The role of adrenomedullin in the pathogenesis of gastric cancer

// Fuhao Qiao 1, 2 , Jian Fang 1 , Jinfeng Xu 1 , Wenqiu Zhao 1 , Ying Ni 1 , Bufugdi Andreas Akuo 1 , Wei Zhang 1 , Yun Liu 1 , Fangfang Ding 1 , Guanlin Li 3 , Baoguo Liu 4 , Hua Wang 1 and Shihe Shao 1 1 School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China 2 Medical Laboratory, Xintai Hospital of Traditional Chinese Medicine, Xintai 271200, Shandong, PR China 3 School of The Environment and Safety Engineering, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China 4 Nuclear Medicine Laboratory, Taian Jiangong Hospital, Taian 271001, Shandong, PR China Correspondence to: Hua Wang, email: wangjiahan1979@163.com Shihe Shao, email: shaoshihe2006@163.com Keywords: adrenomedullin, autophagy, gastric cancer, RNA interference, signaling pathway Received: August 27, 2016      Accepted: June 13, 2017      Published: June 29, 2017 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.