Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Am J Pathol. 2011 Jan;178(1):361-72. doi: 10.1016/j.ajpath.2010.11.021. Epub 2010 Dec 23.
Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 laser-microdissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis.
胰腺导管腺癌（DPC）是一种致命疾病，发病率为每年每 10 万人中有 9 例，死亡率接近 100%。在许多人类恶性肿瘤中，染色体 9 长臂的等位基因缺失很常见，但目前尚无关于 DPC 的数据。我们筛选了 40 个激光微切割的 DPC 样本和 6 个前侵袭性病变，以检测 9q21.3 至 9q34.2 区域的 9 个微卫星图谱标记物。在 D9S127 和 D9S105 之间确定了一个跨越 800 万个碱基对的小重叠缺失区域。映射到 9q31.1 至 9q32 的两个基因，RSG3 和 KLF4，进一步进行了研究。在 KLF4 基因表达水平和基因组状态之间发现了高度显著的关联。同样，在 86.8%的 DPC（33/38）病例中发现 KLF4 蛋白的免疫组织化学表达缺失。在人胰腺癌细胞系中过表达 KLF4 会导致与 p21 上调和细胞周期蛋白 D1 下调相关的增殖显著减少。总之，我们确定了一个位于 9q31.1-3 位的新的肿瘤抑制区域，在 DPC 中高频丢失。KLF4 表达的缺失与基因组缺失密切相关，其恢复抑制了癌细胞的增殖，提示在胰腺肿瘤发生中具有关键的抑制作用。
