Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions.
Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions.
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DOI：
10.1053/j.gastro.2011.05.041
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发表时间：
2011-09
期刊：
影响因子：
29.4
通讯作者：
Korc M
中科院分区：
文献类型：
--
作者：
Carrière C;Gore AJ;Norris AM;Gunn JR;Young AL;Longnecker DS;Korc M
Rb1编码的细胞周期调节因子在大多数人类癌症中被功能性破坏。胰腺导管腺癌（PDACs）在KRAS和INK4A/CDKN2A中具有高频率的突变，这可能允许细胞绕过RB的调节作用。为了确定RB功能丧失在PDAC进展中的作用，我们研究了由致癌Kras引发的胰腺恶性转化过程中RB破坏的影响。我们在没有或存在致癌Kras的情况下产生了胰腺特异性Rb破坏的小鼠，以检查Rb在胰腺癌发生中的作用。在致癌Kras存在的情况下，胰腺上皮Rb的缺失加速了胰腺上皮内瘤变（PanIN）的形成，增加了囊性肿瘤的频率，并促进了PDAC的快速进展。早期癌症的特点是急性胰腺炎症，与胰腺内促炎细胞因子的上调有关。尽管存在与癌基因诱导的衰老相关的标志物，但低级别PanIN具有高增殖性，并表达高水平的p53。来源于这些小鼠的胰腺癌细胞系表达高水平的细胞因子，p53的转录活性受损。Rb编码一种肿瘤抑制因子，通过介导衰老反应和促进肿瘤抑制因子p53的活性，减轻胰腺癌中致癌kras诱导的癌变的进展。
Rb1 encodes a cell cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of RB. To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras. We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis. In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early-stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of pro-inflammatory cytokines within the pancreas. Despite of the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines and transcriptional activity of p53 was impaired. Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53.
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DOI：
10.1073/pnas.0701117104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Carriere, Catherine;Seeley, Elliott S.;Korc, Murray
通讯作者：
Korc, Murray
影响因子：
10.5
作者：
Ancrile, Brooke;Lim, Kian-Huat;Counter, Christopher M.
通讯作者：
Counter, Christopher M.
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
2.9
作者：
Brady, M;Bhatia, M;Slavin, J
通讯作者：
Slavin, J