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Signal Transducers and Activators of Transcription 3 Activation Is Involved in Nuclear Accumulation of ß-Catenin in Colorectal Cancer

Departments of ¹ Gastroenterology and Hepatology and ² Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

Requests for reprints: Hiroshi Seno, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Japan, 54 Shogoin-Kawara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. Phone: 81-75-751-4319; Fax: 81-75-751-4303; E-mail: seno{at}kuhp.kyoto-u.ac.jp.

Nuclear accumulation of ß-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of ß-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 ß-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 ß-catenin. The nuclear staining of both p-STAT3 and ß-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 ß-catenin staining and there was a significant correlation between p-STAT3 and ß-catenin nuclear staining (P < 0.01). Coexpression of nuclear p-STAT3 and ß-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 ß-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of ß-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 ß-catenin, resulting in poor patient survival. (Cancer Res 2006; 66(6): 2913-7)

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