IMP1 suppresses breast tumor growth and metastasis through the regulation of its target mRNAs.

Guangli Wang,Shaoying Chen,Wei Gu,Zhenqiang Huang,Wenhe Huang,Robert H. Singer,Xin Liu,Deling Li,Yanchun Zhou

doi:10.18632/oncotarget.7464

Abstract

We have previously reported the ability of IMP1 in inhibiting proliferation and invasiveness of breast carcinoma cells in vitro. In the current study, we utilized a mouse xenograft model to further investigate the function of IMP1 in breast tumor progression and its underlying mechanism. We demonstrated that IMP1 expression significantly suppressed the growth of MDA231 cell-derived xenograft tumors and subsequent lung metastasis. Microarray analyses and differential gene expression identified handful mRNAs, many of which were involved in breast tumor-growth and metastasis. Further studies revealed that these mRNAs were directly interacted with the KH34 domain of IMP1 and this interaction post-transcriptionally regulated their corresponding protein expression. Either deletion of the KH34 domain of IMP1 or alteration of the expression of IMP1-bound mRNAs affected cell proliferation and tumor growth, producing the same phenotypes as IMP1 knockdown. Correlation of increased IMP1 expression with the reduced levels of its bound mRNAs, such as PTGS2, GDF15 and IGF-2 transcripts, was also observed in human breast tumors. Our studies provide insights into a molecular mechanism that the positive function of IMP1 to inhibit breast tumor growth and metastasis could be through the regulation of its target mRNAs.

Highlights

Breast cancer is the most common cancer diagnosed and the second leading cause of cancer deaths in women [1]
Previous studies indicated that gain of IMP1 function in human metastatic MDA231 cells, which essentially lack IMP1 expression, increased cell polarity and attenuated invasive ability [7]
A statistical analysis of the tumor volumes in two xenograft groups showed that the average volume of tumors that formed in mice injected with MDA231/GFP-IMP1 cells was about half of those injected with MDA231/GFP cells (Figure 1C, P < 0.01)

Summary

Introduction

Breast cancer is the most common cancer diagnosed and the second leading cause of cancer deaths in women [1]. In a variety of cell types, IMP1 regulates the localization of β-actin mRNA, resulting in the asymmetric translation of β-actin protein and enhances cell polarity [5]. The human IMP1 was originally identified as a translational repressor of mRNA encoding insulin-like growth factor 2 (IGF-2), but has since been found to involve in the localization of many other mRNAs, including H19, tau, CD44, β-catenin and E-cadherin mRNAs [4, 7]. Local translation of β-actin, CD44 or E-cadherin mRNA mediated by IMP1 has been shown to involve in actin dynamics, invadopodia formation and cell-cell adhesions. Loss of IMP1 function deregulates mRNAs normally associated with the protein and alters many important cellular processes, such as cell polarity and migration [7,8,9]

Methods

Results

Conclusion