Association of cyclin D and estrogen receptor alpha 36 with hepatocellular adenomas of female mice under chronic endoplasmic reticulum stress

作者：Lau Mo Yin; Han Hui; Hu Jay; Ji Cheng^*

来源：Journal of Gastroenterology and Hepatology, 2013, 28(3): 576-583.

DOI：10.1111/jgh.12084

• abnormal function of cyclin D
• hepatocellular tumorigenesis
• high-fat diet (HFD)
• metabolic stress
• sex hormone receptor variants
• unfolded protein response (UPR)

Background and Aims: Hepatocellular adenomas (HCAs) are benign tumors that can lead to medical complications. Chronic inflammation and mutations in beta-catenin, hepatocyte nuclear factor 1 alpha, 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 alpha 36), active transcription activator 4/6, glycogen synthase kinase 3 beta, and extracellular signal-regulated protein kinases 1 and 2 were detected, whereas no change of hepatocyte nuclear factor 1 alpha, beta-catenin, p-53, androgen receptor a, or estrogen receptor a 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 alpha 36. Additional stress such as HFD may promote malignant transformation of HCA through the Janus kinase-signal transducers and activators of transcription pathway.

• 出版日期2013-3