Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells
Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells
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DOI：
10.1158/0008-5472.can-06-0404
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Berasain, Carmen
中科院分区：
文献类型：
--
作者：
Castillo, Josefa;Erroba, Elena;Berasain, Carmen
肝细胞癌是癌症相关死亡的主要原因。目前的治疗方法并不有效，并且非常需要确定相关的途径和新的治疗靶点。越来越多的证据表明，表皮生长因子受体（EGFR）的激活是肝癌发生发展的重要机制。我们先前描述了EGFR的配体双调蛋白（AR）在健康肝脏中不表达，但在慢性肝损伤期间上调，这是大多数肝脏肿瘤发展的背景。目前，我们对AR在人肝癌中的表达及作用进行了研究。在人肝肿瘤和细胞系中研究所有表达和功能。AR在人肝细胞癌组织和细胞系中表达，是一种促有丝分裂和抗凋亡的生长因子。我们提供了几条证据，包括小干扰RNA的所有沉默和中和抗体对双调蛋白的抑制，表明存在AR介导的自分泌环，有助于转化表型。事实上，干扰内源性AR产生导致组成型EGFR信号传导减少、细胞增殖抑制、锚定非依赖性生长和细胞凋亡增强。此外，AR敲低增强转化生长因子β和阿霉素诱导的细胞凋亡。相反，AR在SK-Hep 1细胞中的过表达增强了它们的增殖率、非贴壁依赖性生长、耐药性和体内致瘤潜力。这些观察结果表明，AR参与了肝脏肿瘤特征的获得，因此构成了人类肝癌的新治疗靶点。
Hepatocellular carcinoma is a major cause of cancer-related deaths. Current treatments are not effective, and the identification of relevant pathways and novel therapeutic targets are much needed. Increasing evidences point to the activation of the epidermal growth factor receptor (EGFR) as an important mechanism in the development of hepatocarcinoma. We previously described that amphiregulin (AR), a ligand of the EGFR, is not expressed in healthy liver but is upregulated during chronic liver injury, the background on which most liver tumors develop. Now, we have studied the expression and role of AR in human hepatocarcinoma. All expression and function was studied in human liver tumors and cell lines. AR is expressed in human hepatocellular carcinoma tissues and cell lines and behaves as a mitogenic and antiapoptotic growth factor for hepatocarcinorna cells. We provide several lines of evidence, including All silencing by small interfering RNAs and inhibition of amphiregulin by neutralizing antibodies, showing the existence of an AR-mediated autocrine loop that contributes to the transformed phenotype. Indeed, interference with endogenous AR production resulted in reduced constitutive EGFR signaling, inhibition of cell proliferation, anchorage-independent growth, and enhanced apoptosis. Moreover, knockdown of AR potentiated transforming growth factor-beta and doxorubicin-induced apoptosis. Conversely, overexpression of AR in SK-Hep1 cells enhanced their proliferation rate, anchorage-independent growth, drug resistance, and in vivo tumorigenic potential. These observations suggest that AR is involved in the acquisition of neoplastic traits in the liver and thus constitutes a novel therapeutic target in human hepatocarcinoma.