ERα通过调节circ-SMG1.72/miR-141-3p/Gelsolin通路抑制肝癌细胞侵袭

Hepatocellular carcinoma (HCC) is the fifth and seventh most frequently diagnosed cancer in men and women, and the second and sixth cause of cancer death, respectively, across the globe. According to population-based Surveillance Epidemiology and End Results registry data, the apparent male prevalence (4:1 male to female ratio) in HCC occurrence, smoking and occupational factors do not fully explain the significantly higher incidence of male hepatocellular carcinoma than females，suggested that HCC may be regulated by sex hormones during its initiation. Estrogen receptor α（ERα） plays an important role in HCC. We found that ERα could down-regulate circ-SMG1.72 to suppress HCC invasion. Bioinformatics analysis revealed that circ-SMG1.72 has binding sites with miR-141-3p sequence. While miR-141-3p can directly target and inhibit GSN expression. GSN is an important oncogene in HCC. Together, we hypothesized that ERα could down-regulate the expression of circ-SMG1.72 to suppress HCC invasion via miR-141-3p/GSN. In this research, we will study the mechanism of circ-SMG1.72 in HCC and may help us to develop a new theoretical foundation and experimental means for the diagnosis and treatment of HCC.

肝细胞癌（HCC）在全球男性和女性中发病率分别排名第五位和第七位，也是排在第二位和第六位癌症死因，其发病中具有明显的男性优势（男女性别比4：1），吸烟和职业因素并不能完全解释男性肝癌发病率明显高于女性。因此，HCC在其发病期间可能受性激素的调控，雌激素受体α（ERα）在HCC的发生发展中发挥着重要的作用，我们前期实验发现，ERα可通过下调环状RNA circ-SMG1.72抑制HCC侵袭。生物信息学分析显示：circ-SMG1.72系列中存在miR-141-3p序列结合位点。而miR-141-3p可直接作用于靶基因GSN，抑制其表达。GSN是HCC的重要癌基因，促进肝癌侵袭。我们猜测，ERα通过下调circ-SMG1.72，进而通过miR-141-3p/GSN通路抑制HCC侵袭。本项目将对circ-SMG1.72在HCC侵袭中的作用及机制进行研究，为HCC的诊疗提供新的理论基础和实验手段。

早期研究表明雌激素受体α (ERα)可能影响肝细胞癌(HCC)的进展。然而，其具体机制，特别是其与凝胶蛋白(GSN)介导的细胞侵袭的联系尚不清楚。我们发现ERα可以通过直接结合宿主基因SMG1的5'启动子区域，通过转录调节抑制环状RNA- smg1.72 (circRNA-SMG1.72)的表达，从而降低HCC细胞的侵袭能力。我们发现ERα抑制的circ-SMG1.72可以海绵和抑制微RNA (miRNA, miR) miR-141-3p的表达，然后通过减少miR与其3'非翻译区(3' UTR)的结合，从而增加GSN信使RNA的翻译。采用肝癌原位异种移植小鼠体内模型的临床前研究证实了体外数据，人类HCC临床样本调查和组织染色也证实了ERα/miR-141-3p/GSN信号通路与HCC进展的关联。总之，我们的研究结果表明，ERα可以通过改变ERα/circRNA-SMG1.72/miR-141-3p/GSN信号通路来抑制HCC细胞的侵袭，用小分子靶向这一新发现的信号通路可能有助于开发新的治疗方法，更好地抑制HCC的进展。