Mhc class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma
Mhc class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma
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DOI：
10.1002/ijc.11681
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发表时间：
2004-03-20
影响因子：
6.4
通讯作者：
Seliger, B
中科院分区：
文献类型：
--
作者：
Atkins, D;Breuckmann, A;Seliger, B
结直肠肿瘤的发生与多种遗传改变的进行性获得有关。其中包括密码子12和13中Ki-ras原癌基因的突变，这些突变占结直肠癌遗传变化的85%。在小鼠体外致癌转化模型中，ras介导的转化与MHC 1类抗原加工机制（APM）不同组分的下调之间存在关联。为了研究这种关联是否也存在于人类肿瘤，10例高级别上皮内瘤变（HIN），以及原发性肿瘤和自体淋巴结转移42例结直肠癌患者，监测等位基因特异性限制性分析Ki-ras突变。同时，通过免疫组织化学分析APM组分表达和肿瘤细胞增殖。与自体结直肠粘膜相比，在HIN中分别发现68%、67%和80%的TAP 1、LMP 2和tapasin丢失。与此相反，受损的TAPI，LMP 2和tapasin的表达被发现在42%，42%和63%的原发性腺癌的III期疾病和63%，47%和79%的匹配的淋巴结转移，分别。超过60%的具有TAP 1、LMP 2和/或tapasin缺陷的结直肠肿瘤病变显示Ki-ras突变。TAP I、LMP 2和tapasin丢失的频率在33%的原发性腺癌、40%的HIN至约67%的转移瘤之间变化。这些数据表明，i）APM组分缺陷更频繁地发生在Ki-ras突变的结直肠癌病变和ii）APM异常与Ki-ras突变似乎与疾病阶段相关。这些发现支持了Ki-ras突变可能通过下调MHC 1类APM组分表达而促进肿瘤免疫逃逸机制的假设。(C)2003 Wiley-Liss，Inc.
Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class 1 antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAPI, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP I, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class 1 APM component expression. (C) 2003 Wiley-Liss, Inc.