BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: a potential target for gene therapy

// Hua-chuan Zheng 1 , Jing Li 2 , Dao-fu Shen 1 , Xue-feng Yang 1 , Shuang Zhao 1 , Ya-zhou Wu 1 , Yasuo Takano 3 , Hong-zhi Sun 1 , Rong-jian Su 4 , Jun-sheng Luo 1 , Wen-feng Gou 1 1 Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China 2 Department of Gastroenterology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China 3 School of Health Science, Tokyo University of Technology, Ohta-ku, Tokyo, Japan 4 Experimental Center, Liaoning Medical University, Jinzhou, China Correspondence to: Wen-feng Gou, e-mail: xiaogouaeiou@163.com Keywords: gastric cancer, BTG1, pathobiological behaviors, carcinogenesis, gene therapy Received: March 11, 2015      Accepted: May 23, 2015      Published: June 05, 2015 ABSTRACT Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G 2 /M arrest, differentiation, senescence and apoptosis in BGC-823 and MKN28 cells ( p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax , but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock ( p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners ( p < 0.05) with the hypoexpression of chemoresistance-related genes ( slug , CD147 , GRP78 , GRP94 , FBXW7 TOP1 , TOP2 and GST-π ). BTG1 expression was restored after 5-aza-2′-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node ( p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis ( p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones ( p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.