Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku, Tokyo, 160-8582, Japan.
Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.
Histochem Cell Biol. 2022 Jun;157(6):671-684. doi: 10.1007/s00418-022-02093-1. Epub 2022 Mar 30.
Gastric gland mucin consists of core protein MUC6 with residues heavily glycosylated by unique O-glycans carrying α1,4-linked N-acetylglucosamine (αGlcNAc). αGlcNAc-glycosylated MUC6 protein is seen in normal gastric and duodenal glands. Decreased αGlcNAc glycosylation on MUC6-positive tumor cells is often observed in premalignant lesions of the stomach, pancreas, and bile duct, and decreased MUC6 expression is seen in invasive cancer of these organs. Lung cancer (LC) is the most common cause of cancer death worldwide. Recently, the adenocarcinoma subtype has become the most common histological subtype of LC, and one of its invasive forms is invasive mucinous adenocarcinoma (IMA). Currently, prognostic markers of LC IMA are unknown. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression in 54 IMA LC cases. MUC5AC was positively expressed in 50 (93%), MUC6 in 38 (70%), and αGlcNAc in 19 (35%). Each expression level was scored from 0 to 3. The αGlcNAc expression score was significantly decreased relative to MUC6 (P < 0.001). Interestingly, disease-free survival was significantly higher in MUC6-positive than MUC6-negative cases based on the log-rank test (P = 0.021). For in vitro analysis, we ectopically expressed MUC6 in A549 cells, derived from LC and harboring a KRAS mutation. MUC6-expressing A549 cells showed significantly lower proliferation, motility, and invasiveness than control cells. Finally, F-actin staining in MUC6-expressing cells revealed a decrease or loss of filopodia associated with decreased levels of FSCN transcripts, which encodes an actin-bundling protein fascin1 necessary for cell migration. We conclude that MUC6 expression is a preferable prognostic biomarker in IMA LC.
胃腺体黏液由核心蛋白 MUC6 组成，其残基被独特的 O-聚糖高度糖基化，带有α1,4 连接的 N-乙酰葡萄糖胺（αGlcNAc）。αGlcNAc 糖基化的 MUC6 蛋白可见于正常胃和十二指肠腺体中。在胃、胰腺和胆管的癌前病变中，常观察到 MUC6 阳性肿瘤细胞上的αGlcNAc 糖基化减少，而在这些器官的浸润性癌中，MUC6 表达减少。肺癌（LC）是全球癌症死亡的最常见原因。最近，腺癌亚型已成为 LC 最常见的组织学亚型，其侵袭形式之一为浸润性黏液性腺癌（IMA）。目前，LCIMA 的预后标志物尚不清楚。在这里，我们分析了 54 例 IMA LC 病例中 MUC5AC、MUC6 和αGlcNAc 的表达。MUC5AC 在 50 例（93%）中呈阳性表达，MUC6 在 38 例（70%）中呈阳性表达，αGlcNAc 在 19 例（35%）中呈阳性表达。每个表达水平从 0 到 3 进行评分。αGlcNAc 表达评分与 MUC6 相比显著降低（P<0.001）。有趣的是，根据对数秩检验，MUC6 阳性病例的无病生存期明显高于 MUC6 阴性病例（P=0.021）。在体外分析中，我们在源自 LC 并携带 KRAS 突变的 A549 细胞中异位表达 MUC6。与对照细胞相比，表达 MUC6 的 A549 细胞的增殖、运动和侵袭能力明显降低。最后，MUC6 表达细胞中的 F-肌动蛋白染色显示与 FSCN 转录物水平降低相关的丝状伪足减少或缺失，FSCN 转录物编码肌动蛋白束蛋白 fascin1，该蛋白对于细胞迁移是必需的。我们得出结论，MUC6 表达是 IMA LC 的一种较好的预后生物标志物。
