TSPAN12：改善卵巢癌化疗耐药的潜在新靶点

Chemo-resistance proves to be crucial factors leading to poor prognosis of ovarian cancer (OC). Our preliminary results showed that TSPAN12 gene had a critical influence on chemo-resistance of OC cells, and regulated the proliferation and clone formation of paclitaxel resistant OC cells. This implicated the important function of TSPAN12 gene in regulating chemo-resistance of OC. However, its mechanism remains to be elucidated. Wnt pathway, as well as its downstream player EMT, both have fundamental effect on modulating chemo-resistance of various cancer types. Our further investigation demonstrated that deregulation of TSPAN12 can monitor the expression of Wnt pathway molecules and EMT markers in paclitaxel resistant OC cells, which indicated that Wnt-EMT pathway might be downstream partners of TSPAN12 gene in the context of chemo-resistance. These findings led to our hypothesis: TSPAN12 can regulate the chemo-resistance of OC via Wnt-EMT pathway. In order to clarify this mechanism in OC, we will explore the association of TSPAN12 and chemo-resistance in vitro, in vivo as well as in human tissues by using a serious of experimental strategies as three-dimensional cell culture, gene editing technique, chemotherapy intervention in animal models etc. Our project aims to elucidate the mechanism and clinical significance of using TSPAN12 as the potential target to improve the efficacy of chemotherapy in clinical practice of ovarian cancer, thus providing more information for further studies in this area.

化疗耐药是导致卵巢癌预后不良的关键因素。我们前期研究发现TSPAN12基因的表达可以显著影响卵巢癌细胞对化疗药物的耐药性，同时可以调控紫杉醇耐药的卵巢癌细胞系的增殖和克隆形成能力，这表明TSPAN12基因是调控卵巢癌化疗耐药的重要分子。但其机制尚不明确，文献报道，Wnt通路和其下游EMT途径与肿瘤的化疗耐药关系密切。进一步研究发现，TSPAN12基因的表达可以调控卵巢癌化疗耐药细胞系的WNT信号通路分子及EMT 标记蛋白的表达，因此我们认为：TSPAN12可以通过Wnt-EMT途径调控卵巢癌化疗耐药。为证明这个假设，本项目拟从人体、动物和细胞到分子水平，利用3D细胞培养、基因编辑技术、动物模型药物干预实验等手段，系统而全面的探讨TSPAN12基因调控卵巢癌化疗耐药及其分子机制，明确TSPAN12基因作为改善卵巢癌化疗耐药靶点的潜在临床意义，为改善卵巢癌化疗耐药，提供新的理论依据。

化疗耐药是导致卵巢癌预后不良的关键因素。我们前期研究发现TSPAN12基因的表达改变可以影响卵巢癌细胞对化疗药物的耐药性，同时可以改变紫杉醇耐药的卵巢癌细胞系的增殖和克隆形成能力，因此我们假设TSPAN12基因可能是调控卵巢癌化疗耐药的重要分子。.为了明确以上初步假设，本项目从人体、动物和细胞到分子水平，利用基因编辑技术、在体外细胞系及动物模型中进行化疗药物干预实验，利用免疫组织化学技术、基于肿瘤开源数据库（如TCGA数据库）的统计学分析方法，对TSPAN12与卵巢癌化疗耐药的关系进行验证。.我们发现在人体肿瘤样本中，TSPAN12基因mRNA水平的高表达频发于卵巢癌患者，并与患者的恶性表型与不良预后显著相关；TSPAN12高表达使得接受铂类和紫杉醇化疗的卵巢癌患者预后不良。这表明人体肿瘤样本中TSPAN12的高表达可以增强卵巢癌患者对化疗药物的耐药。在原位和皮下移植瘤模型中，我们发现TSPAN12敲除使得肿瘤体积和重量呈现显著降低，提示TSPAN12基因敲除使得卵巢癌细胞对化疗药物卡铂的敏感性显著增加。在卡铂或紫杉醇耐药的卵巢癌细胞系中，进一步敲除TSPAN12使得耐药细胞的IC50显著降低，且在药物处理情况下细胞增殖能力也显著降低。以上结果提示降低TSPAN12的表达水平可以增强卵巢癌细胞对化疗药物的敏感性和恶性度，即TSPAN12的高表达与卵巢癌细胞卡铂或紫杉醇耐药有显著相关。.本研究结果在不同水平，系统而全面的证明了TSPAN12基因可以调控卵巢癌化疗耐药，明确了TSPAN12基因作为改善卵巢癌化疗耐药靶点的潜在临床意义，为改善卵巢癌化疗耐药，提供新的理论依据。