Atkins Derek, Breuckmann Aldona, Schmahl Gerd E, Binner Priska, Ferrone Soldano, Krummenauer Frank, Störkel Stephan, Seliger Barbara
Johannes Gutenberg-University, Third Department of Internal Medicine, Mainz, Germany.
Int J Cancer. 2004 Mar 20;109(2):265-73. doi: 10.1002/ijc.11681.
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 I 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 TAP1, 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 TAP1, 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 I APM component expression.
结直肠癌的发生与多种基因改变的逐步获得有关。这些改变包括第12和13密码子处的Ki-ras原癌基因突变，其占结直肠癌基因变化的85%。在致癌转化的小鼠体外模型中，已描述了ras介导的转化与MHC I类抗原加工机制（APM）不同成分的下调之间的关联。为了研究这种关联是否也存在于人类肿瘤中，通过等位基因特异性限制性分析监测了10例高级别上皮内瘤变（HIN）以及42例结直肠癌患者的原发性肿瘤和自体淋巴结转移灶中的Ki-ras突变。同时，通过免疫组织化学分析APM成分表达和肿瘤细胞增殖。与自体结直肠黏膜相比，分别在68%、67%和80%的HIN中发现TAP1、LMP2和塔帕辛缺失。相比之下，在III期疾病的原发性腺癌中，分别有42%、42%和63%以及在匹配的淋巴结转移灶中有63%、47%和79%发现TAP1、LMP2和塔帕辛表达受损。超过60%的具有TAP1、LMP2和/或塔帕辛缺陷的结直肠肿瘤病变显示Ki-ras突变。TAP1、LMP2和塔帕辛缺失的频率在原发性腺癌的33%、HIN的40%至转移灶的约67%之间变化。这些数据表明：i）APM成分缺陷在Ki-ras突变的结直肠癌病变中更频繁发生；ii）APM异常与Ki-ras突变似乎与疾病分期相关。这些发现支持了Ki-ras突变可能通过下调MHC I类APM成分表达促进肿瘤免疫逃逸机制的假说。
