Department of Pathology, Affiliated Hospital of Yanbian University, Jilin, China.
Division of GI and Hepatology, Departments of Internal Medicine, The Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Mol Carcinog. 2021 Apr;60(4):252-264. doi: 10.1002/mc.23288. Epub 2021 Feb 26.
The ErbB3 binding protein 1 (Ebp1) has been reported in several cancers, in which it can act as either a pro-oncogenic regulator or a tumor suppressor. However, the biological function and molecular mechanism of Ebp1 p48 in hepatocellular carcinoma (HCC) remain unclear. Here, we report that the long isoform of Ebp1, p48, is highly expressed in HCC tissues compared with normal tissues. Ebp1 p48 expression was correlated with the tumor size in HCC patients. Silencing Ebp1 p48 by transduction with lentiviral shEbp1 dramatically reduced the proliferation rate, soft agar colony generation, and tumor formation in vivo. We further demonstrated that Ebp1 p48 knockdown resulted in decreased p38 phosphorylation, which subsequently reduced hypoxia-inducible factor 1α (HIF1α) expression. Moreover, Ebp1 p48 knockdown led to an upregulation of p53 expression through MDM2 downregulation. Taken together, these results suggest that the Ebp1/p38/HIF1α signaling pathway and the Ebp1-mediated downregulation of p53 are involved in hepatocarcinogenesis. Therefore, Ebp1 and its downstream signaling pathways may be promising therapeutic targets of HCC.
ErbB3 结合蛋白 1（Ebp1）已在多种癌症中被报道，在这些癌症中，它可以作为致癌调节因子或肿瘤抑制因子发挥作用。然而，Ebp1 p48 在肝细胞癌（HCC）中的生物学功能和分子机制尚不清楚。在这里，我们报告说，Ebp1 的长异构体 p48 在 HCC 组织中的表达明显高于正常组织。Ebp1 p48 的表达与 HCC 患者的肿瘤大小相关。通过慢病毒 shEbp1 转导沉默 Ebp1 p48 可显著降低细胞增殖率、软琼脂集落生成和体内肿瘤形成。我们进一步证明，Ebp1 p48 敲低导致 p38 磷酸化减少，随后降低缺氧诱导因子 1α（HIF1α）的表达。此外，Ebp1 p48 敲低通过下调 MDM2 导致 p53 表达上调。综上所述，这些结果表明 Ebp1/p38/HIF1α 信号通路和 Ebp1 介导的 p53 下调参与了肝癌的发生。因此，Ebp1 及其下游信号通路可能是 HCC 有前途的治疗靶点。
