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Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma

Authors :
Shuichi Kaneko
Yosui Nojima
Nobuhiko Asakura
Atsushi Muroi
Naohiko Koshikawa
Takashi Suzuki
Taro Yamashita
Naotoshi Nakamura
Kazuki Ikeda
Source :
International Journal of Molecular Sciences, Vol 22, Iss 8652, p 8652 (2021), International Journal of Molecular Sciences, Volume 22, Issue 16
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
16616596 and 14220067
Volume :
22
Issue :
8652
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....0d43db23328d911944728b32f3cb21e4