Dysregulated cyclin D1 expression early in head and neck tumorigenesis:: in vivo evidence for an association with subsequent gene amplification
Dysregulated cyclin D1 expression early in head and neck tumorigenesis:: in vivo evidence for an association with subsequent gene amplification
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DOI：
10.1038/sj.onc.1202153
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发表时间：
1998-11-05
期刊：
影响因子：
8
通讯作者：
Hittelman, WN
中科院分区：
文献类型：
--
作者：
Izzo, JG;Papadimitrakopoulou, VA;Hittelman, WN
细胞周期蛋白D_1原癌基因是哺乳动物细胞周期的关键调控因子，位于染色体11q13上的细胞周期蛋白D_1位点扩增，以及细胞周期蛋白D_1蛋白在多种人类恶性肿瘤中的过度表达已被报道。本研究采用荧光原位杂交和免疫组织化学技术相结合的方法，研究头颈部肿瘤形成过程中细胞周期蛋白D1基因的复制状态和蛋白表达情况。从29例头颈部鳞癌患者中，我们分析了46例石蜡包埋组织标本，这些组织标本除了原发肿瘤外，还存在邻近的正常组织和/或癌前病变。在16例扩增病例中，9例表现为从癌前病变向浸润性癌的连续进展，其中7例(77.7%)癌前病变中有细胞周期蛋白D1基因扩增。在所有16例扩增的肿瘤和5例未扩增的肿瘤中，Cyclin D1蛋白表达均升高(38.4%)。有趣的是，在所有16个扩增的肿瘤旁的癌前病变中也发现了细胞周期蛋白D1的异常表达，并且似乎先于细胞周期蛋白D1基因的扩增。相反，在未扩增的肿瘤的癌前病变中未检测到异常表达。综上所述，这些发现为肿瘤发生过程中细胞周期蛋白D1表达的早期失调提供了强有力的证据，并提示失调的表达增加先于并可能使基因扩增成为可能。
Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1, Amplification of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of fluorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of amplification at the 11q13 band, we analysed 46 paraffin-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 amplified cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene amplification in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 amplified tumors' and five of the 13 (38.4%) nonamplified tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 amplified tumors, and it appeared to precede cyclin D1 gene amplification. In contrast no dysregulated expression was detected in the premalignant lesions of the non-amplified tumors. In conclusion, these findings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene amplification.