Molecular pathology of pancreatic cancer - In quest of tumor suppressor genes
Molecular pathology of pancreatic cancer - In quest of tumor suppressor genes
复制标题
DOI：
10.1097/00006676-200404000-00007
复制
发表时间：
2004-04-01
期刊：
影响因子：
2.9
通讯作者：
Horii, A
中科院分区：
文献类型：
--
作者：
Furukawa, T;Horii, A
为了寻找有助于胰腺癌早期发现和有效治疗的分子线索，我们首先采用比较基因组杂交和微卫星分析的方法进行了基因组分析。我们在多个染色体区域发现了非常复杂的分子改变，包括1p、6q、9p、12q、17p、18q和21q的缺失，以及8q和20q的获得。这些不同的变化是胰腺癌的特征，根据这些信息，我们开发了一种方法，通过荧光原位杂交检测从胰液中收集的细胞中特定染色体区域的异常拷贝数，用于胰腺肿瘤的早期诊断。这些缺失区域表明存在肿瘤抑制基因（TSGs）。我们在12q21-q22位点鉴定出DUSP6/MKP-3为强候选TSG；在侵袭性胰腺癌的部分组织中表现出表观遗传失活，并通过体外过表达抑制生长和凋亡。为了确定18q的病理作用，我们将18号染色体的正常拷贝导入培养的胰腺癌细胞。该药物的引入对体内肿瘤形成和转移形成有明显的抑制作用。我们将继续致力于更全面地了解胰腺癌发生的复杂分子机制，并将所获得的信息应用于胰腺癌的临床治疗。
To find molecular clues useful for early detection and effective therapy for pancreatic cancer, we first carried out genomic analysis by means of comparative genomic hybridization and microsatellite analysis. We found very complicated molecular alterations in multiple chromosomal regions, including 1p, 6q, 9p, 12q, 17p, 18q, and 21q for losses and 8q and 20q for gains. These diverse changes are very characteristic of pancreatic cancer, and from this information, we developed a method for detecting the aberrant copy numbers of specific chromosomal regions by fluorescence in situ hybridization in cells collected from pancreatic juice for early diagnosis of pancreatic neoplasms. The regions of losses suggest the existence of tumor suppressor genes (TSGs). We identified DUSP6/MKP-3 at 12q21-q22 as a strong candidate TSG; it showed epigenetic inactivation in some fractions of invasive pancreatic cancer and growth suppression and apoptosis by overexpression in vitro. To determine the pathologic roles of 18q, we introduced a normal copy of chromosome 18 into cultured pancreatic cancer cells. The introduction induced marked suppressions of tumor formation and metastasis formation in vivo. We continue work to more completely understand the complex molecular mechanisms of pancreatic carcinogenesis and to apply the information gained to the clinical treatment of pancreatic cancer.