BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of β-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis.
BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of β-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis.
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DOI：
10.4254/wjh.v13.i3.343
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发表时间：
2021-03-27
影响因子：
2.4
通讯作者：
Du CY
中科院分区：
文献类型：
--
作者：
Vilfranc CL;Che LX;Patra KC;Niu L;Olowokure O;Wang J;Shah SA;Du CY
含有BIR重复序列的泛素结合酶(Bruce)是一种肝脏肿瘤抑制因子，在大量肝病患者中表达下调。布鲁斯促进DNA损伤修复，以保护小鼠肝脏免受致癌物二乙基亚硝胺(DEN)依赖的急性肝损伤和癌变的影响。虽然肝纤维化与肝细胞癌之间存在着明确的病理联系，但仅接触DEN并不能诱导强烈的肝纤维化。有必要进行进一步的研究，以确定导致DEN诱导的纤维化和肝细胞癌的新的抑制机制。探讨Bruce在肝纤维化和肝细胞癌发生中的抑制机制。雄性C57/BL6/J对照小鼠[loxP/loxP；白蛋白-Cre(Alb-cre)-]和Bruce Alb-Cre KO小鼠(loxP/loxP；Alb-Cre+)在出生后第15天一次性注射DEN，并在不同时间点处死动物，观察肝脏疾病进展情况。通过使用肝脏特异的Bruce基因敲除(LKO)小鼠模型，我们发现Bruce缺乏症与DEN暴露相结合，在癌前和恶性两个阶段都诱导了肝纤维化，从而概括了经常在肝细胞癌患者中观察到的慢性纤维化背景。在肝纤维化和肝细胞癌中被激活，β-连环蛋白的活性依赖于它的稳定和随后的核转位。有趣的是，我们观察到Bruce KO小鼠的肝脏在癌变的三个阶段：癌前病变、肿瘤起始和肝细胞癌，表现出核聚集增加和β-连环蛋白活性升高。这表明，在肝病进展过程中，布鲁斯负向调节β-连环蛋白的活性。β-连环蛋白可被蛋白激酶激活，如蛋白激酶A，使其在Ser-675(pSer-675-β-连环蛋白)磷酸化。机制上，Bruce和PKA共定位于肝细胞胞浆中，PKA活性维持在基础水平。然而，在Bruce缺陷的小鼠肝脏或人肝癌细胞系中，PKA活性和pSer675-β-catenin水平都被观察到升高。我们的数据支持在小鼠肝脏中存在一个“Bruce-PKA-β-Catenin”信号轴。在肝细胞中，Bruce与PKA的相互作用抑制了PKA依赖的磷酸化和β-连环蛋白的激活。这项研究表明，在慢性肝病进展中，布鲁斯是一种新的PKA和β-连环蛋白的负性调节因子。此外，布鲁斯肝脏特异性KO小鼠可作为研究PKA和β-连环蛋白异常激活患者的肝纤维化和肝细胞癌的良好模型。
BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) is a liver tumor suppressor, which is downregulated in a large number of patients with liver diseases. BRUCE facilitates DNA damage repair to protect the mouse liver against the hepatocarcinogen diethylnitrosamine (DEN)-dependent acute liver injury and carcinogenesis. While there exists an established pathologic connection between fibrosis and hepatocellular carcinoma (HCC), DEN exposure alone does not induce robust hepatic fibrosis. Further studies are warranted to identify new suppressive mechanisms contributing to DEN-induced fibrosis and HCC. To investigate the suppressive mechanisms of BRUCE in hepatic fibrosis and HCC development. Male C57/BL6/J control mice [loxp/Loxp; albumin-cre (Alb-cre)-] and BRUCE Alb-Cre KO mice (loxp/Loxp; Alb-Cre+) were injected with a single dose of DEN at postnatal day 15 and sacrificed at different time points to examine liver disease progression. By using a liver-specific BRUCE knockout (LKO) mouse model, we found that BRUCE deficiency, in conjunction with DEN exposure, induced hepatic fibrosis in both premalignant as well as malignant stages, thus recapitulating the chronic fibrosis background often observed in HCC patients. Activated in fibrosis and HCC, β-catenin activity depends on its stabilization and subsequent translocation to the nucleus. Interestingly, we observed that livers from BRUCE KO mice demonstrated an increased nuclear accumulation and elevated activity of β-catenin in the three stages of carcinogenesis: Pre-malignancy, tumor initiation, and HCC. This suggests that BRUCE negatively regulates β-catenin activity during liver disease progression. β-catenin can be activated by phosphorylation by protein kinases, such as protein kinase A (PKA), which phosphorylates it at Ser-675 (pSer-675-β-catenin). Mechanistically, BRUCE and PKA were colocalized in the cytoplasm of hepatocytes where PKA activity is maintained at the basal level. However, in BRUCE deficient mouse livers or a human liver cancer cell line, both PKA activity and pSer-675-β-catenin levels were observed to be elevated. Our data support a “BRUCE-PKA-β-catenin” signaling axis in the mouse liver. The BRUCE interaction with PKA in hepatocytes suppresses PKA-dependent phosphorylation and activation of β-catenin. This study implicates BRUCE as a novel negative regulator of both PKA and β-catenin in chronic liver disease progression. Furthermore, BRUCE-liver specific KO mice serve as a promising model for understanding hepatic fibrosis and HCC in patients with aberrant activation of PKA and β-catenin.
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