Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
Lab Invest. 2024 Jun;104(6):102057. doi: 10.1016/j.labinv.2024.102057. Epub 2024 Apr 4.
Ovarian carcinoma is usually diagnosed at an advanced stage with peritoneal dissemination and/or lymph node metastasis, and the prognosis for such advanced carcinoma is very poor. Therefore, new biomarkers to predict patient prognosis are needed. Miyamoto et al. previously showed that keratan sulfate (KS) detected by the 5D4 monoclonal antibody was expressed in ovarian carcinoma. However, the detailed structure of such KS was not determined, and the biological significance of this finding remained to be clarified. We previously generated the 297-11A monoclonal antibody, which recognizes galactose (Gal)-6-O-sulfated N-acetyllactosamine (LacNAc) located at the nonreducing terminus. Because the 297-11A epitope overlaps with that of 5D4, here we chose to use the 297-11A antibody as a tool to analyze KS and related structures. We conducted immunohistochemical analysis of 98 ovarian carcinoma cases with 297-11A antibody combined with a series of glycosidases and performed mass spectrometry analysis of the human serous ovarian carcinoma cell line OVCAR-3 to deduce the glycan structure of 297-11A-sulfated glycans. We also performed western blot analysis to assess a potential association of 297-11A-sulfated glycans with the mucin core protein mucin 16 (MUC16; also known as cancer antigen 125 (CA125)). Finally, we examined the relationship between 297-11A expression and patient prognosis. Consequently, 297-11A-sulfated glycans were primarily expressed in serous and endometrioid carcinomas and poorly expressed in mucinous and clear cell carcinomas. We reveal that structurally, 297-11A-sulfated glycans expressed in ovarian carcinoma are O-glycans carrying partially sialylated, Gal-6-O-sulfated LacNAc and that these glycans are likely displayed on MUC16 mucin core proteins. Of clinical importance is that expression of 297-11A-sulfated glycans correlated with shorter progression-free survival in patients. Thus, 297-11A-sulfated glycans may serve as a predictor of ovarian carcinoma recurrence.
卵巢癌通常在晚期被诊断,伴有腹膜扩散和/或淋巴结转移,且此类晚期癌的预后非常差。因此,需要新的生物标志物来预测患者的预后。Miyamoto 等人之前表明,5D4 单克隆抗体检测到的硫酸角质素 (KS) 在卵巢癌中表达。然而,这种 KS 的详细结构尚未确定,其发现的生物学意义仍有待阐明。我们之前生成了 297-11A 单克隆抗体,该抗体识别位于非还原末端的半乳糖 (Gal)-6-O-硫酸化 N-乙酰乳糖胺 (LacNAc)。由于 297-11A 表位与 5D4 重叠,因此我们选择使用 297-11A 抗体作为工具来分析 KS 和相关结构。我们用 297-11A 抗体结合一系列糖苷酶对 98 例卵巢癌病例进行了免疫组织化学分析,并对人浆液性卵巢癌细胞系 OVCAR-3 进行了质谱分析,以推断 297-11A 硫酸化糖的聚糖结构。我们还进行了 Western blot 分析,以评估 297-11A 硫酸化糖与粘蛋白核心蛋白 mucin 16(也称为癌症抗原 125(CA125))之间的潜在关联。最后,我们检查了 297-11A 表达与患者预后之间的关系。结果,297-11A 硫酸化糖主要在浆液性和子宫内膜样癌中表达,在粘液性和透明细胞癌中表达较差。我们揭示,在结构上,卵巢癌中表达的 297-11A 硫酸化糖是携带部分唾液酸化的 Gal-6-O-硫酸化 LacNAc 的 O-聚糖,并且这些糖可能在 MUC16 粘蛋白核心蛋白上展示。具有临床重要意义的是,297-11A 硫酸化糖的表达与患者无进展生存期较短相关。因此,297-11A 硫酸化糖可能是卵巢癌复发的预测因子。