Prognostic value of decreased expression of RBM4 in human gastric cancer.

Hongmei Yong,Hongmei Yong,Hongmei Yong,Huaidong Liu,Huaidong Liu,Jinbo Wen,Yongjie Zhang,Yongjie Zhang,Xing Kang,Huijun Zhu,Huijun Zhu,Jin Zhu,Jin Zhu,Baorui Liu,Wei Wang,Wei Wang,Chen Chen,Chen Chen,Lun Zhu,Wei Zhao,Ziyuan Zhu,Ziyuan Zhu,Guipeng Ding,Shu Zhang,Shu Zhang,Zhenqing Feng

doi:10.1038/srep28222

Abstract

RNA-binding motif 4 (RBM4) is a multifunctional protein that participates in regulating alternative splicing and mRNA translation. Its reduced expression has been associated with poor overall survival in lung cancer, breast cancer and ovarian cancer. We assessed RBM4 protein expression levels with immunohistochemistry in tissue microarrays containing malignant gastric cancer tissues and benign tissues from 813 patients. We also examined the expression levels of RBM4 mRNA in twenty-five paired gastric cancer samples and adjacent noncancerous tissues. Both RBM4 protein and mRNA expression levels were significantly lower in gastric cancer tissues compared with the adjacent noncancerous tissues. There was a significant association between reduced RBM4 protein expression and differentiation (P < 0.001), lymph node metastasis (P = 0.026), TNM state (P = 0.014) and distant metastasis (P = 0.036). Patients with reduced RBM4 expression (P < 0.001, CI = 0.315–0.710) and TNM stage III and IV (P < 0.001, CI = 4.757–11.166) had a poor overall survival. These findings suggest that RBM4 is a new biomarker in gastric cancer, as the reduced expression of this protein is correlated with poor differentiation, lymph node status and distant metastasis. Further, lower RBM4 expression is an independent prognostic marker for gastric cancer.

Highlights

Mouse ortholog and 53% homology with the Xenopus homolog
The results showed that 19 primary gastric cancer samples had substantially reduced RBM4 expression levels on mRNA compared with the paired adjacent noncancerous tissues, with an average downregulation fold of 0.643 (P < 0.001) (Fig. 1)
Using tissue microarray (TMA), we analyzed RBM4 protein expression in 813 (94.4%) of the 861 samples in the TMA, The remaining samples were lost during antigen retrieval or there were no tumor tissues found in the core

Summary

Introduction

Mouse ortholog and 53% homology with the Xenopus homolog. Two RNA recognition motifs (RRMs) and a CCHC-type zinc finger in the N-terminal region have been found in RBM4, whereas a low-complexity region is located in the C-terminal that can interact with other proteins[11]. RBM4 is a multifunctional protein that participates at least in modulating alternative splicing and mRNA translation[12,13]. RBM4 can regulate exon selection and alternative splicing in both in vivo and in vitro splicing models[14,15]. RBM4 has been shown to regulate translation, under cell stress by interacting directly with argonaute 216, inhibiting cap-dependent translation[13], mediating an oxygen-regulated translation switch[11] or activating internal ribosomal entry site-mediated translation[17]. RBM4 is able to selectively associate with specific microRNAs in muscle cells and repress their translation activity by promoting micro-ribonucleoprotein connection with target mRNAs18. Overexpression of RBM4 promotes differentiation of pancreas and muscle cells[19,20]. The association of RBM4 expression with clinicopathologic characteristics and overall survival (OS) was evaluated as well

Methods

Results

Conclusion