三氧化二砷通过诱导胃癌细胞中 SHP-1 的表达来抑制 STAT-3 活性和上皮-间充质转化。
Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells.
机构信息
Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea.
Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Anam Hospital, 73, Inchon-ro, Seongbuk-gu, Seoul, 136-705, Republic of Korea.
出版信息
BMC Cancer. 2018 Feb 6;18(1):150. doi: 10.1186/s12885-018-4071-9.
BACKGROUND
We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process.
METHODS
We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route.
RESULTS
Treatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate.
CONCLUSION
Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.
背景
我们研究了三氧化二砷（ATO）对抑制信号转导子和转录激活子 3（STAT3）和上皮-间充质转化（EMT）在胃癌细胞中的作用，以及 SH2 结构域含磷酶-1（SHP-1）在此过程中的作用。
方法
我们使用 AGS 细胞，其 SHP-1 表达最低且 STAT3 表达持续存在。用划痕愈合试验、Matrigel 侵袭试验和 3-D 培养侵袭试验评估 ATO 处理后细胞的迁移和侵袭。为了验证 SHP-1 的作用，使用过钒酸钠，一种药理磷酸酶抑制剂，和 SHP-1 siRNA。制作异种移植肿瘤，并通过腹腔（IP）途径给予 ATO 或过钒酸钠。
结果
ATO 5 和 10 μM 处理显著降低细胞迁移和侵袭，呈剂量依赖性。Western blot 显示 ATO 上调 SHP-1 表达并下调 STAT3 表达，免疫荧光显示 ATO 处理后 E-钙粘蛋白（上皮标志物）上调和 Snail1（间充质标志物）下调。ATO 的抗迁移和侵袭作用以及 SHP-1/STAT3 轴的调节作用被过钒酸钠或 SHP-1 siRNA 减弱。ATO 的 IP 注射显著降低了异种移植肿瘤的体积，并上调了 SHP-1 的表达，而过钒酸钠的共同 IP 注射减弱了这种作用。
结论
我们的数据表明，ATO 通过上调胃癌细胞中的 SHP-1 抑制 STAT3 活性和 EMT 过程。
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