The role of adrenomedullin in the pathogenesis of gastric cancer.

Fuhao Qiao,Jinfeng Xu,Shihe Shao,Bufugdi Andreas Akuo,Guanlin Li,Ying Ni,Yun Liu,Jian Fang,Baoguo Liu,Wei Zhang,Wenqiu Zhao,Hua Wang,Fangfang Ding

doi:10.18632/oncotarget.18881

Abstract

Adrenomedullin has been shown to be overexpressed in many tumors, including gastric cancer tumors; however, its mechanism of action remains unclear. In this study, we examined the role of adrenomedullin in the pathogenesis of gastric cancer. Using clinical specimens and immunohistochemistry, we found that the expression levels of adrenomedullin and its receptors are inordinately elevated as compared to the adjacent non-tumor gastric tissues. We used siRNA gene silencing, in BGC-823 gastric cancer cell lines, to target adrenomedullin genes, and found that increased adrenomedullin expression results in the proliferation of tumor cells, tumor invasion, and metastasis. Furthermore, we found that under hypoxic conditions, gastric cancer BGC-823 cells exhibit higher expression levels of adrenomedullin and various other related proteins. Our results indicate the involvement of adrenomedullin in microvessel proliferation and partially in the release of hypoxia in solid tumors. Knockdown of adrenomedullin expression, at the protein level, reduced the levels of phosphoprotein kinase B and B-cell lymphoma 2 but increased the levels of cleaved-caspase3 and Bcl 2 associated x protein (Bax). Therefore, we hypothesized siRNA targeting of adrenomedullin genes inhibits various serine/threonine kinases via a signaling pathway that induces cell apoptosis. SiRNA targeting of adrenomedullin genes and green fluorescent control vectors were used to transfect BGC-823 cells, and western blot analyses were used to detect changes in the rates of autophagy in related proteins using confocal laser scanning microscopy. No significant changes were detected. Therefore, the knockdown of adrenomedullin and its receptors may represent a novel treatment strategy for gastric cancer.

Highlights

Andrenomedullin (AM) is a ubiquitous peptide, expressed throughout the body, that can cause pheochromocytoma [1]
Using clinical specimens and immunohistochemistry, we found that the expression levels of adrenomedullin and its receptors are inordinately elevated as compared to the adjacent non-tumor gastric tissues
That in 65% of the gastric cancer samples examined, AM protein levels were elevated as compared to the adjacent, non-tumor gastric tissues (Figure 1A)

Summary

Introduction

Andrenomedullin (AM) is a ubiquitous peptide, expressed throughout the body, that can cause pheochromocytoma [1]. Gastric carcinoma is the most common type of malignant cancer after lung and liver cancer, and it is the third leading cause of cancer death worldwide [2, 3]. Many www.impactjournals.com/oncotarget studies have shown that the level of AM is significantly elevated in various cancerous tumors, including osteosarcomas [10], pancreatic adenocarcinomas [11], and plexiform neurofibromas [12]. AM plays a role in gastric mucosal defense and repair [14, 15]. In endometrial cancer tissues and chromophobe renal carcinomas, AM mRNA levels have been shown to be elevated, whereas protein expression levels were attenuated [16, 17], indicating a putative, complex posttranscriptional regulatory network. We examined the role of AM in gastric cancer, and analyzed its localization and relationship to the pathogenesis of gastric cancer in clinical samples

Methods

Results

Conclusion