Shengjing Hospital of China Medical University, Department of Obstetrics and Gynecology, Shenyang, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.
University Hospital, LMU Munich, Department of Obstetrics and Gynecology, Munich, Germany.
Int Immunopharmacol. 2022 Jun;107:108726. doi: 10.1016/j.intimp.2022.108726. Epub 2022 Mar 23.
TMEFF1 is a newly discovered protein involved in the physiological functions of the central nervous system, embryonic development, and other biological processes. Our previous study revealed that TMEFF1 acts as a tumor-promoting gene in ovarian cancer. AHNAK, as a giant scaffolding protein, plays a role in the formation of the blood-brain barrier, cell architecture and the regulation of cardiac calcium channels. However, its role in ovarian cancer remains poorly researched. In this study, we detected the expression of AHNAK and TMEFF1 in 148 different ovarian cancer tissues, determined their relationship with pathological parameters and prognosis, clarified the interaction between the two proteins, and explored the related cancer-promoting mechanisms through immunohistochemistry, immunoprecipitation, immunofluorescence double staining, western blotting, and bioinformatics. The high expression of ANHAK and TMEFF1 in ovarian cancer indicated a higher degree of tumor malignancy and a worse prognosis. Furthermore, the expression of TMEFF1 and AHNAK was significantly positively correlated. The results also showed that AHNAK and TMEFF1 co-localized and interacted with each other in ovarian cancer tissues and cells. And knockdown of AHNAK promoted proliferation, migration and invasion of ovarian cancer cells in vitro. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that AHNAK and related genes were enriched during mitosis regulation, cytoskeleton formation, gene epigenetics, etc., whereas TMEFF1 and related genes are enriched during immune regulation and other processes. We also clarified the network of kinases, microRNA, and transcription factor targets, and the impact of genetic mutations on prognosis. Notably, AHNAK was regulated by the expression of TMEFF1 and can activate the MAPK pathways. Overall, high expression of AHNAK and TMEFF1 in ovarian cancer cells indicated a higher degree of tumor malignancy and a worse prognosis. Therefore, the interaction between AHNAK and TMEFF1 may become a potential anti-tumor target for ovarian cancer treatment.
TMEFF1 是一种新发现的蛋白，参与中枢神经系统的生理功能、胚胎发育和其他生物学过程。我们之前的研究表明，TMEFF1 在卵巢癌中作为一种促进肿瘤的基因发挥作用。AHNAK 作为一种巨大的支架蛋白，在血脑屏障的形成、细胞结构和心脏钙通道的调节中发挥作用。然而，其在卵巢癌中的作用仍研究甚少。在这项研究中，我们检测了 148 例不同卵巢癌组织中 AHNAK 和 TMEFF1 的表达，确定了它们与病理参数和预后的关系，阐明了这两种蛋白之间的相互作用，并通过免疫组化、免疫沉淀、免疫荧光双染色、western blot 和生物信息学探讨了相关的促癌机制。卵巢癌中 AHNAK 和 TMEFF1 的高表达表明肿瘤恶性程度更高，预后更差。此外，TMEFF1 和 AHNAK 的表达呈显著正相关。结果还表明，AHNAK 和 TMEFF1 在卵巢癌组织和细胞中共定位并相互作用。并且敲低 AHNAK 可促进卵巢癌细胞在体外的增殖、迁移和侵袭。基因本体论和京都基因与基因组百科全书通路分析显示，AHNAK 和相关基因在有丝分裂调控、细胞骨架形成、基因表观遗传学等过程中富集，而 TMEFF1 和相关基因在免疫调节和其他过程中富集。我们还阐明了激酶、microRNA 和转录因子靶标的网络以及遗传突变对预后的影响。值得注意的是，AHNAK 受 TMEFF1 表达的调控，并能激活 MAPK 通路。总之，卵巢癌细胞中 AHNAK 和 TMEFF1 的高表达表明肿瘤恶性程度更高，预后更差。因此，AHNAK 和 TMEFF1 之间的相互作用可能成为卵巢癌治疗的潜在抗肿瘤靶点。
