Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma.
Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma.
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DOI：
10.3390/ijms22168652
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发表时间：
2021-08-11
影响因子：
5.6
通讯作者：
Suzuki T
中科院分区：
文献类型：
--
作者：
Asakura N;Nakamura N;Muroi A;Nojima Y;Yamashita T;Kaneko S;Ikeda K;Koshikawa N;Suzuki T
肝细胞癌（HCC）是全球癌症死亡的第三大原因。此外，多种酪氨酸激酶抑制剂靶向分子疗法的疗效有限。在本研究中，我们关注不同HCC细胞共有的细胞信号通路，并使用定量逆相蛋白阵列（RPPA）和统计分析来阐明其恶性程度的分子机制。我们通过对17种肝癌细胞系CD90和EpCAM肿瘤干细胞标志物的表达进行聚类分析，检验了它们的异质性。高斯混合模型聚类鉴定出三个优势簇：CD90阳性和EpCAM阴性（CD90+）、EpCAM阳性和CD90阴性（EpCAM+）和EpCAM阴性和CD90阴性（中性）。多变量偏最小二乘法分析显示，前两种细胞群在EGFR和EphA2信号通路中表现出不同的蛋白表达和磷酸化模式。CD90+细胞在Ser897位点表现出更高的AKT、EphA2及其磷酸化形式，而EpCAM+细胞则表现出更高的ERK、RSK及其磷酸化形式。这表明，与EpCAM+细胞相比，在具有更高运动性和转移活性的CD90+细胞中，促癌、不依赖配体的EphA2信号通路起主导作用。我们还发现AKT抑制剂可以降低CD90+细胞的增殖和存活，但对EpCAM+细胞没有影响。综上所述，我们的研究结果表明AKT的激活可能是HCC中一个关键的促癌调节因子。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser897, whereas the EpCAM+ cells exhibited higher abundance of ERK, RSK and its phosphorylated form. This demonstrates that pro-oncogenic, ligand-independent EphA2 signaling plays a dominant role in CD90+ cells with higher motility and metastatic activity than EpCAM+ cells. We also showed that an AKT inhibitor reduced the proliferation and survival of CD90+ cells but did not affect those of EpCAM+ cells. Taken together, our results suggest that AKT activation may be a key pro-oncogenic regulator in HCC.
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