Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions.
Aldoketoreductase family 1B10 (AKR1B10) as a biomarker to distinguish hepatocellular carcinoma from benign liver lesions.
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DOI：
10.1016/j.humpath.2013.12.002
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发表时间：
2014-04
期刊：
影响因子：
3.3
通讯作者：
Yang, Guang-Yu
中科院分区：
文献类型：
--
作者：
Matkowskyj, Kristina A.;Bai, Han;Liao, Jie;Zhang, Wanying;Li, Haonan;Rao, Sambasiva;Omary, Reed;Yang, Guang-Yu
肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的高度侵袭性恶性肿瘤之一。AKR 1B 10首先从HCC中分离出来，并被进一步鉴定为在来自各种器官的许多癌症中过表达。AKR 1B 10通过脂质过氧化作用和代谢生理底物如法尼醛、视黄醛和羰基化合物来促进外源性物质的解毒。代谢这些脂质底物在促进癌发生中起着至关重要的作用。在本研究中，进行免疫组化分析，以确定在HCC中AKR 1B 10表达的流行率/模式，以及其在区分良性肝脏病变和HCC中的有用性。在体外肝细胞癌细胞中，使用蛋白质印迹和shRNA敲低方法检测AKR 1B 10的致癌功能，重点是细胞凋亡和对化疗的反应。免疫组化分析显示，AKR 1B 10在97%（86/89）的肝细胞癌中过表达，在邻近肝组织中表达极低或无表达，而肝腺瘤和局灶性结节性增生不显示AKR 1B 10的表达。在肝癌细胞中，shRNA介导的AKR 1B 10表达沉默导致1）细胞凋亡增加，2）集落形成和大小减少，以及3）暴露于阿霉素化疗后细胞减少反应增强。我们的研究结果首次证明AKR 1B 10是一种独特的生物标志物，通过调节增殖，细胞凋亡和化疗耐药性参与肝细胞癌的发生，并且是一种潜在的有希望的生物标志物，以区分HCC和良性肝脏病变。
Hepatocellular carcinoma (HCC) is one of the most common highly aggressive malignant tumors worldwide. AKR1B10 was first isolated from HCC and further identified to be over-expressed in many cancers from various organs. AKR1B10 contributes to detoxification of xenobiotics by lipid peroxidation and metabolizes physiological substrates such as farnesal, retinal and carbonyls. Metabolizing these lipid substrates plays a crucial role in promoting carcinogenesis. In the present study, immunohistochemical analysis was performed to determine the prevalence/pattern of AKR1B10 expression in HCC, and its usefulness to differentiate benign liver lesions from HCC. Oncogenic function of AKR1B10 was examined in hepatocellular carcinoma cells in vitro using western blotting and shRNA knockdown approaches, with emphasis on cell apoptosis and response to chemotherapy. Immunohistochemistry analysis revealed AKR1B10 was over-expressed in 97% (86/89) of hepatocellular carcinomas, with minimal to no expression in adjacent hepatic tissue, while hepatic adenomas and focal nodular hyperplasia did not exhibit expression of AKR1B10. shRNA-mediated silencing of AKR1B10 expression in hepatocellular carcinoma cells resulted in 1) increased cell apoptosis, 2) decreased colony formation and size, and 3) enhanced cytoreductive response following exposure to doxorubicin chemotherapy. Our findings provide first time evidence that AKR1B10 is a unique biomarker involved in hepatocellular carcinogenesis via modulation of proliferation, cell apoptosis and chemoresistance, and is a potential promising biomarker to differentiate HCCs from benign hepatic lesions.
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