Izzo J G, Papadimitrakopoulou V A, Li X Q, Ibarguen H, Lee J S, Ro J Y, El-Naggar A, Hong W K, Hittelman W N
Department of Clinical Investigation, University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Oncogene. 1998 Nov 5;17(18):2313-22. doi: 10.1038/sj.onc.1202153.
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%) non-amplified 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.
细胞周期蛋白D1原癌基因是哺乳动物细胞周期的关键调节因子，作用于G1晚期的限制点。位于11号染色体q13区的细胞周期蛋白D1基因座的扩增以及细胞周期蛋白D1蛋白的过表达已在多种人类恶性肿瘤中被报道。本研究的目的是结合荧光原位杂交和免疫组织化学技术，评估细胞周期蛋白D1基因拷贝状态和蛋白表达在头颈部肿瘤发生多步骤过程中的情况。从29例患有头颈部鳞状细胞癌的患者中选取，这些患者的肿瘤细胞涂片先前已筛查过11q13带是否存在扩增（16例）或不存在扩增（13例），我们分析了46个石蜡包埋组织标本，这些标本除了原发性肿瘤外，还显示有连续的相邻正常组织和/或癌前病变。在16例扩增病例中，9例显示从癌前病变到浸润性癌的连续进展，其中7例（77.7%）在浸润性癌发生之前的癌前病变中显示细胞周期蛋白D1基因扩增。在所有16例扩增肿瘤以及13例非扩增肿瘤中的5例（38.4%）中观察到细胞周期蛋白D1蛋白表达增加。有趣的是，在所有16例扩增肿瘤相邻的癌前病变中也发现细胞周期蛋白D1表达失调，并且似乎先于细胞周期蛋白D1基因扩增。相比之下，在非扩增肿瘤的癌前病变中未检测到表达失调。总之，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有力证据，并表明失调的表达增加先于并可能导致基因扩增。
