Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-catenin in colorectal cancer.
Nuclear accumulation of beta-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of beta-catenin from the cytoplasm or the membrane to the nucleus. The present study examined whether signal transducers and activators of transcription 3 (STAT3) activation is involved in the nuclear accumulation of beta-catenin in colorectal cancer cells. Of the 90 primary colorectal cancer tissues, 40 (44.4%) were positive for nuclear staining of p-STAT3 and 63 (70.0%) were positive for nuclear staining of beta-catenin. The nuclear staining of both p-STAT3 and beta-catenin were observed predominantly in the periphery of the cancer tissues. Importantly, of the 40 tumors with p-STAT3 nuclear staining, 37 (92.5%) were also positive for nuclear beta-catenin staining and there was a significant correlation between p-STAT3 and beta-catenin nuclear staining (P < 0.01). Coexpression of nuclear p-STAT3 and beta-catenin was associated with lower patient survival (P < 0.01). In an in vitro study using a human colon cancer cell line, SW480, inhibition of STAT3 by dominant negative STAT3 or the Janus kinase inhibitor, AG490, induced translocation of beta-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of beta-catenin/T-cell factor transcription in association with significant inhibition of cell proliferation (P < 0.05). These findings suggest that in colorectal cancer, STAT3 activation is involved in the nuclear accumulation of beta-catenin, resulting in poor patient survival.
Department of Gastroenterology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mayumi
M
Kawada
Hiroshi
H
Seno
Yoshito
Y
Uenoyama
Tateo
T
Sawabu
Naoki
N
Kanda
Hirokazu
H
Fukui
Yasuyuki
Y
Shimahara
Tsutomu
T
Chiba
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051176:beta Catenin