Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Benxi, Liaoning, China.
Adv Ther. 2022 Jan;39(1):360-378. doi: 10.1007/s12325-021-01941-1. Epub 2021 Nov 5.
Ovarian cancer has a high mortality rate due to difficulties in early detection and chemotherapy resistance. Human epididymal protein 4 (HE4) has been adopted as a novel serum biomarker for early ovarian cancer diagnosis, and the presence of Lewis y antigen modifications on HE4 in ovarian cancer cell lines has been detected in previous studies. The aim of this study was to analyze the expression of HE4 and Lewis y antigen in human ovarian cancer in order to find a correlation between them, as well as with the clinical pathological parameters of patients with ovarian cancer.
Immunohistochemistry was used to detect the respective expression of these compounds in two patient groups (chemotherapy-resistant and chemotherapy-sensitive) containing a total of 95 patients. Then, a bioinformatic approach was adopted and online large sample databases (TCGA, CCLE, and GTEx; Metascape, Cytoscape) were used to explore the potential mechanisms of action of these compounds.
The results of this study demonstrate that high HE4 and Lewis y expression could be used as markers for chemotherapy resistance and poor prognosis in patients with ovarian cancer. These two expression events were widely correlated in various cancer tissues and are thought to act by activating the p38 mitogen-activated protein kinases (MAPK) pathway and inducing Vascular Endothelial Growth Factor A (VEGFA), Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Early Growth Response 1 (EGR1), and Hypoxia-Inducible Factor 1-Alpha (HIFI1A), thereby promoting malignant biological behavior and resistance in ovarian cancer.
These findings not only reveal the possible mechanism by which HE4 and Lewis y antigen affect ovarian cancer but also identify a four-gene signature that could be very useful in ovarian cancer detection and/or the development of new targeted therapies.
卵巢癌由于早期检测困难和化疗耐药而死亡率较高。人附睾蛋白 4（HE4）已被采用为早期卵巢癌诊断的新型血清生物标志物，并且先前的研究已经检测到卵巢癌细胞系中 HE4 上 Lewis y 抗原修饰的存在。本研究旨在分析人卵巢癌中 HE4 和 Lewis y 抗原的表达，以寻找它们之间以及与卵巢癌患者临床病理参数之间的相关性。
采用免疫组织化学法检测了包含 95 例患者的两个患者组（化疗耐药和化疗敏感组）中这些化合物的各自表达。然后，采用生物信息学方法并使用在线大型样本数据库（TCGA、CCLE 和 GTEx；Metascape、Cytoscape）探索这些化合物的潜在作用机制。
本研究的结果表明，高 HE4 和 Lewis y 表达可作为卵巢癌患者化疗耐药和预后不良的标志物。这两个表达事件在各种癌症组织中广泛相关，被认为通过激活丝裂原活化蛋白激酶（MAPK）通路并诱导血管内皮生长因子 A（VEGFA）、前列腺素内过氧化物合酶 2（PTGS2）、早期生长反应 1（EGR1）和缺氧诱导因子 1-α（HIFI1A）而起作用，从而促进卵巢癌的恶性生物学行为和耐药性。
这些发现不仅揭示了 HE4 和 Lewis y 抗原影响卵巢癌的可能机制，而且还确定了一个四基因特征，该特征在卵巢癌检测和/或新的靶向治疗的开发中可能非常有用。
