CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells (Retracted article. See FEB, 2023)
CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells (Retracted article. See FEB, 2023)
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DOI：
10.1038/sj.onc.1207036
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发表时间：
2004-01-15
期刊：
影响因子：
8
通讯作者：
Whang, EE
中科院分区：
文献类型：
--
作者：
Duxbury, MS;Ito, H;Whang, EE
失巢凋亡是正常细胞中由于与底物的粘附不足或不适当而诱导的凋亡反应。据推测，抗失巢凋亡促进肿瘤发生和转移。癌胚抗原相关细胞粘附分子6（CEACAM 6）是一种免疫球蛋白超家族成员，在许多人类癌症中过表达，并参与抗失巢凋亡。我们测试了CEACAM 6基因沉默对胰腺癌细胞系中失巢凋亡的影响。通过在聚甲基丙烯酸2-羟乙酯包被的威尔斯孔中培养，在PANC 1、Capan 2、MiaPaCa 2和Mia（AR）（MiaPaCa 2衍生的抗失巢凋亡亚系）中诱导失巢凋亡。通过YO-PRO-1/碘化丙啶染色和流式细胞术定量失巢凋亡。使用荧光分析和半胱天冬酶抑制剂Z-Val-Ala-Asp-氟甲基酮（Z-VAD-fetamine）测定半胱天冬酶激活的作用。通过RNA干扰抑制CEACAM 6表达。使用裸鼠原位异种移植模型，我们评估了这种治疗对体内转移能力的影响。失巢凋亡抵抗与CEACAM 6表达增加相关。CEACAM 6特异性短干扰核糖核酸（siRNA），而不是对照siRNA，增加了对胱天蛋白酶介导的失巢凋亡的易感性，Z-VAD-fatal消除了这种作用，并在锚定非依赖性条件下降低了Akt磷酸化（Ser-473）。CEACAM 6基因沉默可逆转Mia（AR）的获得性失巢凋亡抗性，并抑制其体内转移能力。CEACAM 6作为胰腺癌治疗的新靶点值得进一步研究。
Anoikis is the apoptotic response induced in normal cells by inadequate or inappropriate adhesion to substrate. It is postulated that resistance to anoikis facilitates tumorigenesis and metastasis. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily member overexpressed in a number of human cancers and implicated in anoikis resistance. We tested the effect of CEACAM6 gene silencing on anoikis in pancreatic adenocarcinoma cell lines. Anoikis was induced in PANC1, Capan2, MiaPaCa2 and Mia(AR) (a MiaPaCa2-derived anoikis-resistant subline) by culture in poly-2-hydroxyethylmethacrylate-coated wells. Anoikis was quantified by YO-PRO-1/propidium iodide staining and flow cytometry. The role of caspase activation was determined using fluorometric profiling and the caspase inhibitor Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-fmk). CEACAM6 expression was suppressed by RNA interference. Using a nude mouse orthotopic xenograft model, we assessed the effect of this treatment on in vivo metastatic ability. Anoikis resistance was associated with increased CEACAM6 expression. CEACAM6-specific short interfering ribonucleic acid (siRNA), but not control siRNA, increased susceptibility to caspase-mediated anoikis, an effect abrogated by Z-VAD-fmk, and decreased Akt phosphorylation (Ser-473) under anchorage-independent conditions. CEACAM6 gene silencing reversed the acquired anoikis resistance of Mia(AR) and inhibited its in vivo metastatic ability. CEACAM6 warrants further investigation as a novel therapeutic target for the treatment of pancreatic adenocarcinoma.