LncRNA-C17orf91上调MYC表达促进卵巢癌血行转移的分子机制研究

Recently, hematogenous metastasis have been demonstrated to play critical roles in the metastasis of ovarian cancer. However, the underlying mechanisms remain to be elucidated. Because lymphovascular space invasion(LVSI) is a risk factor for and closely correlated with tumor hematogenous metastasis, identification of differentially expressed genes between LVSI positive and LVSI negative ovarian cancer tissues may help to determine the key genes involved in hematogenous metastasis. By bioinformatics analyses, we found that the expression of C17orf91 was closely correlated with the LVSI status in ovarian cancer. Interestingly, C17orf91 expression was also higher in omental metastases than that in primary ovarian cancer tissues. Moreover, patients with higher expression of C17orf91 had a poorer prognosis. Functional studies revealed that C17orf91 could promote the invasion, migration, and proliferation of ovarian cancer cells. Molecularly, C17orf91 could upregulate the expression of miR-24-3p and MYC. Previous studies have indicated that miR-24-3p could activate the Wnt signaling pathway and that MYC was a downstream target of Wnt signaling pathway. Based on the above findings, the present project proposes that C17orf91 promote the hematogenous metastasis of ovarian cancer by upregulating miR-24-3p expression, consequently activating the Wnt signaling pathway and MYC expression. To test this hypothesis, we first explore whether the role of C17orf91 in promoting the hematogenous metastasis of ovarian cancer is dependent on the upregulation of MYC expression in vitro and in vivo. Second, we make efforts to decode whether the regulation of C17orf91 on MYC expression is dependent on the activation of miR-24-3p expression and the Wnt signaling pathway. Hopefully, it will help to identify new prognostic markers and therapeutic targets for ovarian cancer patients.

研究证实血行转移在卵巢癌侵袭转移中发挥重要作用，但其机制不清楚。肿瘤发生血行转移首要条件是淋巴脉管内浸润（LVSI）。我们发现：C17orf91和卵巢癌LVSI相关，C17orf91在卵巢癌转移灶中表达高于原发灶，其高表达的卵巢癌患者预后差；C17orf91能促进卵巢癌细胞浸润、迁移和增殖；C17orf91能上调miR-24-3p和MYC表达。既往研究发现miR-24-3p能激活Wnt信号通路，而Wnt信号通路激活能促进MYC基因转录。基于上述发现，本研究提出C17orf91通过上调miR-24-3p，激活Wnt信号通路，上调MYC表达，促进卵巢癌血行转移的假说。为验证该假说，本项目通过体内外实验分析C17orf91在卵巢癌血行转移中的作用，探索该作用是否通过上调MYC介导；并解析C17orf91对MYC的调控是否通过上调miR-24-3p来激活Wnt信号通路介导，为卵巢癌的防治提供依据。

卵巢癌确诊时多为侵袭转移的晚期阶段，侵袭转移是影响卵巢癌患者预后的重要因素之一。研究证实血行转移在卵巢癌侵袭转移中发挥重要作用，但其机制尚待深入解析。肿瘤发生血行转移的首要条件是肿瘤细胞侵入血管或淋巴管，发生淋巴脉管内浸润（LVSI）。探索LVSI阳性和LVSI阴性卵巢癌组织间的基因表达谱差异，对寻找调控卵巢癌血行转移的关键基因和提高患者的预后具有重要的临床意义。我们通过分析TCGA数据库中136例LVSI阴性和56例LVSI阳性卵巢癌组织的基因表达差异，筛选出包括C17orf91在内的70个差异表达基因。我们首先探究了C17orf91在卵巢癌中的表达及其与卵巢癌临床病理因素、预后的关系，发现C17orf91在卵巢癌组织中的表达低于正常对照组，其在卵巢癌转移灶中的表达高于原发灶中的表达，高表达C17orf91的卵巢癌患者预后差。功能学试验证实，C17orf91能促进卵巢癌细胞的浸润、迁移和增殖，其机制可能是通过上调miR-24-3p和MYC基因的表达介导。而动物实验发现，过表达C17orf91能显著抑制肿瘤的生长。此外，我们还分析了其他LVSI相关差异基因在卵巢癌侵袭转移中的作用及其和预后的关系，相关研究正在进行中，旨在寻找卵巢癌治疗的潜在靶点和预测预后的标记物。