Expression of phosphorylated Ser70 of Bcl-2 correlates with malignancy in human colorectal neoplasms.
OBJECTIVE
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.


METHODS
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.
Kondo
Eisaku
E
Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. ekondo@md.okayama-u.ac.jp
Miyake
Takayoshi
T
Shibata
Masao
M
Kimura
Toshikazu
T
Iwagaki
Hiromi
H
Nakamura
Shin-Ichi
S
Tanaka
Takehiro
T
Ohara
Nobuya
N
Ichimura
Koichi
K
Oka
Takashi
T
Yanai
Hiroyuki
H
Shibasaki
Futoshi
F
Yoshino
Tadashi
T
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016019:Survival Analysis; D014162:Transfection
D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D012694:Serine