Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Prev Res (Phila). 2011 Dec;4(12):1961-72. doi: 10.1158/1940-6207.CAPR-10-0280. Epub 2011 Aug 31.
Loss of terminal cell differentiation promotes tumorigenesis. 15-Lipoxygenase-1 (15-LOX-1) contributes to terminal cell differentiation in normal cells. The mechanistic significance of 15-LOX-1 expression loss in human cancers to terminal cell differentiation suppression is unknown. In a screen of 128 cancer cell lines representing more than 20 types of human cancer, we found that 15-LOX-1 mRNA expression levels were markedly lower than levels in terminally differentiated cells. Relative expression levels of 15-LOX-1 (relative to the level in terminally differentiated primary normal human-derived bronchial epithelial cells) were lower in 79% of the screened cancer cell lines than relative expression levels of p16 (INK4A), which promotes terminal cell differentiation and is considered one of the most commonly lost tumor suppressor genes in cancer cells. 15-LOX-1 was expressed during terminal differentiation in three-dimensional air-liquid interface cultures, and 15-LOX-1 expression and terminal differentiation occurred in immortalized nontransformed bronchial epithelial but not in lung cancer cell lines. 15-LOX-1 expression levels were lower in human tumors than in paired normal lung epithelia. Short hairpin RNA-mediated downregulation of 15-LOX-1 in Caco-2 cells blocked enterocyte-like differentiation, disrupted tight junction formation, and blocked E-cadherin and ZO-1 localization to the cell wall membrane. 15-LOX-1 episomal expression in Caco-2 and HT-29 colon cancer cells induced differentiation. Our findings indicate that 15-LOX-1 downregulation in cancer cells is an important mechanism for terminal cell differentiation dysregulation and support the potential therapeutic utility of 15-LOX-1 reexpression to inhibit tumorigenesis.
细胞终末分化丧失促进肿瘤发生。15-脂氧合酶-1（15-LOX-1）促进正常细胞的细胞终末分化。在人类癌症中，15-LOX-1 表达缺失对细胞终末分化抑制的机制意义尚不清楚。在对代表超过 20 种人类癌症的 128 种癌细胞系进行的筛选中，我们发现 15-LOX-1 mRNA 表达水平明显低于终末分化细胞的水平。与终末分化的原代正常人支气管上皮细胞相比，在筛选的 79%的癌细胞系中，15-LOX-1 的相对表达水平较低，而 p16（INK4A）的相对表达水平较低，p16（INK4A）促进细胞终末分化，被认为是癌细胞中最常见的失活肿瘤抑制基因之一。在三维气液界面培养中，15-LOX-1 在细胞终末分化过程中表达，并且在永生化非转化的支气管上皮细胞中发生 15-LOX-1 表达和细胞终末分化，而不是在肺癌细胞系中。与配对的正常肺上皮相比，人类肿瘤中的 15-LOX-1 表达水平较低。在 Caco-2 细胞中用短发夹 RNA 下调 15-LOX-1 阻断肠上皮样分化，破坏紧密连接形成，并阻断 E-钙粘蛋白和 ZO-1 定位于细胞壁。Caco-2 和 HT-29 结肠癌细胞中的 15-LOX-1 附加表达诱导分化。我们的研究结果表明，癌细胞中 15-LOX-1 的下调是细胞终末分化失调的重要机制，并支持 15-LOX-1 重新表达抑制肿瘤发生的潜在治疗效用。
