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Sulindac treatment alters collagen and matrilysin expression in adenomas of ApcMin/+ mice.

机译:舒林酸治疗可改变ApcMin / +小鼠腺瘤中胶原蛋白和基质溶素的表达。

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Non-steroidal anti-inflammatory drugs (NSAIDs) have shown potential as chemopreventive agents against cancer formation, especially colorectal cancers. However, the mechanisms by which these drugs act are not fully understood. In this study, Apc(Min/+) mice, a genetic model of human familial adenomatous polyposis, were treated with sulindac, and these mice demonstrated tumor reduction of >80%, consistent with previous reports. Gene microarray analyses of RNA from adenoma-derived dysplastic epithelial cells revealed that collagen genes, viz. Col1a2, Col5a2, Col6a2 and Col6a3, were upregulated, and matrilysin matrix metalloproteases-7 (Mmp7) was downregulated, in sulindac-treated mice. Reverse transcription-polymerase chain reaction validated gene expression of the Col6a2 subunit of collagen VI and of Mmp7. Confocal microscopy and immunofluorescence showed that within the tumors of non-treated mice, collagen VI was present in low amounts, but was enhanced within the tumors of sulindac-treated mice. Collagens I and V demonstrated similar patterns, but were not as prominent as collagen VI. Mmp7 was found in 'hot spot' areas within the tumors of Apc(Min/+) mice treated with the vehicle, but was greatly diminished in those mice treated with sulindac. Studies with Apc(Min/+)/Mmp7(-/-) double-deficient mice demonstrated the reciprocal relationships of Mmp7 expression and the levels of these three collagens in vivo. The results of this study demonstrated that sulindac was effective in increasing the expression of different collagens and decreasing the expression of Mmp7, effects that may contribute to altered tumor burden in cancer patients undergoing NSAIDs treatments.
机译:非甾体类抗炎药(NSAIDs)已显示出作为化学预防剂对抗癌症形成,尤其是结直肠癌的潜力。但是,这些药物起作用的机制尚未完全了解。在这项研究中,使用舒林酸治疗了人类家族性腺瘤性息肉病的遗传模型Apc(Min / +)小鼠,这些小鼠的肿瘤减少率> 80%,与先前的报道一致。腺瘤来源的增生异常上皮细胞中RNA的基因微阵列分析显示胶原基因,即。在舒林酸治疗的小鼠中,Col1a2,Col5a2,Col6a2和Col6a3被上调,而基质金属蛋白酶7(Mmp7)被下调。逆转录聚合酶链反应验证了胶原VI和Mmp7的Col6a2亚基的基因表达。共聚焦显微镜和免疫荧光显示,在未经治疗的小鼠的肿瘤中,胶原蛋白VI的含量较低,但在舒林酸治疗的小鼠的肿瘤中含量较高。 I型和V型胶原蛋白表现出相似的模式,但不如VI型胶原蛋白突出。在用媒介物处理过的Apc(Min / +)小鼠肿瘤内的“热点”区域发现了Mmp7,但在用舒林酸治疗的那些小鼠中Mmp7大大减少了。用Apc(Min / +)/ Mmp7(-/-)双缺陷小鼠进行的研究证明了Mmp7表达与体内这三种胶原蛋白水平的相互关系。这项研究的结果表明,舒林酸可以有效地增加不同胶原蛋白的表达并降低Mmp7的表达,这种作用可能有助于改变接受NSAIDs治疗的癌症患者的肿瘤负担。

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