Epigenetic inactivation and tumor suppressor activity of HAI-2/SPINT2 in gastric cancer.
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.
Dong
Wenjie
W
Department of Gastroenterology, Rui-jin Hospital, Shanghai Jiao Tong University, Shanghai, China.
Chen
Xiaobing
X
Xie
Jing
J
Sun
Pinghu
P
Wu
Yunlin
Y
D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D017931:DNA Primers; D005753:Gastric Mucosa / Q000473:pathology; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D013489:Suppression, Genetic
D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C109148:SPINT2 protein, human