Yarbrough W G, Shores C, Witsell D L, Weissler M C, Fidler M E, Gilmer T M
Division of Otolaryngology/Head & Neck Surgery, University of North Carolina School of Medicine, Chapel Hill.
Laryngoscope. 1994 Nov;104(11 Pt 1):1337-47. doi: 10.1288/00005537-199411000-00005.
Mutational activation and overexpression of the family of ras proto-oncogenes have been associated with many human tumors. The role of mutations of H-ras, K-ras, and N-ras, as well as expression of the respective protein products (p21s) in normal mucosa, dysplastic mucosa, and squamous cell carcinomas (SCCs) of the head and neck has not been fully described. In our study, 51 tumors (40 paraffin embedded and 11 fresh frozen) were examined to determine if mutational activation of ras is an important molecular event in head and neck SCC. Analyses of codons 12, 13, and 61 of H-ras, K-ras, and N-ras revealed no mutations, suggesting that mutational activation of ras is not important in the majority of head and neck SCCs. Immunocytochemistry (ICC) was used to define the expression of H-ras, K-ras, and N-ras in normal mucosa, dysplastic mucosa, and SCC of the head and neck and to determine if expression of ras family members correlated with early or late events in the development of SCC. Expression of p21N-ras in nine samples of histologically normal head and neck mucosa revealed moderate staining in the basal proliferative layers with progressively less staining as cells matured. The most superficial layers of normal mucosa failed to express p21N-ras. A low level of p21H-ras was expressed in all layers of normal mucosa while K-ras was not expressed. ICC of SCC tumor sections revealed cytoplasmic expression of N-ras in nine of nine tumors, H-ras in five of nine tumors, and K-ras in one of nine tumors. Expression of H-ras, K-ras, and N-ras in head and neck SCC was not related to histologic differentiation or TNM staging; however, p21N-ras was overexpressed in seven of nine tumors. Furthermore, the pattern of N-ras expression in dysplastic lesions revealed expression in all layers of the mucosa in contrast to normal mucosa, which expresses p21N-ras primarily in the basal proliferative layer. The change in p21N-ras expression pattern in dysplastic mucosa and its overexpression in the majority of tumors suggest that loss of control of N-ras expression may be an early step in carcinogenesis of head and neck SCC.
ras原癌基因家族的突变激活和过表达与许多人类肿瘤相关。H-ras、K-ras和N-ras的突变作用，以及各自蛋白产物（p21s）在正常黏膜、发育异常黏膜和头颈部鳞状细胞癌（SCC）中的表达尚未得到充分描述。在我们的研究中，检查了51个肿瘤（40个石蜡包埋和11个新鲜冷冻），以确定ras的突变激活是否是头颈部SCC中的一个重要分子事件。对H-ras、K-ras和N-ras的第12、13和61密码子的分析未发现突变，这表明ras的突变激活在大多数头颈部SCC中并不重要。免疫细胞化学（ICC）用于确定H-ras、K-ras和N-ras在正常黏膜、发育异常黏膜和头颈部SCC中的表达，并确定ras家族成员的表达是否与SCC发生发展中的早期或晚期事件相关。在9例组织学正常的头颈部黏膜样本中，p21N-ras的表达显示在基底增殖层有中度染色，随着细胞成熟染色逐渐减少。正常黏膜的最表层未表达p21N-ras。正常黏膜的所有层均表达低水平的p21H-ras，而K-ras未表达。SCC肿瘤切片的ICC显示，9个肿瘤中有9个N-ras呈细胞质表达，9个肿瘤中有5个H-ras呈细胞质表达，9个肿瘤中有1个K-ras呈细胞质表达。头颈部SCC中H-ras、K-ras和N-ras的表达与组织学分化或TNM分期无关；然而，9个肿瘤中有7个p21N-ras过表达。此外，发育异常病变中N-ras的表达模式显示黏膜各层均有表达，这与正常黏膜不同，正常黏膜主要在基底增殖层表达p21N-ras。发育异常黏膜中p21N-ras表达模式的改变及其在大多数肿瘤中的过表达表明，N-ras表达失控可能是头颈部SCC致癌过程中的早期步骤。
