Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas
Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas
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DOI：
10.1038/modpathol.3800383
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发表时间：
2005-08-01
期刊：
影响因子：
7.5
通讯作者：
Horii, A
中科院分区：
文献类型：
--
作者：
Furukawa, T;Fujisaki, R;Horii, A
DUSP6/MKP-3被确定为胰腺癌的候选肿瘤抑制基因。本研究的目的是通过与其他主要肿瘤抑制通路的参与比较，阐明DUSP6在胰腺上皮内瘤变和/或导管内乳头状-粘液瘤发生过程中的作用，这两种肿瘤都被认为是胰腺浸润性癌的前驱病变。采用免疫组化方法，对52例浸润性导管癌和51例导管内乳头状-黏液性肿瘤的206例导管发育不良前体病变和癌组织中DUSP6、CDKN2A、TP53和SMAD4的表达进行了研究。对不同非典型分级的病变进行染色强度评价，并进行统计学比较。采用等位基因特异性寡核苷酸杂交和核苷酸测序方法分析KRAS2基因突变。在胰腺浸润性导管癌中，DUSP6的表达在浸润性癌细胞中完全消失，而在胰腺上皮内瘤变中则完全保留。在胰腺导管内乳头状-黏液性肿瘤中，在相对较小比例的导管内腺瘤/交界性癌和导管内癌中观察到DUSP6的不表达。大多数DUSP6缺失的导管内腺瘤/交界性病变含有KRAS2突变。在任何级别的病变中，这些分子都没有相互关联。我们对导管内乳头状-黏液性肿瘤的乳头状瘤的形态变化进行了评估和分析，以确定它们与分子取消的关系，结果发现没有显著的关联。我们的研究结果表明，DUSP6的缺失只与胰腺上皮内瘤变向浸润性导管癌的进展相关，而它可能与KRAS2突变的导管内乳头状-粘液瘤的发生有关，KRAS2突变在这两种类型的肿瘤中独立于其他主要的肿瘤抑制途径。
DUSP6/MKP-3 is identified as a candidate tumor suppressor gene for pancreatic cancer. The aim of this study was to elucidate the roles of DUSP6 in the pancreatic carcinogenesis through the pancreatic intraepithelial neoplasia and/or intraductal papillary-mucinous neoplasms, both of which are considered to be precursor lesions of invasive carcinoma of the pancreas, by comparing with involvements of other major tumor suppressive pathways. Expressions of DUSP6, CDKN2A, TP53, and SMAD4 were investigated by immunohistochemistry in a total of 206 lesions of dysplastic ductal precursors and carcinomas retrieved from 52 pancreata with invasive ductal carcinomas and 51 of those with intraductal papillary-mucinous neoplasms. The intensity of staining was evaluated in lesions at different atypical grades and statistically compared among them. Mutations of KRAS2 were analyzed by methods of the allele-specific oligonucleotide hybridization and nucleotide sequencing. In pancreata with invasive ductal carcinomas, expressions of DUSP6 were abrogated exclusively in the invasive carcinoma cells in contrast to its fairly preserved expressions in pancreatic intraepithelial neoplasia. In pancreata with intraductal papillary-mucinous neoplasms, abrogated expressions of DUSP6 were observed in a relatively small fraction of intraductal adenoma/borderlines and intraductal carcinomas. Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2. None of the molecules was associated with each other in any grade of lesions. Morphological variations of papillae of the intraductal papillary-mucinous neoplasms were evaluated and analyzed for their associations with abrogations of the molecules, which resulted in finding of no significant associations. Our results suggest that the abrogation of DUSP6 is associated exclusively with progression from pancreatic intraepithelial neoplasia to the invasive ductal carcinoma while it is potentially associated with initiation of intraductal papillary-mucinous neoplasms with mutated KRAS2, which is independent of other major tumor suppressive pathways in both types of neoplasms.