Epigenetic inactivation and tumor suppressor activity of HAI-2/SPINT2 in gastric cancer

被引：47
作者：
Dong, Wenjie
Chen, Xiaobing [2 ]
Xie, Jing [3 ]
Sun, Pinghu
Wu, Yunlin [1 ]
机构：
[1] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Dept Gastroenterol, Shanghai 200025, Peoples R China
[2] Henan Tumor Hosp, Dept Med Oncol, Zhengzhou, Peoples R China
[3] Shanghai Jiao Tong Univ, Dept Pathol, Rui Jin Hosp, Shanghai 200025, Peoples R China
来源：
INTERNATIONAL JOURNAL OF CANCER | 2010年 / 127卷 / 07期
关键词：
gastric cancer; methylation; HAI-2/SPINT2; HEPATOCYTE GROWTH-FACTOR; FACTOR ACTIVATOR INHIBITOR; RENAL-CELL CARCINOMA; HUMAN BREAST-CANCER; C-MET; OVARIAN-CANCER; PROTEASE INHIBITOR; BIKUNIN HAI-2/PB; MOUSE MODEL; EXPRESSION;
D O I：
10.1002/ijc.25161
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Hepatocyte growth factor (HGF) activator inhibitor type 2 (HAI-2/SPINT2) encodes Kunitz-type protease inhibitor that regulates HGF activity. Inspection of the human HAI-2/SPINT2 locus uncovered a large and dense CpG island within the 5' region of this gene. Analysis of cultured human gastric tumor lines indicated that HAI-2/SPINT2 expression is either undetectable or in low abundance in several lines; however, enhanced gene expression was measured in cells cultured on the DNA demethylating agent 5-aza-2'-deoxycytidine. Bisulfite DNA sequencing confirmed the densely methylated HAI-2/SPINT2 promoter region. Forced expression of HAI-2/SPINT2 induced cell apoptosis, suppressed anchorage independent growth in vitro and tumor growth in vivo. We investigated HAI-2/SPINT2 aberrant methylation in patients with gastric cancer. The HAI-2/SPINT2 methylation was found preferentially in cancerous tissues (30 of 40, 75%) compared with nontumor tissues (no methylation was detected), indicating that this aberrant characteristic is common in gastric malignancies. In conclusion, epigenetic inactivation of HAI-2/SPINT2 is a common event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.
引用
收藏
页码：1526 / 1534
页数：9
相关论文
共 50 条
[31]   RAI2 acts as a tumor suppressor with functional significance in gastric cancer [J].
Lou, Xiaoli ;
Deng, Wei ;
Shuai, Lixiong ;
Chen, Yijing ;
Xu, Mengmeng ;
Xu, Jingze ;
Zhang, Yongsheng ;
Wu, Yongyou ;
Cao, Zhifei .
AGING-US, 2023, 15 (21) :11831-11844
[32]   Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients [J].
Li, X. ;
Cheung, K. F. ;
Ma, X. ;
Tian, L. ;
Zhao, J. ;
Go, M. Y. Y. ;
Shen, B. ;
Cheng, A. S. L. ;
Ying, J. ;
Tao, Q. ;
Sung, J. J. Y. ;
Kung, H-F ;
Yu, J. .
ONCOGENE, 2012, 31 (29) :3419-3430
[33]   Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation [J].
Szabo, Roman ;
Sales, Katiuchia Uzzun ;
Kosa, Peter ;
Shylo, Natalia A. ;
Godiksen, Sine ;
Hansen, Karina K. ;
Friis, Stine ;
Gutkind, J. Silvio ;
Vogel, Lotte K. ;
Hummler, Edith ;
Camerer, Eric ;
Bugge, Thomas H. .
PLOS GENETICS, 2012, 8 (08)
[34]   MicroRNA-212 functions as an epigenetic-silenced tumor suppressor involving in tumor metastasis and invasion of gastric cancer through down-regulating PXN expression [J].
Li, Daojiang ;
Li, Zhengrong ;
Xiong, Jianbo ;
Gong, Binbin ;
Zhang, Guoyang ;
Cao, Chao ;
Jie, Zhigang ;
Liu, Yi ;
Cao, Yi ;
Yan, Yufeng ;
Xiong, Hong ;
Qiu, Lingyu ;
Yang, Miantian ;
Chen, Hongping ;
Jiang, Shuping ;
Yang, Xiongwen ;
Chen, Heping .
AMERICAN JOURNAL OF CANCER RESEARCH, 2015, 5 (10) :2980-+
[35]   Differential subcellular distribution renders HAI-2 a less effective protease inhibitor than HAI-1 in the control of extracellular matriptase proteolytic activity [J].
Chiu, Yi-Lin ;
Wu, Yi-Ying ;
Barndt, Robert B. ;
Lin, Yu-Wen ;
Sytwo, Hou-Ping ;
Cheng, Amy ;
Yang, Kacy ;
Chan, Khee-Siang ;
Wang, Jehng-Kang ;
Johnson, Michael D. ;
Lin, Chen-Yong .
GENES & DISEASES, 2022, 9 (04) :1049-1061
[36]   Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines [J].
K Terasawa ;
M Toyota ;
S Sagae ;
K Ogi ;
H Suzuki ;
T Sonoda ;
K Akino ;
R Maruyama ;
N Nishikawa ;
K Imai ;
Y Shinomura ;
T Saito ;
T Tokino .
British Journal of Cancer, 2006, 94 :914-921
[37]   Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines [J].
Terasawa, K ;
Toyota, M ;
Sagae, S ;
Ogi, K ;
Suzuki, H ;
Sonoda, T ;
Akino, K ;
Maruyama, R ;
Nishikawa, N ;
Imai, K ;
Shinomura, Y ;
Saito, T ;
Tokino, T .
BRITISH JOURNAL OF CANCER, 2006, 94 (06) :914-921
[38]   Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer [J].
Wu, Chi-Sheng ;
Lu, Yen-Jung ;
Li, Hsin-Pai ;
Hsueh, Chuen ;
Lu, Chang-Yi ;
Leu, Yu-Wei ;
Liu, Hao-Ping ;
Lin, Kwang-Huei ;
Huang, Tim Hui-Ming ;
Chang, Yu-Sun .
INTERNATIONAL JOURNAL OF CANCER, 2010, 126 (11) :2542-2552
[39]   Hypoexpression and Epigenetic Regulation of Candidate Tumor Suppressor Gene CADM-2 in Human Prostate Cancer [J].
Chang, Guimin ;
Xu, Shuping ;
Dhir, Rajiv ;
Chandran, Uma ;
O'Keefe, Denise S. ;
Greenberg, Norman M. ;
Gingrich, Jeffrey R. .
CLINICAL CANCER RESEARCH, 2010, 16 (22) :5390-5401
[40]   ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer [J].
Ozturk, Harun ;
Cingoz, Harun ;
Tufan, Turan ;
Yang, Jiekun ;
Adair, Sara J. ;
Tummala, Krishna Seshu ;
Kuscu, Cem ;
Kinali, Meric ;
Comertpay, Gamze ;
Nagdas, Sarbajeet ;
Goudreau, Bernadette J. ;
Luleyap, Husnu Umit ;
Bingul, Yagmur ;
Ware, Timothy B. ;
Hwang, Wiliam L. ;
Hsu, Ku-lung ;
Kashatus, David F. ;
Ting, David T. ;
Chandel, Navdeep S. ;
Bardeesy, Nabeel ;
Bauer, Todd W. ;
Adli, Mazhar .
DEVELOPMENTAL CELL, 2022, 57 (11) :1331-+
12345