Azoxymethane-induced pre-adipocyte factor 1 (Pref-1) functions as a differentiation inhibitor in colonic epithelial cells
Azoxymethane-induced pre-adipocyte factor 1 (Pref-1) functions as a differentiation inhibitor in colonic epithelial cells
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DOI：
10.1093/carcin/bgh237
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发表时间：
2004-11-01
期刊：
影响因子：
4.7
通讯作者：
Rosenberg, DW
中科院分区：
文献类型：
--
作者：
Dong, M;Guda, K;Rosenberg, DW
近亲繁殖的小鼠对结肠致癌物氧化偶氮甲烷（AOM）的敏感性差异很大。在小鼠中识别与这种差异易感性相关的基因可能最终揭示结肠癌发生的分子机制。采用cDNA芯片技术研究AOM诱导的敏感（A/J）和抗性（AKR）小鼠结肠基因表达变化。在阵列上代表的基因中，前脂肪细胞因子1（Pref-1），以前与抑制脂肪细胞分化相关，在敏感A/J小鼠的远端结肠中被AOM特异性诱导（5.4倍）。逆转录-PCR序列分析揭示了四个选择性剪接变异体的Pref-1 mRNA在结肠中的存在。在用含有主要剪接变体的逆转录病毒构建体感染的结肠癌细胞中探索Pref-1在结肠肿瘤发生中的潜在意义。Pref-1A在HT-29细胞中的过表达导致对丁酸盐诱导的分化和生长抑制的显著抗性。我们的数据表明，Pref-1，一种抑制分化和促进结肠细胞生长的蛋白质，可能部分解释了A/J小鼠对AOM诱导的致癌作用的敏感性。此外，在人结肠肿瘤细胞系中检测到Pref-1表明它也可能参与人结肠肿瘤发生。
Inbred mice differ dramatically in their sensitivity to the colon carcinogen, azoxymethane (AOM). Identifying genes associated with this differential susceptibility in mice may ultimately reveal molecular mechanisms responsible for colon carcinogenesis. A cDNA array approach was taken to study gene expression changes induced by AOM in the colons of sensitive (A/J) and resistant (AKR) mice. Among the genes represented on the array, pre-adipocyte factor 1 (Pref-1), associated previously with suppression of adipocyte differentiation, was induced specifically by AOM in the distal colons of sensitive A/J mice (5.4-fold). Reverse transcription-PCR followed by sequence analysis revealed the presence of four alternative splice variants of Pref-1 mRNA in the colon. The potential significance of Pref-1 in colon tumorigenesis was explored in colon cancer cells infected with a retroviral construct containing the major splice variant. Over-expression of Pref-1A in HT-29 cells led to a marked resistance to butyrate-induced differentiation and growth inhibition. Our data indicate that Pref-1, a protein that suppresses differentiation and promotes colonocyte growth, may account in part for the sensitivity of A/J mice to AOM-induced carcinogenesis. In addition, detection of Pref-1 in a human colon tumor cell line suggests that it may also participate in human colon tumorigenesis.