RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells
RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells
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DOI：
10.1007/s10120-014-0454-z
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发表时间：
2016-01-01
期刊：
影响因子：
7.4
通讯作者：
Kato, Junji
中科院分区：
文献类型：
--
作者：
Tamura, Fumito;Sato, Yasushi;Kato, Junji
ST 6 GalNAc I是一种控制唾液酸-Tn抗原（STn）表达的唾液酸转移酶，STn在包括胃癌在内的几种上皮癌中过表达，并与癌症转移高度相关。然而，ST 6 GalNAc I对胃癌发生或进展的功能贡献仍不清楚。本研究采用ST 6 GalNAc I siRNA转染胃癌细胞株，通过细胞增殖、迁移和侵袭实验，观察ST 6 GalNAc I对胃癌细胞的抑制作用。我们还评估了ST 6 GalNAc I siRNA治疗在腹膜播散小鼠模型中的作用。通过聚合酶链反应（PCR）阵列分析MKN 45细胞中与肿瘤转移相关的所选信号分子mRNA水平的差异。通过Western blot分析调控胰岛素样生长因子-1（IGF-1）的信号转导子和转录激活子5 b（STAT 5 b）信号通路，ST 6 GalNAc I siRNA抑制胃癌细胞体外生长、迁移和侵袭。此外，腹腔内施用ST 6 GalNAc I siRNA-脂质体显著抑制胃癌腹膜转移的异种移植模型小鼠的腹膜转移，并且延长具有腹膜转移的胃癌的异种移植模型小鼠的存活。PCR阵列证实，ST 6 GalNAc I的抑制引起IGF-1 mRNA表达的显著降低。ST 6 GalNAc I siRNA抑制MKN 45细胞IGF-1表达，同时下调STAT 5 b的磷酸化水平，ST 6 GalNAc I可能通过激活STAT 5 b调控胃癌细胞IGF-1基因表达，可能成为治疗转移性胃癌的潜在靶点。
ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo.Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot.ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b.ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.