Zheng Q, Cui X, Zhang D, Yang Y, Yan X, Liu M, Niang B, Aziz F, Liu S, Yan Q, Liu J
Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian, People's Republic of China.
Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, People's Republic of China.
Oncogenesis. 2017 Jul 10;6(7):e358. doi: 10.1038/oncsis.2017.58.
Aberrant protein fucosylation is associated with cancer malignancy. Fucosyltransferase IV (FUT4) is the key enzyme catalyzing the biosynthesis of α1,3-linkage fucosylated glycans carried by glycoproteins on the cell surface, such as the tumor-associated sugar antigen Lewis Y (LeY). An abnormal increase in the levels of FUT4 and LeY is observed in many cancers and correlated with cell proliferation and metastasis. Some microRNAs (miRNAs) are known to negatively regulate gene expression. FUT4 is an oncogenic glycogene, and thus it is important to identify the specific miRNA targeting FUT4. In current study, we first identified miR-200b as a specific miRNA that inhibited FUT4 expression. We found that miR-200b level was decreased, whereas that of FUT4 was increased in tissues and serum of breast cancer compared with that in the control by real-time PCR, western blotting and enzyme-linked immunosorbent assay. The alterations of miR-200b and FUT4 level were recovered after chemotherapy. The results also showed that miR-200b suppressed FUT4 expression and inhibited tumor growth and metastasis in MCF-7 and MDA-MB-231 breast cancer cells, as well as in the xenografted tumor tissues and metastatic lung tissues. miR-200b decreased the α1,3-fucosylation and LeY biosynthesis on epidermal growth factor receptor (EGFR), as well as inactivation of EGFR and downstream phosphoinositide-3 kinase/Akt signaling pathway. In conclusion, the study highlights that FUT4 could apply as a novel target for miR-200b that suppress the proliferation and metastasis of breast cancer cells by reducing α1,3-fucosylation and LeY biosynthesis of glycoproteins. miR-200b and FUT4 are potential diagnostic and therapeutic targets for breast cancer.
异常的蛋白质岩藻糖基化与癌症恶性程度相关。岩藻糖基转移酶IV（FUT4）是催化细胞表面糖蛋白上α1,3-连接岩藻糖基化聚糖生物合成的关键酶，如肿瘤相关糖抗原Lewis Y（LeY）。在许多癌症中观察到FUT4和LeY水平异常升高，并与细胞增殖和转移相关。已知一些微小RNA（miRNA）可负向调节基因表达。FUT4是一种致癌糖基因，因此鉴定靶向FUT4的特异性miRNA很重要。在本研究中，我们首先鉴定出miR-200b是一种抑制FUT4表达的特异性miRNA。通过实时PCR、蛋白质印迹和酶联免疫吸附测定，我们发现与对照组相比，乳腺癌组织和血清中miR-200b水平降低，而FUT4水平升高。化疗后miR-200b和FUT4水平的改变得以恢复。结果还表明，miR-200b抑制FUT4表达，并抑制MCF-7和MDA-MB-231乳腺癌细胞以及异种移植肿瘤组织和转移性肺组织中的肿瘤生长和转移。miR-200b降低了表皮生长因子受体（EGFR）上的α1,3-岩藻糖基化和LeY生物合成，以及EGFR的失活和下游磷酸肌醇-3激酶/蛋白激酶B信号通路。总之，该研究强调FUT4可作为miR-200b的新靶点，通过减少糖蛋白的α1,3-岩藻糖基化和LeY生物合成来抑制乳腺癌细胞的增殖和转移。miR-200b和FUT4是乳腺癌潜在的诊断和治疗靶点。
