Liu Tingjiao, Zhu Enxin, Wang Lihong, Okada Toshie, Yamaguchi Akira, Okada Norihiko
Section of Oral Pathology, Graduate School of Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
Hum Pathol. 2005 Sep;36(9):962-70. doi: 10.1016/j.humpath.2005.06.014.
Salivary gland acinic cell carcinoma (ACC) is a relatively rare neoplasm, and limited information is available regarding its molecular pathogenesis. Because the deregulation of Rb pathway is common to most human tumors, we immunohistochemically investigated the expression of Rb pathway-related proteins, including Rb, Rb proteins phosphorylated at serine 780 and 795 (pRb-S780 and pRb-S795, respectively), cyclin D1, and p16INK4a in 18 cases of ACC. The expression of topoisomerase II-alpha and Ki-67 was also examined to evaluate cell proliferation. All the ACCs exhibited substantial numbers of positive cells against Rb antibody that recognizes both unphosphorylated and phosphorylated Rb proteins. The numbers of positive cells for pRb-S795 and cyclin D1 significantly increased in ACCs as compared with normal salivary glands. Double immunofluorescent staining demonstrated that pRb-S795 was colocalized with cyclin D1 in most tumor cells. However, neither significant change of the expression of Rb protein phosphorylated at serine 780 nor its colocalization with cyclin D1 was observed. The loss of p16INK4a is infrequent, but its expression was correlated with phosphorylated Rb proteins. Our results suggest that serine 795 but not serine 780 is the preferred phosphorylation site induced by cyclin D1. This phosphorylation appeared to be critical for inactivation of Rb-mediated growth suppression and may play an important role in the pathogenesis of ACC.
涎腺腺泡细胞癌（ACC）是一种相对罕见的肿瘤，关于其分子发病机制的信息有限。由于Rb通路失调在大多数人类肿瘤中很常见，我们采用免疫组织化学方法研究了18例ACC中Rb通路相关蛋白的表达，包括Rb、丝氨酸780和795磷酸化的Rb蛋白（分别为pRb-S780和pRb-S795）、细胞周期蛋白D1和p16INK4a。还检测了拓扑异构酶II-α和Ki-67的表达以评估细胞增殖。所有ACC均显示大量细胞对识别未磷酸化和磷酸化Rb蛋白的Rb抗体呈阳性。与正常涎腺相比，ACC中pRb-S795和细胞周期蛋白D1的阳性细胞数量显著增加。双重免疫荧光染色显示，在大多数肿瘤细胞中pRb-S795与细胞周期蛋白D1共定位。然而，未观察到丝氨酸780磷酸化的Rb蛋白表达有显著变化，也未观察到其与细胞周期蛋白D1的共定位。p16INK4a缺失不常见，但其表达与磷酸化Rb蛋白相关。我们的结果表明，丝氨酸795而非丝氨酸780是细胞周期蛋白D1诱导的首选磷酸化位点。这种磷酸化似乎对Rb介导的生长抑制失活至关重要，可能在ACC的发病机制中起重要作用。
