Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma
Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma
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N-乙酰半乳糖胺基转移酶 4 的缺失协调肝细胞癌中的致癌性 MicroRNA-9
DOI：
10.1074/jbc.m116.751685
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发表时间：
2017-02-24
影响因子：
4.8
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
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作者：
Liu, Yidong;Liu, Haiou;Gu, Jianxin
N-乙酰半乳糖胺基转移酶 (GALNT) 负责粘蛋白型 O-糖基化的初始步骤，其表达失调可能产生异常截短的 O-聚糖，从而在恶性转化过程中发挥关键功能。 GALNT4 是少数倾向于催化部分 GalNAc 糖基化底物并修饰其他已知 GALNT 未利用的位点的亚型之一。本研究旨在评估GALNT4表达对肝细胞癌（HCC）恶性转化的影响。采用免疫组织化学和原位杂交分析分别评估临床标本中的 GALNT4 和 miR-9 水平。 GALNT4 表达在原发性 HCC 组织中显着受到抑制，并且 GALNT4 表达的降低与 HCC 患者的不良生存显着相关。功能研究表明，抑制 GALNT4 可以促进体外 HCC 细胞的迁移、侵袭、失巢凋亡抵抗和干细胞性以及体内肿瘤生长。野生型GALNT4可以修饰EGFR上的O-连接糖基化，从而调节EGFR的活性。荧光素酶活性测定进一步确定 microRNA-9 (miR-9) 是 HCC 细胞中 GALNT4 表达的关键特异性仲裁者。此外，恢复 GALNT4 表达会减弱 miR-9 介导的致癌功能。 Kaplan-Meier 生存分析表明 miR-9/GALNT4 表达特征对于细化 HCC 患者的风险分层具有良好的预后意义。总之，本研究将 miR-9/GALNT4 轴确立为 HCC 患者的潜在不良预后因素和治疗靶点。
Deregulated expression of N-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-type O-glycosylation, could produce abnormal truncated O-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry and in situ hybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cells in vitro as well as tumor growth in vivo. The wild-type GALNT4 could modify O-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.