Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
Department of Gynaecology and Obstetrics, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
Cell Death Dis. 2022 Dec 15;13(12):1043. doi: 10.1038/s41419-022-05501-5.
The expression, biological functions and underlying molecular mechanisms of endothelial cell-specific molecule 1 (ESM1) in human cervical cancer remain unclear. Bioinformatics analysis revealed that ESM1 expression was significantly elevated in human cervical cancer tissues, correlating with patients' poor prognosis. Moreover, ESM1 mRNA and protein upregulation was detected in local cervical cancer tissues and various cervical cancer cells. In established and primary cervical cancer cells, ESM1 shRNA or CRISPR/Cas9-induced ESM1 KO hindered cell proliferation, cell cycle progression, in vitro cell migration and invasion, and induced significant apoptosis. Whereas ESM1 overexpression by a lentiviral construct accelerated proliferation and migration of cervical cancer cells. Further bioinformatics studies and RNA sequencing data discovered that ESM1-assocaited differentially expressed genes (DEGs) were enriched in PI3K-Akt and epithelial-mesenchymal transition (EMT) cascades. Indeed, PI3K-Akt cascade and expression of EMT-promoting proteins were decreased after ESM1 silencing in cervical cancer cells, but increased following ESM1 overexpression. Further studies demonstrated that SYT13 (synaptotagmin 13) could be a primary target gene of ESM1. SYT13 silencing potently inhibited ESM1-overexpression-induced PI3K-Akt cascade activation and cervical cancer cell migration/invasion. In vivo, ESM1 knockout hindered SiHa cervical cancer xenograft growth in mice. In ESM1-knockout xenografts tissues, PI3K-Akt inhibition, EMT-promoting proteins downregulation and apoptosis activation were detected. In conclusion, overexpressed ESM1 is important for cervical cancer growth in vitro and in vivo, possibly by promoting PI3K-Akt activation and EMT progression. ESM1 represents as a promising diagnostic marker and potential therapeutic target of cervical cancer.
内皮细胞特异性分子 1（ESM1）在人宫颈癌中的表达、生物学功能及其潜在的分子机制尚不清楚。生物信息学分析显示，ESM1 在人宫颈癌组织中表达明显上调，与患者的预后不良相关。此外，在局部宫颈癌组织和各种宫颈癌细胞中均检测到 ESM1 mRNA 和蛋白的上调。在已建立的和原代宫颈癌细胞中，ESM1 shRNA 或 CRISPR/Cas9 诱导的 ESM1 KO 抑制细胞增殖、细胞周期进展、体外细胞迁移和侵袭，并诱导明显的细胞凋亡。而通过慢病毒构建体过表达 ESM1 则加速了宫颈癌细胞的增殖和迁移。进一步的生物信息学研究和 RNA 测序数据发现，ESM1 相关差异表达基因（DEGs）富集在 PI3K-Akt 和上皮-间充质转化（EMT）级联中。事实上，在宫颈癌细胞中沉默 ESM1 后，PI3K-Akt 级联和促进 EMT 的蛋白表达减少，但在 ESM1 过表达后增加。进一步的研究表明，SYT13（突触结合蛋白 13）可能是 ESM1 的主要靶基因。SYT13 沉默强烈抑制 ESM1 过表达诱导的 PI3K-Akt 级联激活和宫颈癌细胞迁移/侵袭。在体内，ESM1 敲除抑制 SiHa 宫颈癌异种移植在小鼠中的生长。在 ESM1 敲除的异种移植组织中，检测到 PI3K-Akt 抑制、促进 EMT 的蛋白下调和凋亡激活。总之，过表达的 ESM1 对体外和体内宫颈癌的生长是重要的，可能通过促进 PI3K-Akt 激活和 EMT 进展。ESM1 可能成为宫颈癌有前途的诊断标志物和潜在治疗靶点。
