The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and.
FASEB J. 2019 Jul;33(7):7995-8007. doi: 10.1096/fj.201900017R. Epub 2019 Mar 21.
Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.-Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Maller, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model.
慢性肝脏炎症（CLI）是肝细胞癌（HCC）发展的危险因素。半乳糖凝集素-1（Gal1）参与炎症、血管生成和肿瘤发生的调节，表现出多种抗炎和促肿瘤活性。我们旨在使用建立的 CLI 介导的 HCC 发展模型，即表达高水平 Gal1 的 Abcb4 [多药耐药 2（Mdr2）] -敲除（KO）小鼠，探索其在 CLI 和 HCC 进展中的调节作用。我们在 C57BL/6 和 FVB/N 遗传背景上生成了 Gal1-KO/Mdr2-KO 双敲除（dKO）小鼠，并将生成的品系与它们的亲本 Mdr2-KO 品系的 HCC 发展进行了比较。在两种品系的 dKO 小鼠中，Gal1 的缺失从早期开始就增加了肝脏损伤、炎症、纤维化和胆管反应。与对照 Mdr2-KO 小鼠相比，年老的 dKO 突变体显示出更早的肝癌发生和更大的肿瘤大小。我们发现，骨桥蛋白，一种众所周知的 HCC 发展调节剂，以及致癌蛋白 Ntrk2（TrkB）和 S100A4 在 dKO 中表达高于 Mdr2-KO 肝脏。我们的结果表明，在 Mdr2-KO 小鼠中，一种 CLI 介导的 HCC 模型，Gal1 介导的对肝炎、肝纤维化和 HCC 起始的保护在 HCC 发展的后期阶段超过了其已知的促癌活性。这些发现表明，抗 Gal1 治疗可能不适用于 CLI 介导的 HCC 的所有阶段。-波蒂卡，T.，帕波，O.，米兹拉希，L.，奥拉姆，D.，马勒，S.M.，拉比诺维奇，G.A.，加利恩，E.，戈尔登伯格，D.S.缺乏半乳糖凝集素-1 会加剧小鼠肝细胞癌模型中的慢性肝炎、肝纤维化和癌发生。
