Phosphorylation of intestine-specific homeobox by ERK1 modulates oncogenic activity and sorafenib resistance

Li Ting Wang, Kwei Yan Liu, Shyh Shin Chiou, Shau Ku Huang, Shih Hsien Hsu*, Shen Nien Wang

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

摘要

Nuclear translocation regulated by phosphorylation is a key step in providing activated mitogen-activated protein kinases (MAPKs) access to their nuclear targets; however, the mechanisms linking MAPK-induced nuclear translocation and target gene expression mediating oncologic activity remain obscure. Here, we show that the MAPK extracellular signal-regulated kinase (ERK) 1, but not ERK2, phosphorylated intestine-specific homeobox (ISX), leading to its nuclear translocation and downstream oncogenic signaling. Mechanistically, ERK1 phosphorylated serine 183 of ISX, facilitating its nuclear translocation and downstream target gene expression. In contrast, dominant-negative ERK1 expression in hepatoma cells inhibited the nuclear translocation of ISX and the expression of downstream genes involved in cell proliferation, malignant transformation, and epithelial-mesenchymal transition in vitro and in vivo. An activating mutation in ISX (S183D) exhibited a constitutive nuclear localization and resistance to sorafenib. Additionally, in 576 paired clinical hepatocellular carcinoma (HCC) samples and adjacent normal tissues, ERK1 and ISX were co-expressed in a tumor-specific manner at mRNA and protein levels, while their mRNA levels showed significant correlation with survival duration, tumor size, number, and stage. These results highlight the significance of ERK1/ISX signaling in HCC progression and its potential as a prognostic and therapeutic target in HCC.

原文英語
頁(從 - 到)160-171
頁數12
期刊Cancer Letters
520
DOIs
出版狀態已發佈 - 2021 十一月 1

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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