Targeting migration inducting gene-7 inhibits carcinoma cell invasion, early primary tumor growth, and stimulates monocyte oncolytic activity.
Targeting migration inducting gene-7 inhibits carcinoma cell invasion, early primary tumor growth, and stimulates monocyte oncolytic activity.
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DOI：
10.1158/1535-7163.mct-09-0186
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Lindsey JS
中科院分区：
文献类型：
--
作者：
Petty AP;Wright SE;Rewers-Felkins KA;Yenderrozos MA;Vorderstrasse BA;Lindsey JS
迁移诱导基因7 （Mig-7）的表达仅限于肿瘤细胞，迄今未在正常组织中发现。多种肿瘤微环境因子，如表皮和肝细胞生长因子，协同αvβ5整合素连接诱导Mig-7 mRNA的表达。米格-7蛋白的获得或丢失研究表明，米格-7促进结肠癌和子宫内膜癌细胞的侵袭。这些数据使我们假设，通过各种方法靶向米格-7可以减少侵袭，增强单核细胞对肿瘤细胞的杀伤，抑制疾病进展。为了开始验证这一假设，我们使用了Mig-7特异性抗体或对照抗体处理的子宫内膜癌细胞的体外化学侵袭试验。与对照组相比，Mig-7抗体显著减少了60%的侵袭。另一种验证这一假设的方法是，对肽刺激的人外周血单核细胞（MC）及其对MCF-7乳腺癌细胞的杀伤进行体外分析。Mig-7肽处理使MCF-7细胞的肿瘤坏死因子表达和杀伤比无肽刺激增加30倍，比MUC-1或对照肽处理增加3倍。此外，在异种移植裸鼠模型中，稳定表达米格-7特异性短发夹RNA可显著降低米格-7蛋白水平和早期原发性肿瘤生长。降低ERK1/2、Akt和S6激酶磷酸化以及降低膜型基质金属蛋白酶活性是米格-7蛋白引起这些作用的机制。基于这些集体数据，米格-7的表达可能是未来靶向癌症治疗的潜在候选者。
Expression of Migration inducting gene-7 (Mig-7) is limited to tumor cells and to date not found in normal tissues. Multiple tumor microenvironment factors, such as epidermal and hepatocyte growth factors, in concert with αvβ5 integrin ligation induce Mig-7 mRNA expression. Gain or loss of Mig-7 protein studies demonstrate that Mig-7 promotes invasion of colon and endometrial carcinoma cells. These data led us to hypothesize that targeting Mig-7 through various methods could decrease invasion, enhance monocyte cell killing of tumor cells and inhibit disease progression. To begin testing this hypothesis an in vitro chemoinvasion assay of endometrial carcinoma cells treated with Mig-7 specific or control antibodies was used. Mig-7 antibody significantly reduced invasion by >60% compared to controls. In another approach to test this hypothesis, an in vitro analysis of peptide-stimulated human peripheral blood monocyte cells (MC) and their killing of MCF-7 breast carcinoma cells was used. Mig-7 peptide treatment increased MC tumor necrosis factor expression and killing of MCF-7 cells 30-fold over no peptide stimulation and 3-fold over MUC-1 or control peptide treatments. Furthermore, stably expressing Mig-7-specific short hairpin RNA resulted in significantly reduced Mig-7 protein levels and early primary tumor growth in a xenograft nude mouse model. Reduced phosphorylation of ERK1/2, Akt, and S6 kinase as well as decreased membrane-type 1 matrix metalloproteinase activity were mechanisms through which Mig-7 protein caused these effects. Based on these collective data, Mig-7 expression could be a potential candidate for future targeted cancer therapies.