长链非编码RNA SOX2OT调控SOX2在卵巢癌发生发展过程中的作用及其分子机制

Ovarian carcinoma has the hightest mortality of the gynecological malignancies. Due to general or non-descript symptoms of early stage disease, ovarian carcinoma is mostly diagnosed at advanced metastatic stages. The treatment of ovarian carcinoma is little benefit. We found that SOX2OT and SOX2 highly expressed in tumor tissues vs. non-tumor tissues. The SOX2OT and SOX2 were co-expressed in the same tissues. A study about breast cancer showed that the expression of SOX2OT and SOX2 is concordant. Importantly, ectopic expression of SOX2OT led to a significantly expression increase, together with a reduced proliferation. We proposed that SOX2OT plays a key role in the induction and/or maintenance of SOX2 expression in tumor. We intent to find the occurrence mechanism of SOX2OT in ovarian carcinoma, and further to provide the evidence of SOX2OT regulated SOX2 expression. This finding will clarify the molecular mechanism of SOX2OT regulated SOX2 expression and promotes ovarian cancer cells proliferation and anti-apoptosis. This finding will provide powerful evidence to raising new therapeutic target and formulating individualized treatment protocols in ovarian carcinoma.

卵巢癌是妇科三大恶性肿瘤之一，其死亡率位于妇科恶性肿瘤之首。其治疗上的难点主要有：起病隐匿，缺乏早期典型症状，易早期侵袭、转移，以及缺乏成熟的早期诊断方法。我们前期的研究发现：与癌旁组织相比，肿瘤组织中长链非编码RNA SOX2OT和SOX2的表达水平均显著升高。而且SOX2和SOX2OT的共表达分析发现他们存在显著相关性。一项基于乳腺癌的研究中也发现了SOX2OT和SOX2协调表达，SOX2OT的异位表达上调SOX2表达且抑制细胞的增殖。以上研究提示我们SOX2OT可能通过调控SOX2表达而影响肿瘤的发生发展。因此，本课题拟分析SOX2OT高表达在卵巢癌发生发展中的作用，进一步研究SOX2OT通过调节SOX2表达，促进卵巢癌细胞增殖、抑制凋亡的分子机制。可望为卵巢癌提出新的治疗靶点，为肿瘤个体化治疗方案的制定提供参考。

卵巢癌是妇科三大恶性肿瘤之一，其死亡率远超宫颈癌和子宫内膜癌，位于妇科恶性肿瘤之首，尽管手术和化疗技术都有很大进步，但是卵巢癌病人的五年生存率仍然只有30%左右，卵巢癌治疗上的难点主要有：起病隐匿，缺乏早期的典型症状，易早期侵袭、转移，以及缺乏成熟的早期诊断方法。本研究对卵巢癌组织、卵巢良性肿瘤组织及正常卵巢组织SOX2、RRS1和SOX2OT的表达进行检测，分析他们与卵巢癌临床病理及预后的相关性。探讨他们对卵巢癌细胞生物学行为的影响。采用Co-IP鉴定RRS1相互作用的蛋白了解其可能的调控机制。结果显示：SOX2、SOX2OT和RRS1在卵巢癌中阳性表达率显著增加，其中SOX2表达与卵巢癌病人的年龄相关。SOX2OT和RRS1低表达与高表达的卵巢癌病人相比5年生存期更短。对ES-2和SK-OV-3细胞进行RRS1 shRNA慢病毒感染后，细胞增殖速率受到显著抑制，发生凋亡的细胞显著增加，细胞的周期分布改变，裸鼠成瘤能力降低。Co-IP分析发现增殖相关蛋白PTEN和SOX2在RRS1过表达细胞中差异表达。因此，RRS1基因沉默可能通过PTEN通路调控SOX2表达从而抑制卵巢癌的增殖迁移。