The EGF/hnRNP Q1 axis is involved in tumorigenesis via the regulation of cell cycle-related genes

Yu-Chu Wang,Chien-Hsien Lai,Chang-Shen Lin,Bo-Wen Lin,Peng-Chan Lin,Yun Yen,Jenq-Chang Lee,Shiang-Jie Yang,Kung-Chao Chang,Chung-Ta Lee,Liang-Yi Hung,Li-Jyuan Lin

doi:10.1038/s12276-018-0101-6

Abstract

Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) enhances both binding between hnRNP Q1 and Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. In addition, we show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and the SAC genes in human colorectal cancer tissues. In summary, our data suggest that hnRNP Q1 plays an important role in regulating the expression of a group of cell cycle-related genes. Therefore, it may contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.

Highlights

Genetic instability is a major event in the tumorigenesis of various cancers, including colorectal cancer
We demonstrate that Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1 acts as a trans-acting factor to up-regulate Aurora-A expression, and epidermal growth factor (EGF) enhances the hnRNP Q1-induced translational efficacy of Aurora-A mRNA. hnRNP Q1induced Aurora-A mRNA translation might be mediated by the mTOR and ERK pathways
The results showed that hnRNP Q1 and EGF each increases the protein level of Aurora-A and that treating cells with both EGF and hnRNP Q1 result in a synergistic effect on Aurora-A expression

Summary

Introduction

Genetic instability is a major event in the tumorigenesis of various cancers, including colorectal cancer. To maintain genome integrity and fidelity, it is important that cells regulate the expression of proteins involved in the cell cycle checkpoint mechanism, as well as control chromosome replication and separation during cell division[1]. Overexpression of Aurora-A has been found in many cancer cells, including breast, colon, pancreas, liver, and stomach cancer[3]. The deregulation of Aurora-A kinase may result in chromosomal instability, indicating a link with tumorigenesis[4]. Previous studies have suggested that the overexpression of Aurora-A in cancers may result from gene amplification[6,7], transcriptional up-regulation[8,9] or enhanced protein stability[10,11]. The mechanism by which EGF mediates the translational up-regulation of Aurora-A expression and the translational regulatory factors that

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Results

Conclusion