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Expression of Phosphorylated Ser⁷⁰ of Bcl-2 Correlates with Malignancy in Human Colorectal Neoplasms

Authors' Affiliations: Departments of ¹ Pathology and ² Gastroenterological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; ³ Ina Institute, Medical and Biological Laboratories Co., Ltd., Nagoya, Japan; ⁴ Division of Pathology, Central Clinical Laboratory, Iwate Medical University, Morioka, Japan; and ⁵ Department of Cellular Physiology, Tokyo Metropolitan Institute of Medicine, Tokyo, Japan

Requests for reprints: Eisaku Kondo, Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7152; Fax: 81-86-235-7156; E-mail: ekondo{at}md.okayama-u.ac.jp.

Purpose: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser⁷⁰ to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser⁷⁰ of Bcl-2 (pSer⁷⁰) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer⁷⁰ Bcl-2.

Experimental Design: An antibody specific against pSer⁷⁰ Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas.

Results: Loss of pSer⁷⁰ Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer⁷⁰ Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P < 0.01). It was further observed that loss of pSer⁷⁰ Bcl-2 expression was associated with significantly shorter survival (P < 0.05) and correlated with clinical stages and lymph node metastasis (P < 0.05 and P < 0.05, respectively).

Conclusions: Loss of pSer⁷⁰ Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.