The role of chromosome 18 abnormalities in the progression of pancreatic adenocarcinoma
The role of chromosome 18 abnormalities in the progression of pancreatic adenocarcinoma
复制标题
DOI：
10.1097/00006676-200404000-00019
复制
发表时间：
2004-04-01
期刊：
影响因子：
2.9
通讯作者：
Matsuno, S
中科院分区：
文献类型：
--
作者：
Sunamura, M;Lefter, LP;Matsuno, S
迄今为止，在胰腺癌中调节肿瘤进展的事件仍然知之甚少。人胰腺癌的细胞遗传学、等位基因和体细胞杂交研究表明，18号染色体可能携带肿瘤抑制基因(TSG)，包括Smad4。我们先前发现Smad4基因18q的杂合性缺失以及17p和12q的杂合性缺失与胰腺癌患者的不良预后呈正相关。然而，Smad4基因的恢复并不能抑制含有Smad4基因纯合缺失的胰腺癌细胞的体外增殖。导管内乳头状黏液性肿瘤(IPMN)被认为是进展为癌症的胰腺癌前病变之一。虽然IPMN组织中Smad4基因发生了频繁的杂合性缺失(7/14，50%)，但免疫组织化学检测到肿瘤细胞中存在Smad4蛋白，且未发现Smad4基因突变，提示抑制细胞生长的可能是18q中Smad4以外的TSG。为了从功能上评估18号染色体在胰腺癌中的活性，我们将正常的染色体副本转移到带有和不带有完全失活的Smad4的胰腺导管癌细胞中。在这项研究中，与亲本细胞相比，杂交细胞的体外生长受到显著抑制，无论最初的Smad4状态如何。为了估计杂交细胞的转移能力，我们使用了肺定植模型。在实验结束时，与注射亲本细胞的小鼠相比，注射杂交细胞的小鼠的表面转移瘤数量受到了显著的抑制。为了识别和表征与胰腺癌进展相关的基因，我们使用了使用20K寡核苷酸阵列系统的微阵列表达分析。结果显示，与亲本细胞相比，18个染色体杂交体细胞中4个与细胞凋亡相关的基因表达增强。我们现在正在分析这些基因的功能。
To date, the events that mediate tumor progression in pancreatic cancer are still poorly understood. Cytogenetic, allelotype, and somatic cell hybrid studies in human pancreatic adenocarcinoma have suggested that chromosome 18 may carry tumor suppressor genes (TSGs), including SMAD4. We previously identified that LOH of 18q at the SMAD4 locus, along with LOHs on 17p and 12q, positively associated with poor prognoses of pancreatic cancer patients. However, restoration of the SMAD4 gene did not suppress in vitro proliferation of pancreatic cancer cells that harbored homozygous deletion of this gene. An intraductal papillary mucinous neoplasm (IPMN) is thought to be one of the premalignant lesions of the pancreas that progresses to carcinoma. Although there were frequent LOH (7/14, 50%) at the SMAD4 locus in IPMN samples, SMAD4 protein was observed immunohistochemically in tumor cells, and no mutations of the SMAD4 gene were observed, suggesting that it is the existence of a TSG in 18q, other than SMAD4, that suppresses cell growth. To functionally assess the activity of chromosome 18 in pancreatic cancer, we transferred a normal copy of the chromosome into pancreatic ductal carcinoma cells with and without completely inactivated SMAD4. In this study, in vitro growth of the hybrid cells was significantly suppressed compared with the parental cells, regardless of the initial SMAD4 status. To estimate the metastatic ability of the hybrids, we used a lung colonization model. At the end of the experiment, there was significant suppression of the number of surface metastases developing in mice injected with hybrids in comparison with those injected with parental cells. To identify and characterize genes that are involved in the progression of pancreatic cancer, we used microarray expression analysis employing a 20k oligo-array system. It was revealed that there was increased expression of 4 genes relating to apoptosis in the 18 chromosome hybrids cells compared with the parental cells. We are now analyzing the function of these genes.