Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan.
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine , Sendai , Japan.
Am J Physiol Gastrointest Liver Physiol. 2018 Jan 1;314(1):G65-G74. doi: 10.1152/ajpgi.00228.2017. Epub 2017 Sep 28.
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-ras:: p53:: Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer that specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated Pdx-1-Cre::K-ras:: Keap1 (KC::Keap1) and KPC:: Keap1 (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion ( Nrf2 or Nrf2) rescued the pancreatic phenotypes, weight loss, and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice. NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic carcinogenesis. Conditional expression of mutant K-ras and Keap1 deletion did not result in pancreatic cancer development. Instead, these mice developed progressive loss of pancreatic parenchyma, accompanied by body weight loss and hypoglycemia, presumably because of pancreatic exocrine insufficiency. Nrf2 activation by Keap1 deletion concomitant with K-ras activation cause pancreatic atrophy.
Kelch 样 ECH 相关蛋白 1（Keap1）-NF-E2 相关因子 2（Nrf2）系统除了对氧化应激反应具有广泛的影响外，还具有促进癌细胞生长和化疗耐药性等作用。Nrf2 在大多数癌细胞中持续激活。然而，Nrf2 的激活与致癌突变并不总是导致癌症促进。K-ras:: p53:: Pdx-1-Cre（KPC）小鼠是一种已建立的胰腺癌模型，它通过使用 Pdx-1-Cre 在胰腺中特异性表达 K-ras 和 p53 的突变体。我们在这里生成了 Pdx-1-Cre::K-ras:: Keap1（KC::Keap1）和 KPC:: Keap1（KPC::Keap1）小鼠，其中 Nrf2 通过 Keap1 缺失而持续激活。KC::Keap1 和 KPC::Keap1 小鼠在出生后大约 40 天左右开始死亡或出现明显的虚弱。组织学检查显示，KC::Keap1 和 KPC::Keap1 小鼠并未发展为胰腺癌，而是胰腺实质进行性萎缩。在这些小鼠中，淀粉酶阳性的腺泡细胞以及胰岛素和胰高血糖素阳性的胰岛细胞减少，并被纤维组织包围。KC::Keap1 和 KPC::Keap1 小鼠的体重和血糖水平低于 C::Keap1 小鼠，可能是由于胰腺外分泌功能不全所致。C::Keap1 和 PC::Keap1 小鼠的组织学变化不明显。p53 突变的存在并未影响 KC::Keap1 小鼠的表型。同种异体或同源 Nrf2 缺失（Nrf2 或 Nrf2）挽救了 KC::Keap1 小鼠的胰腺表型、体重减轻和低血糖，表明 Nrf2 是 Keap1 的主要下游靶标。总之，K-ras 的同时激活和 Keap1 的缺失导致小鼠胰腺实质进行性萎缩。新的和值得注意的是，Kelch 样 ECH 相关蛋白 1（Keap1）-NF-E2 相关因子 2（Nrf2）系统的异常激活通常会促进致癌作用，我们假设同时激活 K-ras 和 Nrf2 可能会促进胰腺癌的发生。条件表达突变型 K-ras 和 Keap1 缺失并未导致胰腺癌的发展。相反，这些小鼠出现胰腺实质进行性丧失，伴有体重减轻和低血糖，可能是由于胰腺外分泌功能不全所致。Keap1 缺失引起的 Nrf2 激活伴随着 K-ras 的激活导致胰腺萎缩。
