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首页> 外文期刊>Cancer letters >MUC4 enhances gemcitabine resistance and malignant behaviour in pancreatic cancer cells expressing cancer-associated short O-glycans
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MUC4 enhances gemcitabine resistance and malignant behaviour in pancreatic cancer cells expressing cancer-associated short O-glycans

机译：MUC4提高表达癌症相关短卵甘油的胰腺癌细胞中的吉西他滨抗性和恶性行为

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摘要

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. MUC4 (mucin4) is a heavily glycosylated protein aberrantly expressed in PDAC and promotes tumorigenesis via an unknown mechanism. To assess this, we genetically knocked out (KO) MUC4 in PDAC cells that did not express and did express truncated O-glycans (Tn/STn) using CRISPR/Cas9 technology. We found that MUC4 knockout cells possess less tumorigenicity in vitro and in vivo, which was further reduced in PDAC cells that express aberrant overexpression of truncated O-glycans. Also, MUC4(KO) cells showed a further reduction of epidermal growth factor receptors (ErbB) and their downstream signaling pathways in truncated O-glycan expressing PDAC cells. Tn-MUC4 specific 3B11 antibody inhibited MUC4-induced ErbB receptor and its downstream signaling cascades. MUC4 knockout differentially regulates apoptosis and cell cycle arrest in branched and truncated O-glycan expressing PDAC cells. Additionally, MUC4(KO) cells were found to be more sensitive to gemcitabine treatment. They possessed the upregulated expression of hENT1 and hCNT3 compared to parental cells, which were further affected in cells with aberrant O-glycosylation. Taken together, our results indicate that MUC4 enhances the malignant properties and gemcitabine resistance in PDAC tumors that aberrantly overexpress truncated O-glycans via altering ErbB/AKT signaling cascades and expression of nucleoside transporters, respectively.
机译：胰腺导管腺癌（PDAC）是一种高致死性疾病。MUC4（mucin4）是一种在PDAC中异常表达的高度糖基化蛋白，通过未知机制促进肿瘤的发生。为了评估这一点，我们使用CRISPR/Cas9技术从基因上敲除了PDAC细胞中不表达和确实表达截短的O-聚糖（Tn/STn）的（KO）MUC4。我们发现，MUC4敲除细胞在体外和体内的致瘤性较低，在表达截短O-聚糖异常过度表达的PDAC细胞中，这种致瘤性进一步降低。此外，MUC4（KO）细胞显示，在表达截短O-聚糖的PDAC细胞中，表皮生长因子受体（ErbB）及其下游信号通路进一步减少。Tn-MUC4特异性3B11抗体抑制MUC4诱导的ErbB受体及其下游信号级联。MUC4基因敲除对表达支链和截短O-聚糖的PDAC细胞的凋亡和细胞周期阻滞有差异调节作用。此外，发现MUC4（KO）细胞对吉西他滨治疗更敏感。与亲代细胞相比，它们的hENT1和hCNT3表达上调，在O-糖基化异常的细胞中进一步受到影响。综上所述，我们的结果表明，MUC4分别通过改变ErbB/AKT信号级联和核苷转运体的表达，增强了PDAC肿瘤的恶性特性和吉西他滨耐药性，该肿瘤异常过度表达截断的O-聚糖。

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