Bastea Ligia I, Liu Xiang, Fleming Alicia K, Pandey Veethika, Döppler Heike, Edenfield Brandy H, Krishna Murli, Zhang Lizhi, Thompson E Aubrey, Grandgenett Paul M, Hollingsworth Michael A, Fairweather DeLisa, Clemens Dahn, Storz Peter
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Nat Commun. 2024 Dec 4;15(1):10547. doi: 10.1038/s41467-024-55043-x.
The development of pancreatic cancer requires both, acquisition of an oncogenic mutation in KRAS as well as an inflammatory insult. However, the physiological causes for pancreatic inflammation are less defined. We show here that oncogenic KRas-expressing pre-neoplastic lesion cells upregulate coxsackievirus (CVB) and adenovirus receptor (CAR). This facilitates infections from enteroviruses such as CVB3, which can be detected in approximately 50% of pancreatic cancer patients. Moreover, using an animal model we show that a one-time pancreatic infection with CVB3 in control mice is transient, but in the presence of oncogenic KRas drives chronic inflammation and rapid development of pancreatic cancer. We further demonstrate that a knockout of CAR in pancreatic lesion cells blocks these CVB3-induced effects. Our data demonstrate that KRas-caused lesions promote the development of pancreatic cancer by enabling certain viral infections.
胰腺癌的发展既需要在KRAS基因中获得致癌突变，也需要炎症刺激。然而，胰腺炎症的生理原因尚不太明确。我们在此表明，表达致癌KRas的癌前病变细胞会上调柯萨奇病毒（CVB）和腺病毒受体（CAR）。这有利于肠道病毒如CVB3的感染，在大约50%的胰腺癌患者中可检测到这种病毒。此外，我们使用动物模型表明，对照小鼠一次性感染CVB3后胰腺感染是短暂的，但在存在致癌KRas的情况下会引发慢性炎症并加速胰腺癌的发展。我们进一步证明，胰腺病变细胞中CAR基因敲除可阻断这些CVB3诱导的效应。我们的数据表明，KRas导致的病变通过使某些病毒感染得以发生，从而促进胰腺癌的发展。
