视黄醇代谢相关基因LRAT/RDH12在宫颈鳞癌进展中的作用及机制研究

Cervical cancer is one of the most common cancer in females, HPV infection and genes related in tumor growth are critical for the progress of cervical cancer. Our studies have screened the differential expressed genes between squamous cervical carcinoma and matched adjacent non-tumor tissues by RNA-Seq technology for the first time. qRT-PCR, Western blot and immunochemistry were used to validate the expression of differential expressed genes. We discovered that the expression of the retinol metabolism related genes (LRAT and RDH12) were lower in squamous cervical carcinoma tissues and cells than that of matched adjacent non-tumor tissues and normal cervical squamous epithelial cells. In our preliminary experiments, it has been found that in the human squamous cervical cancer cells with overexpression of LRAT or RDH12, the expression of proteins involved in MAPK/NF-kB signal pathway changed accordingly. In this study, we are trying to examine the effect of LRAT, RDH12 genes on proliferation, apoptosis, migration, invasion, as well as tumor growth and metastasis of cervical cancer through p38 MAPK/NF-kB signal pathway in cultured cells and nude mouse model, and analyse the relationship between LRAT/RDH12 genes and the clinical pathological factors of cervical squamous carcinoma. This project aims to clarify the effect and mechanism of retinol metabolism related genes LRAT/RDH12 in the progress of squamous cervical cancer and provide important theoretical supports and molecular targets for squamous cervical carcinoma.

宫颈癌是妇科最常见恶性肿瘤之一，HPV感染及与肿瘤生长相关的基因在宫颈癌进展中有重要作用。我们的前期研究首次通过RNA-Seq技术，检测宫颈鳞癌与癌旁组织的差异基因，经验证后，发现视黄醇代谢相关基因LRAT和RDH12 在宫颈鳞癌组织和细胞中的表达明显低于癌旁组织和正常宫颈鳞状上皮细胞。在过表达LRAT、RDH12基因的宫颈鳞癌细胞中，MAPK/NF-kB 信号通路的蛋白表达发生变化，提示LRAT、RDH12基因可能通过p38 MAPK/NF-kB信号通路调控宫颈鳞癌进展。本课题拟进一步验证LRAT、RDH12基因与p38 MAPK/NF-kB信号通路对宫颈鳞癌细胞增殖、凋亡、侵袭、肿瘤生长和转移的影响，分析LRAT/RDH12与宫颈鳞癌的临床病理因素及预后的关系，旨在阐明视黄醇代谢相关基因LRAT/RDH12基因在宫颈鳞癌进展中的作用及机制，为宫颈癌的防治提供新的理论支持和分子指标。

宫颈癌是妇科常见恶性肿瘤之一，居女性恶性肿瘤患者死亡原因的第4位。宫颈癌的发生发展是多因素共同作用的结果，除高危型HPV病毒的持续性感染外，宿主的基因表达异常在宫颈癌的发病机制中同样具有重要作用。基于RNA-seq测序的前期研究发现，LRAT、RDH12基因在宫颈鳞癌和癌旁组织中具有明显的表达差异。因此，本研究旨在阐明LRAT、RDH12基因在宫颈鳞癌发生发展中的作用机制。. 研究结果显示，LRAT、RDH12基因在宫颈鳞癌组织中的表达水平明显低于癌旁组织，结果与RNA-Seq数据一致。在LRAT、RDH12腺病毒载体转染成功的宫颈癌细胞模型中，过表达 LRAT、RDH12 基因可抑制宫颈鳞癌细胞增殖、抑制细胞周期转化、促进细胞凋亡、降低宫颈癌细胞的侵袭与迁移能力。进一步的研究发现，LRAT、RDH12位于MAPK/NFkB 信号通路的上游，LRAT、RDH12 过表达可抑制MAPK的活化，进而抑制 NF-kB的激活，抑制癌细胞的生长，侵袭和迁移，促进细胞凋亡 。另外，本课题组成功构建裸鼠移植瘤模型，裸鼠体内实验验证了LRAT、RDH12基因对MAPK/NF-kB通路中P38、P50、P65蛋白的下调作用。 . 本研究首次探讨了视黄醇代谢相关基因LRAT、RDH12在宫颈鳞癌发生发展中的抑制作用，同时， 也阐明了LRAT、RDH12基因通过MAPK/NF-kB信号通路调控宫颈鳞癌发生发展的机制，为宫颈癌的预防和治疗提供新的理论支持和分子指标。