Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells

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.

Dihydromyricetin Inhibits Tumor Growth and Epithelial-Mesenchymal Transition through regulating miR-455-3p in Cholangiocarcinoma

“…Previous studies have demonstrated that the ZEB1/PI3K/AKT signaling pathway plays an important role in cell growth and invasion in several cancers 19 , 20 . Thus, we were interested to investigate if DMY could inhibit the ZEB1 downstream PI3K/AKT signaling pathway through regulating miR-455-3p in CCA.…”

“…AGO1 enhances proliferation and invasion through modulating EMT-associated related TGF-β-PI3K-AKT signaling pathways in cholangiocarcinoma 5 . The ZEB1/PI3K/AKT signaling pathway also plays an important role in tumor cell growth and invasion 19 , 20 . For instance, in non-small cell lung cancer cells, downregulation of Rhomboid domain containing 1 (RHBDD1) expressions inhibits cell growth and invasion through reducing the ZEB1/PI3K/AKT signaling pathway activation 19 .…”

The Emerging Role of Stress Granules in Hepatocellular Carcinoma

“…Most of available studies are focused on G3BP1, which is frequently upregulated in a variety of cancers, where it seems to exert an oncogenic function [58]. Recent findings showed that RBPs, such as the Y-box binding protein (YBX1), which is overexpressed in many cancers including HCC [59,60], can upregulate G3BP1 expression by promoting its translation [61]. In HCC, G3BP1 induction was shown to contribute to cancer cells migration by increasing SLUG expression [62], but whether this was associated with increased SG formation was not investigated.…”

Low expression of miR-29a is associated with aggressive biology and worse survival in gastric cancer

“…Metastasis contributes to the higher mortality of GC patients. One of the key signaling pathways that promotes metastasis is the Wnt/β-catenin pathway 10 . This pathway is regulated by several miRNAs in GC, such as miR-204 11 and miR-491-5p 12 .…”