Mo Yin Lau1, Hui Han, Jay Hu, Cheng Ji. 1. Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, California 90033, USA.
Abstract
BACKGROUND AND AIMS: Hepatocellular adenomas (HCAs) are benign tumors that can lead to medical complications. Chronic inflammation and mutations in β-catenin, hepatocyte nuclear factor 1α, or glycoprotein 130 are potential causes for human HCA. However, additional causes may exist due to heterogeneity of HCA. We investigated whether HCA are caused by endoplasmic reticulum (ER) stress. METHODS: Mice with a liver-specific deletion of the major chaperone BiP (LGKO) were used. Liver tumor occurrence was examined in LGKO with or without feeding of a high-fat diet (HFD) and characterized with immunohistochemistry with molecular markers of proliferation/malignancy. Molecular changes were analyzed with immunoblotting. RESULTS: Spontaneous monoclonal liver tumors were observed in 34% of LGKO females with constitutive hepatic ER stress. Lack of portal tracks or central veins, dilated sinusoidal spaces, hemorrhagic areas, active proliferation, and lipid deposits were observed in the liver tumors. HFD feeding induced multiclonal liver tumors in 83% of the LGKO females versus 0 in wild-type females. Hepatocytes reactive to antiglypican 3 antibodies were detected in the HFD-induced, but not spontaneous, tumors. In the liver tumors, inhibition of cyclin D and increase of the 36 kD estrogen receptor variant (estrogen receptor α36), active transcription activator 4/6, glycogen synthase kinase 3β, and extracellular signal-regulated protein kinases 1 and 2 were detected, whereas no change of hepatocyte nuclear factor 1α, β-catenin, p-53, androgen receptor α, or estrogen receptor α was detected. HFD activated Janus kinase and signal transducers and activators of transcription 3. CONCLUSIONS: Our evidence supports a novel link of HCA with ER stress and altered expression of cyclin D and estrogen receptor α36. Additional stress such as HFD may promote malignant transformation of HCA through the Janus kinase-signal transducers and activators of transcription pathway.
BACKGROUND AND AIMS: Hepatocellular adenomas (HCAs) are benign tumors that can lead to medical complications. Chronic inflammation and mutations in β-catenin, hepatocyte nuclear factor 1α, or glycoprotein 130 are potential causes for human HCA. However, additional causes may exist due to heterogeneity of HCA. We investigated whether HCA are caused by endoplasmic reticulum (ER) stress. METHODS:Mice with a liver-specific deletion of the major chaperone BiP (LGKO) were used. Liver tumor occurrence was examined in LGKO with or without feeding of a high-fat diet (HFD) and characterized with immunohistochemistry with molecular markers of proliferation/malignancy. Molecular changes were analyzed with immunoblotting. RESULTS:Spontaneous monoclonal liver tumors were observed in 34% of LGKO females with constitutive hepatic ER stress. Lack of portal tracks or central veins, dilated sinusoidal spaces, hemorrhagic areas, active proliferation, and lipid deposits were observed in the liver tumors. HFD feeding induced multiclonal liver tumors in 83% of the LGKO females versus 0 in wild-type females. Hepatocytes reactive to antiglypican 3 antibodies were detected in the HFD-induced, but not spontaneous, tumors. In the liver tumors, inhibition of cyclin D and increase of the 36 kD estrogen receptor variant (estrogen receptor α36), active transcription activator 4/6, glycogen synthase kinase 3β, and extracellular signal-regulated protein kinases 1 and 2 were detected, whereas no change of hepatocyte nuclear factor 1α, β-catenin, p-53, androgen receptor α, or estrogen receptor α was detected. HFD activated Janus kinase and signal transducers and activators of transcription 3. CONCLUSIONS: Our evidence supports a novel link of HCA with ER stress and altered expression of cyclin D and estrogen receptor α36. Additional stress such as HFD may promote malignant transformation of HCA through the Janus kinase-signal transducers and activators of transcription pathway.
Authors: Wilhelm Engström; Philippa Darbre; Staffan Eriksson; Linda Gulliver; Tove Hultman; Michalis V Karamouzis; James E Klaunig; Rekha Mehta; Kim Moorwood; Thomas Sanderson; Hideko Sone; Pankaj Vadgama; Gerard Wagemaker; Andrew Ward; Neetu Singh; Fahd Al-Mulla; Rabeah Al-Temaimi; Amedeo Amedei; Anna Maria Colacci; Monica Vaccari; Chiara Mondello; A Ivana Scovassi; Jayadev Raju; Roslida A Hamid; Lorenzo Memeo; Stefano Forte; Rabindra Roy; Jordan Woodrick; Hosni K Salem; Elizabeth P Ryan; Dustin G Brown; William H Bisson Journal: Carcinogenesis Date: 2015-06 Impact factor: 4.944