27HC对肺癌的生长促进作用可能通过ERα发挥作用，27HC通过ER的核外作用途径激活ERK通路发挥促进肿瘤细胞生长侵袭的作用。裸鼠移植瘤模型也证实了27HC在体内也可以促进肿瘤细胞生长。本研究通过临床样本回溯性研究、肺癌细胞系体外研究及移植瘤动物模型体内研究，揭示了27HC在女性非吸烟肺癌中的发生机制及其生物学意义；为 27HC作为女性非吸烟肺癌治疗靶点和化学预防靶点提供了依据。