GINS2调控MYC相关通路在骨肉瘤发生发展中的作用和机制

Abnormal gene expression determines the occurrence and development of tumors. The abnormal expression of GINS2 gene exists in kinds of tumors, which is related to the growth, invasion and chemotherapy sensitivity of tumors. At present, the research of GINS2 gene is still in its initial stage, and it is still inexplicit on its expression , function and mechanism in osteosarcoma (OS).. In our preliminary experiments, these are found that GINS2 gene in 40 cases of OS specimens, they have an average of 4.6 times the abnormal high expression compared with normal bone tissue; and there are GINS2 gene high expression abundance in two OS cell lines; after interfering GINS2 gene expression, it was significantly inhibited the proliferation of U-2 OS cells, and promoted the apoptosis of U-2 OS cells, and down regulated the expression of YAP1, SKP2, TFDP1, THBS1 genes associated with MYC pathway.. We hypothesize that GINS2 plays an important role in the occurrence and development of OS by regulating the MYC pathway. In this project, we are going to study the cytological effects of GINS2 gene in two OS cell lines. Secondly, we will analyze the relationship between GINS2 gene expression level and the prognosis of OS by following up the survival status of OS patients, and judge the ability of GINS2 as a potential prognostic indicator of OS. Thirdly, we will construct GINS2 gene PSCSI-GFP lentiviral vector and over expression plasmid, and confirm the effect of GINS2 on the occurrence and development of OS. Fourthly, by regulating key genes of MYC pathway ,it will reveal the molecular mechanism of GINS2 and MYC related pathway. . The successful implementation of the project will further verify the abnormal expression, cytological effects and the relationship with prognosis of GINS2 gene in OS, and elucidate the molecular mechanism of GINS2 regulated MYC related pathway, and providing a new therapeutic target for the treatment of OS.

基因表达异常决定肿瘤的发生、发展。GINS2与多种肿瘤的生长、侵袭和治疗相关，其在骨肉瘤(OS)中的表达、作用与机制仍不清楚。我们发现，GINS2在OS标本中，存在4.6倍的异常高表达；在OS细胞株中也为高表达丰度；干扰GINS2后，U-2 OS细胞的增殖受到显著抑制，促进U-2细胞凋亡，引起与MYC通路相关的YAP1、SKP2、TFDP1、THBS1基因表达显著下调。我们推测，GINS2通过调控MYC通路，对OS的发生发展发挥重要作用。本项目拟确定GINS2在OS中的细胞学作用；随访OS患者，分析GINS2与预后的关系；构建GINS2的干扰慢病毒载体和过表达质粒，证实GINS2对OS发生发展的影响；调控MYC通路不同的关键基因，揭示GINS2与MYC通路的关系。项目的成功实施，将验证GINS2在OS的生物学效应、阐明GINS2调控MYC相关通路的分子机制，为OS的治疗提供新的治疗靶点。

基因表达异常决定肿瘤的发生、发展。GINS2与多种肿瘤的生长、侵袭和治疗相关。本课题组发现，GINS2在OS标本中，存在4.6倍的异常高表达；GINS2基因在U-2OS、MG-63和Saos-2细胞株中均为高表达丰度；干扰GINS2后，OS细胞的增殖、迁移和侵袭均受到显著抑制，同时促进U-2细胞凋亡，引起与MYC通路相关的YAP1、SKP2、TFDP1、THBS1基因表达显著下调。动物体内成瘤实验发现，沉默GINS2基因能抑制OS的发展，相比NC组，KD组瘤体重量减小（p<0.05）。随访OS患者，构建生存分析图显示GINS2高表达组的OS患者死亡率、复发率及转移率均高于低表达患者。本项目的完成，证实GINS2通过MYC/STAT3信号通路促进肿瘤的增殖，侵袭和迁移，为GINS2基因的研究做出有益的探索，并发表科研论文4篇，其中SCI文章3篇，专利1项。