https://scholars.lib.ntu.edu.tw/handle/123456789/551370
Title: | Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells | Authors: | Liao, Li-Zhu Chen, Chih-Ta Li, Nien-Chen Lin, Liang-Chun Huang, Bo-Shih Chang, Ya-Hui LU-PING CHOW |
Keywords: | S102 phosphorylation; YB-1; drug resistance; epithelial-mesenchymal transition; hepatocellular carcinoma cell; sorafenib | Issue Date: | 1-Jan-2021 | Publisher: | MDPI | Journal Volume: | 22 | Journal Issue: | 1 | Source: | International journal of molecular sciences | Abstract: | Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/551370 | ISSN: | 16616596 | DOI: | 10.3390/ijms22010224 | SDG/Keyword: | [SDGs]SDG3 epidermal growth factor receptor; F actin; gelatinase A; phosphatidylinositol 3 kinase; protein Cdc42; protein kinase B; sorafenib; transcription factor Snail; transcription factor ZEB1; Twist related protein 1; vimentin; Y box binding protein 1; zinc finger protein; phosphoserine; protein Cdc42; sorafenib; tumor marker; Y box binding protein 1; YBX1 protein, human; animal cell; animal experiment; animal model; Article; cancer resistance; cell invasion; cell migration; controlled study; enzyme activity; epithelial mesenchymal transition; gene expression; gene mutation; gene rearrangement; human; human cell; in vitro study; liver cell carcinoma; mouse; nonhuman; phosphoproteomics; protein expression; protein function; protein phosphorylation; signal transduction; animal; cell motion; cell proliferation; drug effect; drug resistance; gene expression regulation; genetics; liver cell carcinoma; liver tumor; metabolism; multicellular spheroid; pathology; phosphorylation; prognosis; pseudopodium; reproducibility; tumor cell line; tumor invasion; Animals; Biomarkers, Tumor; Carcinoma, Hepatocellular; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Mice; Neoplasm Invasiveness; Phosphorylation; Phosphoserine; Prognosis; Pseudopodia; Reproducibility of Results; Signal Transduction; Sorafenib; Spheroids, Cellular; Y-Box-Binding Protein 1 |
Appears in Collections: | 生物化學暨分子生物學科研究所 |
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