University of Strasbourg, Unit of Physiopathology and Translational Research EA 4438, Laboratory of Nutritional Cancer Prevention, Faculty of Medicine, 67091 Strasbourg-Cedex, France.
Int J Oncol. 2010 Jun;36(6):1485-90. doi: 10.3892/ijo_00000635.
The rat azoxymethane (AOM)-induced colon carcinogenesis model provides useful information for understanding human colorectal neoplasia. Here, we used the AOM model to measure the gene expression profiles of biomarkers related to tumor progression. We assessed tumor progression stages by computed tomographic (CT) colonography. Messenger RNAs were isolated from tumors and mucosal samples, and gene expression levels were assessed by real-time quantitative polymerase chain reaction (PCR). We show that early stages of tumor progression are associated with an upregulation of matrix metalloproteinase-7 (MMP-7) and of genes involved in the inflammatory response, including interleukin (IL1beta) and tumor necrosis factor-alpha (TNFalpha). The ratio of B-cell lymphoma/leukemia 2 (Bcl-2)-associated X proteins (Bax) to Bcl-2 transcript (proapototic/antiapoptotic signals) is elevated in early stages of tumor progression (Bax/Bcl-2 >1) and reversed in more advanced stages of tumor development (Bax/Bcl-2 <1). These changes are associated with the reduced expression of TNF-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5) and FAS (also known as CD95) apoptotic receptors. Advanced stages of tumor development are characterized by an increase in MMP-9 expression associated with the upregulation of components of the innate immune system: alpha-defensin 5 (DEF-5) and neutrophil gelatinase-associated lipocalin (NGAL). The identification of specific gene expression profiles that correlate with tumor progression stages, as reported in the present study, may represent an important step in evaluating potential chemopreventive and/or chemotherapeutic agents prior to initiating clinical trials.
在利用化学诱导剂（azoxymethane，AOM）建立的结肠癌模型中，我们可以获得与人类结直肠肿瘤发生发展相关的信息。本研究采用 CT 结肠成像来评估肿瘤进展，以确定肿瘤发生发展的阶段，通过实时定量聚合酶链反应（PCR）来检测相关的生物标志物基因的表达水平。结果显示在肿瘤早期进展阶段，基质金属蛋白酶-7（matrix metalloproteinase-7，MMP-7）及其它与炎症反应相关基因的表达上调，如白细胞介素（interleukin，IL）1β和肿瘤坏死因子（tumor necrosis factor，TNF）α；同时 Bcl-2 相关 X 蛋白（B-cell lymphoma/leukemia 2-associated X protein，Bax）/Bcl-2 比值也逐渐升高（Bax/Bcl-2 >1），提示肿瘤发生发展的早期阶段存在抗凋亡作用。在肿瘤进展的晚期阶段，TNF 相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）-死亡受体 5（death receptor 5，DR5）和 Fas（CD95）等凋亡相关受体的表达下调，Bax/Bcl-2 比值降低（Bax/Bcl-2 <1）。肿瘤的进一步进展导致 MMP-9 表达上调，并伴有固有免疫系统成分如α-防御素（alpha-defensin 5，DEF-5）和中性粒细胞明胶酶相关脂质运载蛋白（neutrophil gelatinase-associated lipocalin，NGAL）表达增加。本研究为肿瘤进展的相关基因表达谱的确定提供了理论依据，为临床前阶段评价潜在的化学预防和/或化学治疗药物提供了有价值的信息。
