Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
Cancer Res. 2012 Jul 1;72(13):3414-23. doi: 10.1158/0008-5472.CAN-12-0299. Epub 2012 May 2.
The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β-mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β-mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2-positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β-mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC.
被诊断患有肝细胞癌（HCC）的个体的预后仍然较差，因为侵袭性肿瘤生长、肝内扩散和肝外转移的频率较高。在这里，我们研究了细胞外基质的主要粘附分子和癌症干细胞标志物标准 CD44 同种型（CD44s）在 TGF-β 介导的 HCC 间充质表型中的作用。我们发现 CD44s 是 HCC 细胞中表达的 CD44 mRNA 的主要形式。CD44s 的过表达促进了肿瘤的侵袭性，并增加了 HCC 细胞中间充质标志物波形蛋白的表达。CD44s 的缺失消除了这些变化。同样在 CD44s 过表达的情况下，TGF-β1 处理诱导 HCC 细胞的间充质表型，其特征是 E-钙粘蛋白表达降低和波形蛋白表达升高。CD44s 的缺失抑制了 TGF-β 介导的波形蛋白表达、间充质纺锤形形态和肿瘤侵袭性。临床上，CD44s 的过表达与 E-钙粘蛋白表达降低、波形蛋白表达升高、磷酸化 Smad2 阳性核百分比高以及 HCC 患者预后不良相关，包括疾病无进展和总生存时间缩短。总之，我们的研究结果表明，CD44s 在 TGF-β 介导的间充质表型中起关键作用，因此代表了 HCC 的潜在治疗靶点。
