PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.
PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.
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为了研究PP6基因（Ppp6c）缺乏对胰腺肿瘤发展的影响，我们培育了胰腺特异性的、他莫昔芬诱导的Cre介导的KP （KRAS(G12D) + Trp53缺乏）小鼠（cKP小鼠），并将它们与Ppp6cflox / flox小鼠杂交。纯合子Ppp6c缺失的cKP小鼠在突变诱导后150天内发生胰腺肿瘤，变得瘦弱并需要安乐死，这些表型在杂合子或野生型（WT）小鼠中未见。在第30天，对纯合子Ppp6c cKP小鼠与WT Ppp6c cKP小鼠中常见改变的基因进行比较分析，发现纯合子中Erk和NFκB通路的激活增强。与杂合或WT cKP小鼠相比，Ppp6c纯合小鼠胰腺中肿瘤的数量、大小和癌前病变的数量均显著增加。Ppp6c−/−肿瘤病理诊断为胰腺导管腺癌（PDAC），发生上皮-间质转化（EMT）， 6例中有3例癌细胞浸润周围组织。转录组学和代谢组学分析表明Ppp6c缺失的cKP小鼠癌症特异性糖酵解代谢增强，炎症细胞因子表达增加。Ppp6c−/−cKP小鼠个体表现出体重减轻，骨骼肌和脂肪组织减少，循环肿瘤坏死因子(TNF) α和IL - 6水平升高，提示全身性炎症。总体而言，Ppp6c缺失与K‐ras突变和Trp53基因缺失共同促进胰腺肿瘤发生，伴广泛性恶病质和早期死亡。该研究提供了Ppp6c抑制小鼠胰腺癌发生的第一个证据，并支持将Ppp6c‐缺陷的cKP小鼠作为开发与胰腺癌相关的恶病质治疗的模型。PP6基因（Ppp6c）缺失在K‐ras突变和Trp53基因缺失的情况下促进了广泛性恶病质和早期死亡小鼠胰腺肿瘤的发生。这些小鼠可以作为一个有用的模型，用于阐明与胰腺癌相关的恶病质机制和开发治疗干预措施。本研究首次证实Ppp6c在小鼠胰腺癌发生过程中发挥抑癌作用。
To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas‐specific, tamoxifen‐inducible Cre‐mediated KP (KRAS(G12D) plus Trp53‐deficient) mice (cKP mice) and crossed them with Ppp6cflox / flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild‐type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c −/− tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial–mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer‐specific glycolytic metabolism in Ppp6c‐deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c −/− cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)‐α and IL‐6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K‐ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c‐deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer. PP6 gene (Ppp6c) deficiency in the presence of K‐ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis in mice with generalized cachexia and early death. These mice should serve as a useful model in which to elucidate the mechanisms underlying cachexia associated with pancreatic cancer and for developing therapeutic interventions. This study is the first evidence that Ppp6c functions as a tumor suppressor in mouse pancreatic carcinogenesis.
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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
8.8
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影响因子：
4
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Shima H
影响因子：
5.7
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Kanazawa K;Kishimoto K;Nomura M;Kurosawa K;Kato H;Inoue Y;Miura K;Fukui K;Yamashita Y;Sato I;Tsuji H;Watanabe T;Tanaka T;Yasuda J;Tanuma N;Shima H
通讯作者：
Shima H
影响因子：
5.7
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Kurosawa K;Inoue Y;Kakugawa Y;Yamashita Y;Kanazawa K;Kishimoto K;Nomura M;Momoi Y;Sato I;Chiba N;Suzuki M;Ogoh H;Yamada H;Miura K;Watanabe T;Tanuma N;Tachi M;Shima H
通讯作者：
Shima H