RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization.
Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.
Ito
Kosei
K
Institute of Molecular and Cell Biology, Proteos, Singapore.
Liu
Qiang
Q
Salto-Tellez
Manuel
M
Yano
Takashi
T
Tada
Kotaro
K
Ida
Hiroshi
H
Huang
Canhua
C
Shah
Nilesh
N
Inoue
Masafumi
M
Rajnakova
Andrea
A
Hiong
Kum Chew
KC
Peh
Bee Keow
BK
Han
Hwan Chour
HC
Ito
Tomoko
T
Teh
Ming
M
Yeoh
Khay Guan
KG
Ito
Yoshiaki
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D000918:Antibody Specificity; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D050677:Core Binding Factor Alpha 3 Subunit; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; D014157:Transcription Factors