EIF5A regulates proliferation and chemoresistance in pancreatic cancer through the sHH signalling pathway.

Tao Qin,Jie Jiang,Ying Xiao,Zheng Wang,Liang Han

doi:10.1111/jcmm.14167

Abstract

BackgroundPancreatic cancer (PC) has a very poor prognosis and comparatively short survival. Eukaryotic translation initiation factor 5A (EIF5A) promotes cancer metastasis. Here, we exploited the biological role of EIF5A in PC chemoresistance.MethodsExpression of EIF5A was analysed in PC cells and tissues by real‐time PCR, Western blotting, immunohistochemistry and immunofluorescent. EIF5A expression was specifically suppressed by transfection, and subsequently the alterations of growth behaviour and resistance to anticancer treatment were tested in an orthotopic tumour model.ResultsThe results showed EIF5A was increased in human PC tissues and PC cells. We found EIF5A knockdown reduced the PC proliferation ability in vivo and in vitro. In addition, sonic hedgehog (sHH) signalling pathway may be a downstream of EIF5A in PC cells. Inhibition of EIF5A and sHH signalling pathway could suppress PC cells proliferation and tumour growth. Importantly, EIF5A played an important role in gemcitabine sensitivity for PC.ConclusionTaken together, our results revealed that EIF5A regulated the proliferation of PC through the sHH signalling pathway and decreased the Gem sensitivity in PC, which provided a novel therapeutic strategy for PC patients.

Highlights

Pancreatic cancer (PC), one of the most lethal and aggressive cancers, has a very poor prognosis and comparatively short survival.[1,2] Most PC patients are diagnosed at advanced tumour stages partly ascribed to the tumour rapid progression.[3]
Resection is a unique method for complete cure of PC, it is unusable in most patients due to poor prognosis, late diagnosis and early metastasis.[4]
To determine whether sonic hedgehog (sHH) signalling pathway is the downstream effector of Eukaryotic translation initiation factor 5A (EIF5A) in PC cell proliferation, firstly, we investigated whether the EIF5A knockdown can decrease the protein expression of sHH signalling factors in different PC cell lines (Figure 4A and B)

Summary

| INTRODUCTION

Pancreatic cancer (PC), one of the most lethal and aggressive cancers, has a very poor prognosis and comparatively short survival.[1,2] Most PC patients are diagnosed at advanced tumour stages partly ascribed to the tumour rapid progression.[3]. Gemcitabine (Gem) is the most effective chemotherapeutic treatment against PC, unfor‐ tunately, Gem was not fully effective on each PC patient because of the resistance to chemotherapy.[5,6]. Overexpression of EIF5A promotes PC cells metastasis.[10]. The sHH signalling pathway contributes to can‐ cer cell proliferation, differentiation, metastasis and chemotherapy resistance.[12,13]. Gem, which is a successful compound, frequently is used in PC treatment This drug is effective, its cytotoxic effects and drug resistance limit its application.[14,15]. The sHH signalling pathway was partly involved in the resistance of PC cells to Gem.[12]. The objective of this study was to exploit the relationship and molecular mechanisms between EIF5A expression and the activation of sHH signalling pathway in PC. We attempted to investigate the biological role of EIF5A in PC chemoresistance in vivo and in vitro

| MATERIALS AND METHODS

Findings

| DISCUSSION