Y-box binding protein-1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/β-catenin pathway.

Hsiao-Mei Chao,Hong-Xuan Huang,Atsushi Miyajima,Kuo-Chang Tseng,Po-Hsiang Chang,Edward Chern

doi:10.18632/oncotarget.13733

Hsiao-Mei Chao, Hong-Xuan Huang + Show 4 more

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https://doi.org/10.18632/oncotarget.13733

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Abstract

Y-box binding protein-1 (YB-1) is a pleiotropic molecule that binds DNA to regulate genes on a transcriptional level in the nucleus and binds RNA to modulate gene translation in the cytoplasm. In our previous studies, YB-1 was also characterized as a fetal hepatic protein that regulates the maturation of hepatocytes and is upregulated during liver regeneration. Moreover, YB-1 has been shown to be expressed in human hepatocellular carcinoma (HCC). However, the role of YB-1 in HCC remains unclear. Here, we aimed to characterize the role of YB-1 in HCC. Based on the results of loss-of-function in HCC and gain-of-function in mice liver using hydrodynamic gene delivery, YB-1 promoted hepatic cells proliferation in vitro and in vivo. YB-1 was also involved in HCC cell proliferation, migration, and drug-resistance. The results of extreme limiting dilution sphere forming analysis and cancer initiating cell marker analysis were also shown that YB-1 maintained HCC initiating cells population. YB-1 also induced the epithelial-mesenchymal transition and stemness-related gene expression. Knockdown of YB-1 suppressed the expression of Wnt ligands and β-catenin, impaired Wnt/β-catenin signaling pathway and reduced the numbers of HCC initiating cells. Moreover, YB-1 displayed nuclear localization particularly in the HCC initiating cells, the EpCAM+ cells or sphere cells. Our findings suggested that YB-1 was a key factor in HCC tumorigenesis and maintained the HCC initiating cell population.

Highlights

Y-box binding protein 1 (YB-1) belongs to the family of cold shock binding proteins and binds to the nucleotide sequence invert CCAAT to regulate gene expression
In order to elucidate the function of Y-box binding protein-1 (YB-1) in hepatocellular carcinoma (HCC), we first examined the expression of YB-1 in different HCC cell lines
To examine whether YB-1 was involved in HCC proliferation, we knocked down YB-1 in HCC cells and measured the expression of proliferation related genes and proliferative ability of HCC cells

Summary

Introduction

Y-box binding protein 1 (YB-1) belongs to the family of cold shock binding proteins and binds to the nucleotide sequence invert CCAAT to regulate gene expression. YB-1 is upregulated in some cancers, such as breast, prostate, and ovarian cancers, and functions as a proto-oncogene [1,2,3]. YB-1 promotes the transcription of CD44 and CD49f [6]. YB-1 binds to mRNAs encoding proteins involved in the epithelial-mesenchymal transition (EMT) to regulate gene translation and promote the EMT [7]. Studies have shown that microRNAs (miRNAs) or small molecules target YB-1 to inhibit metastasis of osteosarcoma and prostate cancer [8, 9]. Taken together, these data imply that YB-1 may play a critical role in the tumorigenesis and progression of cancers

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