Li Hao, Zhang Tian, Wang Ke, Lu Meng, Guo Yonghong, Zhang Ye, Chen Zhi-Nan, Bian Huijie
Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China.
J Cell Physiol. 2019 Sep;234(9):16463-16474. doi: 10.1002/jcp.28314. Epub 2019 Feb 14.
Milk fat globule-EGF factor 8 (MFGE8) has been reported to play various roles in acute injury and inflammation response. However, the role of MFGE8 in liver injury is poorly investigated. The present research was designed to clarify the expression and function of MFGE8 in carbon tetrachloride (CCl )-induced liver injury. Using serum cytokine arrays, we selected a promising cytokine MFGE8 as the candidate in the process of hepatitis-fibrosis-hepatocellular carcinoma (HCC) progression, based on the elevated expression in both hepatic fibrosis and HCC models. We validated the increased expression of MFGE8 in liver tissues and serum samples of acute and chronic CCl -induced mice. Immunohistochemistry staining of mouse liver tissues indicated that elevated MFGE8 expression was mainly derived from the injured hepatocytes. In addition, MFGE8 expression in the supernatant of primary hepatocytes was accumulated with prolongation of culture time, and CCl treatment further increased the expression of MFGE8. Moreover, a strong correlation between serum MFGE8 expression and liver transaminase activities suggested that MFGE8 may be a novel candidate in liver injury. Intriguingly, mice pretreated with MFGE8 were protected from CCl -induced liver injury through antiapoptosis role in the early stage and proproliferation role in the late stage. MFGE8 reduced apoptosis by inhibiting the activation of IRE1α/ASK1/JNK pathway and promoted proliferation by phosphorylation of ERK and AKT. Moreover, serum MFGE8 expression was increased in hepatitis patients while decreased in liver cirrhosis patients. All the results suggest MFGE8 as a novel marker and promising therapeutic agent of liver injury.
乳脂肪球表皮生长因子8（MFGE8）已被报道在急性损伤和炎症反应中发挥多种作用。然而，MFGE8在肝损伤中的作用研究较少。本研究旨在阐明MFGE8在四氯化碳（CCl₄）诱导的肝损伤中的表达及功能。通过血清细胞因子阵列，基于肝纤维化和肝癌模型中表达升高，我们选择了一种有前景的细胞因子MFGE8作为肝炎-肝纤维化-肝细胞癌（HCC）进展过程中的候选因子。我们验证了急性和慢性CCl₄诱导小鼠的肝组织和血清样本中MFGE8表达增加。小鼠肝组织的免疫组织化学染色表明，MFGE8表达升高主要来源于受损的肝细胞。此外，原代肝细胞上清液中MFGE8的表达随培养时间延长而积累，CCl₄处理进一步增加了MFGE8的表达。而且，血清MFGE8表达与肝转氨酶活性之间存在强相关性，提示MFGE8可能是肝损伤的一个新候选指标。有趣的是，用MFGE8预处理的小鼠通过早期的抗凋亡作用和晚期的促增殖作用免受CCl₄诱导的肝损伤。MFGE8通过抑制IRE1α/ASK1/JNK通路的激活减少细胞凋亡，并通过ERK和AKT的磷酸化促进细胞增殖。此外，肝炎患者血清MFGE8表达升高，而肝硬化患者血清MFGE8表达降低。所有结果表明MFGE8是肝损伤的一种新型标志物和有前景的治疗药物。
