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Overproduction ofthrombopoietinbyBRAFV600E‐mutatedmouse hepatocytes andcontribution ofthrombopoietin tohepatocarcinogenesis Hiroki TanakaKie HoriokaMasahiro Yamamoto2019 год

Overproduction of thrombopoietin byBRAFV600E‐mutated mouse hepatocytes and contribution of thrombopoietin to hepatocarcinogenesis
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Аннотация: Abstract In hepatocarcinogenesis induced by diethylnitrosamine ( DEN ) in B6C3F1 mice, the Braf V637E mutation, corresponding to the human BRAF V 600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte‐specific human BRAF V 600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN ‐induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin ( TPO ) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN ‐induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C‐type lectin receptor 2 ( CLEC ‐2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAF V 600E‐mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.
Год издания: 2019
Авторы: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Masaru Asari, Katsuhiro Okuda, Kosuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa
Издательство: Wiley
Источник: Cancer Science
Ключевые слова: Angiogenesis and VEGF in Cancer, Renal Diseases and Glomerulopathies, PI3K/AKT/mTOR signaling in cancer
Другие ссылки: Cancer Science (PDF)
Cancer Science (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)