Concordant down-regulation of proto-oncogene PML and major histocompatibility antigen HLA class I expression in high-grade prostate cancer.
Concordant down-regulation of proto-oncogene PML and major histocompatibility antigen HLA class I expression in high-grade prostate cancer.
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发表时间：
2003
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通讯作者：
Huiming Zhang;J. Melamed;P. Wei;K. Cox;W. Frankel;R. Bahnson;Nikki Robinson;R. Pyka;Yang Liu;P. Zheng
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作者：
Huiming Zhang;J. Melamed;P. Wei;K. Cox;W. Frankel;R. Bahnson;Nikki Robinson;R. Pyka;Yang Liu;P. Zheng
细胞溶解T淋巴细胞对肿瘤细胞的识别依赖于细胞表面MHC-I类分子的表达。作为一种逃避T细胞识别的机制，包括前列腺癌在内的许多恶性肿瘤细胞下调MHC I类分子。对于大多数人类癌症，MHC I类分子下调的分子机制尚不清楚，尽管众所周知，MHC I类下调通常与多个专用于抗原提呈的基因下调有关。由于早幼粒细胞白血病(PML)原癌基因在一些小鼠癌细胞中控制着多个抗原提呈基因，我们分析了原癌基因PML和MHC-I类基因在高级别前列腺癌中的表达。我们发现37例Gleason分级为7-8的前列腺癌中有30例(81%)HLAI类表达下调超过50%。其中22例(73.3%)无PML蛋白表达，4例(13.3%)PML蛋白表达部分下调。而细胞表面HLAI类高表达的7例前列腺癌PML均高表达。在前列腺癌的不同组织学类型中，人类白细胞抗原和粒细胞集落刺激因子的表达呈一致性下调。这些结果表明，在高级别前列腺癌中，原癌基因PML的功能障碍是细胞表面HLAI类分子下调的主要因素，而HLAI类分子是细胞溶解T淋巴细胞直接识别癌细胞所必需的靶分子。
Recognition of tumor cells by cytolytic T lymphocytes depends on cell surface MHC class I expression. As a mechanism to evade T cell recognition, many malignant cancer cells, including those of prostate cancer, down-regulate MHC class I. For the majority of human cancers, the molecular mechanism of MHC class I down regulation is unclear, although it is well established that MHC class I down-regulation is often associated with the down-regulation of multiple genes devoted to antigen presentation. Since the promyelocytic leukemia (PML) proto-oncogene controls multiple antigen-presentation genes in some murine cancer cells, we analyzed the expression of proto-oncogene PML and MHC class I in high-grade prostate cancer. We found that 30 of 37 (81%) prostate adenocarcinoma cases with a Gleason grade of 7-8 had more than 50% down-regulation of HLA class I expression. Among these, 22 cases (73.3%) had no detectable PML protein, while 4 cases (13.3%) showed partial PML down-regulation. In contrast, all 7 cases of prostate cancer with high expression of cell surface HLA class I had high levels of PML expression. Concordant down-regulation of HLA and PML was observed in different histological patterns of prostate adenocarcinoma. These results suggest that in high-grade prostate cancer, malfunction of proto-oncogene PML is a major factor in the down-regulation of cell surface HLA class I molecules, the target molecules essential for the direct recognition of cancer cells by cytolytic T lymphocytes.