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Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX-2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60–90 % of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer.

Material and Methods

Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX-2), LeY, gastric markers (CA724 and GRN) in gastric patient’s tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA.

Results

We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R—0.552), LeY (R—0.861), CA724 (R—0.714) and GRN (R—0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01).

Conclusions

Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy.

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Abbreviations

CagA:

Cytotoxin-associated antigen

COX-2:

Cyclo-oxygenase-2

ELISA:

Enzyme-linked immunosorbent assay

ERK1/2:

Extracellular signal-regulated kinases

FUTs:

Fucosyltransferases

GRN:

Granulin

H. pylori :

Helicobacter pylori

HSP:

Heat shock protein

ICC:

Immunocytochemistry

IFC:

Immunofluorescence

IHC:

Immunohistochemistry

LeY:

Lewis Y

MAPKs:

Mitogen-activated protein kinases

PCNA:

Proliferation cell nuclear antigen

RT-PCR:

Reverse transcription polymerase chain reaction

UreA:

Urease A

UreB:

Urease B

VacA:

Vacuolating cytotoxin A

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Acknowledgments

The project was supported by the China 973 Grant No. 2012CB822100, National Natural Science Foundation of China Research Grant Nos. 30672753 and 31270866.

Conflict of interests

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian, 116044, People’s Republic of China

    Faisal Aziz, Xuesong Yang & Qiu Yan

  2. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Xiaoqi Wang

Authors
  1. Faisal Aziz
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  2. Xuesong Yang
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  3. Xiaoqi Wang
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  4. Qiu Yan
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Correspondence to Qiu Yan.

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Aziz, F., Yang, X., Wang, X. et al. Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study. J Cancer Res Clin Oncol 141, 1221–1235 (2015). https://doi.org/10.1007/s00432-014-1892-z

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