αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type
αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type
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DOI：
10.1038/s41598-019-49376-7
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发表时间：
2019-09-10
影响因子：
4.6
通讯作者：
Nakayama, Jun
中科院分区：
文献类型：
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作者：
Ida, Koichi;Yamanoi, Kazuhiro;Nakayama, Jun
胃型宫颈腺癌（GAS）与人乳头状瘤病毒（HPV）感染无关。与HPV感染相关的宫颈腺癌相比，GAS患者的病情明显更糟，因为他们的肿瘤对常规化疗和放疗表现出耐药性。GAS常与小叶性宫颈内腺增生（LEGH）相关，在最新的WHO分类中，LEGH被认为是GAS的前兆。最近，我们报道了在LEGH-GAS序列中的非典型LEGH中，末端α 1，4-连接的N-乙酰葡糖胺（α GlcNAc）的表达相对于MUC 6的表达的减少已经很明显。在此，我们分析了α 1，4-N-乙酰葡糖胺转移酶（α 4GnT）（催化α GlcNAc生物合成的唯一酶）以及α GlcNAc和MUC 6在代表非肿瘤性宫颈内腺（NNEG）（11例）、LEGH（26例）和GAS（12例）的病例中的表达。α 4GnT蛋白在26例LEGH和12例GAS中的5例中均呈“点状”表达，定位于高尔基体。α 4GnT和α GlcNAc阳性细胞在很大程度上重叠，表明α 4GnT基因表达调节α GlcNAc生物合成。有趣的是，所有NNEG病例α 4GnT和α GlcNAc表达均为阴性，但11例NNEG中有7例和所有LEGH病例均为MUC 6阳性。在GAS病例中，肿瘤α 4GnT和α GlcNAc阳性的患者比其他患者预后更好。多因素分析显示α 4GnT和α GlcNAc阳性表达是独立的预后指标。提示α 4GnT和α GlcNAc不仅可作为鉴别LEGH和NNEG的有效标志物，而且可作为评价GAS患者病情的有效指标。
Cervical adenocarcinoma, gastric type (GAS) is not associated with human papilloma virus (HPV) infection. GAS patients prognoses are significantly worse compared with cervical adenocarcinoma associated with HPV infection, as their tumors exhibit resistance to conventional chemotherapy and radiotherapy. GAS is often associated with lobular endocervical glandular hyperplasia (LEGH), which is regarded as a precursor to GAS in the latest WHO classification. Recently, we reported that a decrease in expression of terminal alpha 1,4-linked N-acetylglucosamine (alpha GlcNAc) relative to that of MUC6 was already apparent in atypical LEGH in the LEGH-GAS sequence. Here, we analyzed expression of alpha 1,4-N-acetylglucosaminyltransferase (alpha 4GnT), the sole enzyme catalyzing alpha GlcNAc biosynthesis, and that of alpha GlcNAc and MUC6 in cases representing non-neoplastic endocervical gland (NNEG) (11 cases), LEGH (26 cases) and GAS (12 cases). alpha 4GnT protein was detected in a "dot-like" pattern, indicating localization in the Golgi apparatus in all 26 LEGH cases and 5 of 12 GAS cases. alpha 4GnT- and alpha GlcNAc-positive cells largely overlapped, suggesting that alpha 4GnT gene expression regulates alpha GlcNAc biosynthesis. Interestingly, all NNEG cases were negative for alpha 4GnT and alpha GlcNAc expression, but 7 of 11 NNEG and all LEGH cases were MUC6-positive. In GAS cases, patients whose tumors were alpha 4GnT- and alpha GlcNAc-positive had more favorable prognosis than others. Multivariate analysis revealed that positive expressions of alpha 4GnT and alpha GlcNAc were independent prognostic indicators. These results indicate that alpha 4GnT and alpha GlcNAc could serve as useful markers not only to distinguish LEGH from NNEG but to evaluate prognoses of GAS patients.