MIF-USP13-ACTL6A诱导宫颈癌EMT促进侵袭转移的机制研究

Metastasis is the most common cause of cancer-related death in patients of cervical cancer. Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and metastasis of cervical cancer. Our previous studies showed that macrophage migration inhibitory factor (MIF) induces EMT in cervical cancer cells, whereas ACTL6A, a subunit of chromatin remodeling complex SWI/SNF, mediates this process, but the mechanism remains unclear. Further experiments showed that MIF can reduce the ubiquitination level of ACTL6A and increase its stability. In addition, we used methods of bioinformatics to screen and validate that USP13 deubiquitinates ACTL6A, and the effect of deubiquitination of ACTL6A by MIF is weakened after knockdown of USP13. Therefore, it was hypothesized that MIF modulates the stability of ACTL6A via deubiquitination by USP13. In this research, we intend to verify the function of ACTL6A regulated by USP13 on the EMT of cervical cancer, explore the molecular mechanism of deubiquitination of ACTL6A by USP13 and detect the effect of MIF on the deubiquitination of ACTL6A regulated by USP13. This research project will reveal the new mechanism that MIF can modulate the deubiquitination of ACTL6A through USP13 to induce EMT which promotes the invasion and metastasis of cervical cancer. It may provide a theoretical basis for targeted therapy of metastatic cervical cancer.

宫颈癌发生转移是患者死亡的主因，上皮间质转化（EMT）在侵袭转移中发挥重要作用。我们前期研究表明：巨噬细胞移动抑制因子（MIF）诱导宫颈癌细胞发生EMT，而染色质重构复合体SWI/SNF的亚基ACTL6A介导这一过程，但机制不清。进一步实验发现，MIF能使ACTL6A泛素化水平降低并增加其稳定性。此外，我们利用生物信息学方法筛选并验证USP13使ACTL6A发生去泛素化，敲减USP13后MIF降低ACTL6A泛素化的作用减弱，故提出假说：MIF通过USP13去泛素化调控ACTL6A蛋白稳定性。我们拟深入研究以下内容：开展USP13调控ACTL6A在EMT中的功能验证；探索USP13去泛素化ACTL6A的分子机制；检测MIF对USP13调控ACTL6A去泛素化的影响。本课题将揭示MIF通过USP13去泛素化ACTL6A诱导EMT促进宫颈癌侵袭转移的新机制，为宫颈癌转移的靶向治疗提供理论依据。

宫颈癌发生转移是患者死亡的主因，抑制癌细胞恶性行为表型对于改善宫颈癌治疗效果具有重要意义。我们前期研究表明：染色质重构复合体SWI/SNF的亚基ACTL6A介导了巨噬细胞移动抑制因子（MIF）诱导的宫颈癌细胞侵袭迁移能力。在本项目中，我们明确了ACTL6A通过c-Myc促进肿瘤细胞周期进程，并通过PGK1促进肿瘤细胞糖酵解的分子机制。我们发现了甲基转移酶SMYD2能介导MIF诱导的宫颈癌细胞糖酵解和恶性表型，及胶原蛋白P4HA2以促进糖酵解的方式增加宫颈癌细胞增殖和侵袭能力。此外，通过生物信息学分析，我们进一步探索了ACTL6A与宫颈癌免疫浸润的关系，并发现了多个与患者预后及免疫浸润相关的基因。通过本项目的开展，我们丰富了宫颈癌发生发展的分子机制，为今后宫颈癌治疗的药物研发提供新的潜在靶点。