Expression of phosphorylated Ser70 of Bcl-2 correlates with malignancy in human colorectal neoplasms
Expression of phosphorylated Ser70 of Bcl-2 correlates with malignancy in human colorectal neoplasms
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DOI：
10.1158/1078-0432.ccr-05-0274
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发表时间：
2005-10-15
影响因子：
11.5
通讯作者：
Yoshino, T
中科院分区：
文献类型：
--
作者：
Kondo, E;Miyake, T;Yoshino, T
目的：bcl2是一种模型细胞凋亡抑制因子，被认为促进肿瘤的发生。最近，有报道称，Bcl2通过对其Ser(70)进行磷酸化调节，从而显著改变其分子功能。先前的研究进一步表明，这种磷酸化的Bcl2调控可能影响结直肠癌和其他癌症的进展；然而，Bcl2的丝氨酸(70)在肿瘤中的磷酸化状态仍然不清楚。为了阐明这个可能具有生物学作用的问题，我们对一组人类结直肠腺瘤和腺癌进行了内源性pSer(70)Bcl2表达的分子筛查。实验设计：制备了一种针对pSer(70)Bcl2的抗体，用于对石蜡包埋的肿瘤标本进行彻底的免疫组织化学检查，允许在一系列Bcl2阳性的结直肠肿瘤中检测到内源性表达的抗原，包括75例管状腺瘤，114例腺癌和15例腺瘤癌。结果：pSer(70)在腺癌中的表达呈分化依赖的方式(阳性率：高分化63%，中分化52%，和低分化的12%)，而管状腺瘤保持其表达(88%)。有趣的是，pSer(70)Bcl2和Ki-67抗原在腺瘤中的表达呈负相关(P<；0.01)。PSer70Bcl2的表达缺失与患者的生存期显著相关(P<；0.05)，并与临床分期和淋巴结转移有关(分别为P<；0.05和P<；0.05)。结论：pSer70Bcl2的表达缺失与结直肠癌的生物学侵袭性密切相关，是判断结直肠癌患者预后的重要分子指标。
Purpose: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser(70) 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 Ser(70) of Bcl-2 (pSer(70)) 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 pSer(70) Bcl-2.Experimental Design: An antibody specific against pSer(70) 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 pSer(70) 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 pSer(70) 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 pSer(70) 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.