Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY.
Hepatology. 2014 Jul;60(1):419-421. doi: 10.1002/hep.26956. Epub 2014 May 27.
Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene , a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment.
We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays.
SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo.
SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma.
肝细胞癌是全球癌症相关死亡的第三大主要原因。在异质性的肝细胞癌群体中，那些具有胚胎干细胞和祖细胞基因表达特征的患者预后最差。癌胚基因是具有祖细胞样特征的肝细胞癌亚类的标志物，与预后不良相关，是治疗的潜在靶点。
我们筛选了原发性肝细胞癌患者的标本，检测 SALL4 的表达，并进行临床病理分析。然后进行功能丧失研究，以评估 SALL4 在肝癌发生中的作用及其作为治疗靶点的潜力。为了评估靶向 SALL4 的肽的治疗效果，我们使用了体外功能和体内异种移植实验。
SALL4 是一种癌胚蛋白，在人类胎儿肝脏中表达，在成人肝脏中沉默，但在具有肝细胞癌和不良预后的亚组患者中重新表达。基因表达分析显示，祖细胞样基因特征富集，增殖和转移基因在肝细胞癌中过表达。功能丧失研究证实了 SALL4 在细胞存活和致瘤性中的关键作用。阻断 SALL4-共抑制因子相互作用释放了对 PTEN（磷酸酶和张力蛋白同源物蛋白）的抑制作用，并抑制了体内异种移植模型中的肿瘤形成。
SALL4 是一种具有侵袭性表型的祖细胞亚类肝细胞癌的标志物。健康成人肝脏中 SALL4 表达的缺失增强了 SALL4 作为肝细胞癌治疗靶点的潜力。
