Zhenni Sun¹, Zan Shen², Yong Li¹, Tianjun Li¹, Ruyong Yao³, Lu Yue¹

¹Oncology, the Affiliated Hospital of Qingdao University, ²Medical College of Shanghai Jiao Tong University, The Sixth People’s Hospital, ³Center for Medical Research, the Affiliated Hospital of Qingdao University

Objective:Nucleophosmin (NPM) and human epidermal growth factor receptor 2(Her-2) are abnormally expressed in various kinds of human malignant tumors including gastric cancer and closely related with the chemoresistance of cancer. However, their interaction and function in oxaliplatin resistance are not fully understood. Herein, we elucidated the relationship between NPM and Her-2 in gastric cancer cell lines as well as clinical samples and further investigated their role in oxaliplatin resistance of gastric cancer. Method: We examined the expression of NPM and Her-2 in 133 postoperational gastric cancer tissues and 6 gastric cell lines by immunohistochemistry, western blot and qRT-PCR analysis respectively. Then we altered the expresssion of NPM and Her-2 in gastric cancer cells by plasmid transfection and western blot was performed to detect the expression level of protein. Drug sensitivity of gastric cancer cells with different expression level in NPM and Her-2 was carried out using CCK-8. Result: Our study demonstrated that the level of NPM and Her-2 expression was significantly higher in gastric cancer than in para-cancer tissues (P<0.001) and normal gastric cell lines, while a strong association was found between them. The expression of NPM changed correspondingly with the regulation of Her-2. On the contrary, when we down- or up-regulated NPM expression in gastric cancer cells, the Her-2 expression was not affected. CCK8 assay data showed that the cell sensitivity to oxaliplatin decreased along with the increase of NPM expression. Moreover, inhibition of Her-2 expression with trastuzumab significantly increased the sensitivity of the cells to oxaliplatin treatment, simultaneously with the down-regulation of NPM. Conclusion: Our results indicated that inhibition of NPM, as a Her-2 downstream signal, may be a novel therapeutic strategy in oxaliplatin resistance. Trastuzumab and oxaliplatin can exhibit a synergistic antitumor effect in Her-2-postive gastric cancer cells.

Key Words: Nucleophosmin (NPM)  epidermal growth factor  receptor 2