长链非编码 RNA H19 在慢性炎症介导的肝细胞癌发展中的致癌作用。
The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma.
机构信息
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
出版信息
Oncogene. 2021 Jan;40(1):127-139. doi: 10.1038/s41388-020-01513-7. Epub 2020 Oct 22.
The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients' survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.
癌胚长链非编码 RNA（lncRNA）H19 在大多数组织中是出生后被抑制的，而在许多癌症中，包括肝细胞癌（HCC）中重新表达。H19 在癌症发生中的作用是一个有争议的问题。我们旨在使用 Mdr2/Abcb4 敲除（Mdr2-KO）小鼠，即一种成熟的 HCC 模型，研究 H19 在慢性炎症介导的肝癌发生中的作用。为此，我们生成了 Mdr2-KO/H19-KO 双敲除（dKO）小鼠，并跟踪了 dKO 和对照 Mdr2-KO 小鼠自发肿瘤的发展。在年轻和年老的 Mdr2-KO 小鼠中，确定了 H19 的细胞定位及其在肝脏中的缺失效应。dKO 与 Mdr2-KO 雌性小鼠的肝肿瘤发生率和肿瘤负荷均显著降低。Mdr2-KO 雌性小鼠非肿瘤性肝组织中的 H19 和 Igf2 表达水平不同，且在大多数匹配的肿瘤中均显著下调。在年老的 Mdr2-KO 雌性小鼠的非肿瘤性肝组织中，H19 主要在肝细胞中表达，且与 dKO 雌性小鼠相比，肝细胞增殖增加。在早期，dKO 雌性小鼠的肝损伤和 B 细胞浸润程度较低，双核肝细胞的比例较高。在人类样本中，H19 在女性中表达较高，与肝硬化（非肿瘤性肝样本）呈正相关，与 CTNNB1（β-连环蛋白）突变和患者的生存（肿瘤）呈负相关。我们的数据表明，lncRNA H19 在 Mdr2-KO 小鼠模型中慢性炎症介导的 HCC 发展过程中具有致癌作用，主要通过增加年轻小鼠的肝损伤和减少肝细胞多倍体化。
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