Khiaowichit Juthamas, Talabnin Chutima, Dechsukhum Chavaboon, Silsirivanit Atit, Talabnin Krajang
School of Translational Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
School of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
Life (Basel). 2022 Jan 25;12(2):174. doi: 10.3390/life12020174.
Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 () and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 () in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway.
粘蛋白型O-糖基化的改变与胆管癌（CCA）的肿瘤进展和转移有关。核心1β1-3半乳糖基转移酶（C1GALT1）是一种调节核心1衍生的粘蛋白型O-聚糖延长的主要酶。C1GALT1的失调已在多种癌症中得到记录，并与异常的核心1 O-糖基化和癌症侵袭性相关；然而，C1GALT1的表达及其在CCA进展中的作用仍然未知。我们的研究表明，C1GALT1在CCA组织中的mRNA和蛋白质水平均下调。使用小干扰RNA（siRNA）对C1GALT1的生物学功能研究表明，在CCA细胞系（KKU-055和KKU-100）中抑制C1GALT1会促进CCA进展，表现为：（i）以剂量依赖方式诱导CCA细胞增殖和5-氟尿嘧啶耐药性；（ii）生长相关基因、ABC转运蛋白基因和抗凋亡蛋白的上调；（iii）沉默C1GALT1的细胞中AKT和ERK的激活/磷酸化增加。我们证明，在CCA细胞系中沉默C1GALT1与未成熟的核心1 O-糖基化有关，这表现为在C1GALT1敲低后VVL结合聚糖的高表达以及其他主要O-连接糖基转移酶β1,3-N-乙酰葡糖胺基转移酶6（）和ST6 N-乙酰半乳糖胺α-2,6-唾液酸转移酶1（）的下调。我们的研究结果表明，CCA中C1GALT1的下调会增加未成熟核心1 O-聚糖的表达，通过激活AKT/ERK信号通路促进CCA进展，包括生长和5-氟尿嘧啶耐药性。
