Heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by increasing protein translation of selected transcripts in cancer cells

Elizabeth T Chang,Palak R Parekh,Qingyuan Yang,Duc M Nguyen,France Carrier

doi:10.18632/oncotarget.7020

Abstract

The heterogenous ribonucleoprotein A18 (hnRNP A18) promotes tumor growth by coordinating the translation of selected transcripts associated with proliferation and survival. hnRNP A18 binds to and stabilizes the transcripts of pro-survival genes harboring its RNA signature motif in their 3′UTRs. hnRNP A18 binds to ATR, RPA, TRX, HIF-1α and several protein translation factor mRNAs on polysomes and increases de novo protein translation under cellular stress. Most importantly, down regulation of hnRNP A18 decreases proliferation, invasion and migration in addition to significantly reducing tumor growth in two mouse xenograft models, melanoma and breast cancer. Moreover, tissue microarrays performed on human melanoma, prostate, breast and colon cancer indicate that hnRNP A18 is over expressed in 40 to 60% of these malignant tissue as compared to normal adjacent tissue. Immunohistochemistry data indicate that hnRNP A18 is over expressed in the stroma and hypoxic areas of human tumors. These data thus indicate that hnRNP A18 can promote tumor growth in in vivo models by coordinating the translation of pro-survival transcripts to support the demands of proliferating cells and increase survival under cellular stress. hnRNP A18 therefore represents a new target to selectively inhibit protein translation in tumor cells.

Highlights

HnRNP A18 is a RNA-binding protein that was first identified as a UV-inducible transcript in CHO cells more than two decades ago [1]
Given that hnRNP A18 was originally cloned on the basis of UV induction [1] and that it can confer resistance to UV-induced cellular death [5], we wanted to investigate whether hnRNP A18 could be involved in the UVinduced skin cancer melanoma
Because hnRNP A18 can translocate from the nucleus to the cytosol in response to the hypoxia mimetic agent CoCl2 [6] and that fifty to sixty percent of locally advanced solid tumors, including melanoma, develop hypoxic areas, we investigated whether hypoxic conditions could affect hnRNP A18 levels

Summary

Introduction

HnRNP A18 is a RNA-binding protein that was first identified as a UV-inducible transcript in CHO cells more than two decades ago [1]. The hnRNP A18 protein has been characterized in human cells [2] and in mouse following exposure to mild cold shock. HnRNP A18 is known as CIRP for Cold Inducible RNA Binding Protein [3]. Three hnRNP A18/ CIRP mRNA transcripts, differing mainly in the size of their 5’UTRs, have been described [4]. Immunohistochemistry staining of a variety of tumors from 193 patients indicate that hnRNP A18 is up-regulated in about 30% of human tumors as compared to normal tissue from the same patients [7]. Correlation with tumor grades or its potential tumor promoting activity in in vivo models has not been investigated so far

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Results

Conclusion