IL-37调控IL-6介导的炎症信号通路抑制宫颈癌增殖和转移

IL-37 has a markedly inhibition function on inflammation. It may regulate inflammation associated tumors, such as cervical cancer, through suppressing inflammatory molecular pathway. However, IL-37 and cervical cancer has not been studied as IL-37 is only named for more than 2 years. Until now, there is no manuscript and national natural science funds. The project applicant has studied IL-37 in the IL-37 research group in the United States, and we have constructed the pIRES-IL-37 expression vector which was afterward transferred to cervical cancer cells. As a result, the proliferation and invasive ability of IL-37 decreased dramatically, indicating that IL-37 could inhibit the proliferation and invasion of cervical cancer, but the mechanism remains to be defined.Studies showed that ①interleukin-6 could activate STAT3 and thus promote the proliferation and invasion of cervical cancer; ②IL-37 could significantly inhibit IL-6 expression, suggesting its potential function on the regulation of IL-6 / STAT3 pathway. According to our previous experiments and others' results, we hypothesize that, novel anti-inflammatory factor IL-37 targets IL-6 / STAT3 pathway and inhibits the proliferation, invasion and metastasis of cervical cancer cell. To verify the hypothesis, we plan to explore ①IL-37 targeting and regulating IL-6 / STAT3 in the cervical cancer cell;② the influences on tumor cell proliferation migration and invasion in vitro through introducing or inhibiting IL-37 gene expression. ③confirm that IL-37 inhibits CC metastasis in vivo through the nude mice experiments. This project will provide starting points and therapeutic targets for CC research. The consequences will be of decisive significance for prevention and treatment of diseases associated with inflammation.

IL-37具有强大的抗炎功能，它极可能通过抑制炎症信号通路调控炎症相关性肿瘤如宫颈癌的进展。然而由于它命名仅2年多，目前IL-37与宫颈癌这一重要领域尚无论文发表及国家基金立项。申请人曾赴美国IL-37课题组研习，前期构建IL-37表达载体，转染宫颈癌细胞后发现其增殖侵袭能力显著下降，但机制未明。研究表明：① IL-6/STAT3通路能促进宫颈癌增殖侵袭②IL-37能显著抑制炎症因子IL-6表达，提示其有调控上述通路的潜能。故我们假设，新型抗炎因子IL-37靶向IL-6/STAT3通路抑制宫颈癌增殖和转移。我们将研究：①宫颈癌中IL-37对IL-6/STAT3的靶向调控作用②体外实验：转染/敲减IL-37调节IL-6/STAT3通路调控细胞增殖迁移和侵袭③体内实验：裸鼠实验证实IL-37抑制宫颈癌的增殖转移。本项目将为宫颈癌研究提供新切入点和治疗靶点，对炎症类疾病的防治亦有重要借鉴意义。

最新命名的细胞因子白细胞介素( IL-37)正在受到越来越多的关注。它对肿瘤的作用在很大程度上是未知的。本项目中，我们研究了IL-37对宫颈癌的生物学功能和作用机制。本项目构建了IL-37真核表达载体,将其转染宫颈癌细胞后IL-37的mRNA及蛋白表达水平均显著大幅度上调，并进一步证明宫颈癌细胞Hela及C33a中IL-37的转染表达显著抑制了宫颈癌细胞的增殖迁移及侵袭能力。我们干扰了IL-6及STAT3基因，发现显著抑制了宫颈癌细胞的增殖侵袭能力。IL-37对HPV阳性的宫颈癌HeLa细胞的抗癌能力高于HPV阴性 C33A细胞。IL-37过表达在mRNA和蛋白水平抑制IL-6/STAT3的表达。IL-37也下调STAT3的磷酸化水平。使用siRNA干扰STAT3表达降低了IL-37抑制细胞增殖和侵袭能力。STAT3过表达则恢复了IL-37抑制的细胞增殖和侵袭以及对TNF-α和IL-1β的影响，表明IL-6/STAT3参与了IL-37对宫颈癌的调控通路。在研究期间，我们追踪研究前沿,进行了癌相关基因的新基因新靶点等的探索发掘,目前正在继续探索IL-37对新型癌相关基因NKX2.5，RUNX2，eIF4E、POKEMON等的调控; 到目前为止,发表论文多篇, 于2015年8月在国际上首次发表IL-37调控宫颈癌进展的SCI论文（J Cancer, IF=3.271）, 初步证实其为潜在的新型抗癌分子。在此过程中培养副高职称人员一名（申请人由助理研究员晋升副研究员），研究生2名（硕士毕业论文题目分别为：1.IL-37真核表达载体构建及其调控宫颈癌细胞增殖侵袭的分子机制。2.IL-37 调控宫颈癌细胞凋亡、侵袭及其分子机制的初步研究）。目前，尚有多篇论文待分析数据并撰写投稿后续发表。目前我们的主要方向有1.全面探索IL-37与宫颈癌的增殖侵袭自噬、凋亡、耐药等生物学行为的关系；2.探讨IL-37与肿瘤微环境及其他炎症相关疾病的关系。 这两个方向相辅相成，期待能有更多的研究成果出现。本项目的完成不仅拓展了IL-37的分子功能，更为将来宫颈癌防治提供了新药物和新思路。