Over-expression of BAG-1 in head and neck squamous cell carcinomas (HNSCC) is associated with cisplatin-resistance

Shutong Liu,Xue-Jin Su,Suchan Liao,Yulin Li,Zhixiang Xu,Bo Ren,Ying-Xian Zhai,Qinghua Zeng,Ping Jin,Shirong Li,David Stroncek,Hang Gao

doi:10.1186/s12967-017-1289-2

Abstract

BackgroundIn order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression.MethodsPrimary and advanced (relapsed from parental) University of Michigan squamous cell carcinoma cell lines were tested for sensitivity to cisplatin and gene expression profiles were compared between primary (cisplatin sensitive) and the relapsed (cisplatin resistant) cell lines by using Agilent microarrays. Additionally, differentially expressed genes phosphorylated AKT, and BAG-1, and BCL-xL were evaluated for expression using HNSCC tissue arrays.ResultsAdvanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phosphorylated AKT, BAG-1, and BCL-xL were observed in advanced HNSCC compared to in that of primary HNSCC.ConclusionIncreased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance.

Highlights

In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associ‐ ated with local and/or distant tumor relapses and cancer drug resistance are urgently needed
University of Michigan Squamous Cell Carcinoma (UMSCC) cells response to cisplatin In order to study cisplatin resistance in head and neck cancer, we screened a panel of UMSCC cell lines
We evaluated the effects of cisplatin on the same cells and found that clonogenic survival after treatment with cisplatin was markedly different between primary UMSCC cells 14A and 17A and advanced UMSCC cells 14B and 17B

Summary

Introduction

In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associ‐ ated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. Head and neck squamous cell carcinomas (HNSCC) are the fifth most common non-skin cancer worldwide and the third most common cancer in developing countries [1, 2]. B-cell lymphoma 2-associated athanogene-1 (BAG-1), is a multifunctional protein that regulates a variety of cellular processes: proliferation, cell survival, transcription, apoptosis, and motility [12]. Well-known interacting partners of BAG-1 isoforms are, BCL-2, Raf-1, Hsc70/ Hsp system, nuclear hormone receptors (NHR), ubiquitin/proteasome machinery and DNA [14]

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