卵巢上皮癌中p16和p27基因的表达及其临床意义.doc

卵巢上皮癌中p16和p27基因的表达及其临床意义【关键词】 卵巢肿瘤 Expressions of P16 and P27 in epithelial ovarian carcinoma and its clinical significanceLI HongMei1，, YU YueCheng, SONG TianBao, WEI MaoFu, ZHANG ChunLi1Department of Histology and Embryology, Medical College, Xian Jiaotong University, Xian 710061, China，2Department of Obstetrics and Gynaecology, Xijing Hospital, Fourth Military Medical University, Xian 710033, China, 3Department of Obstetrics and Gynaecology, 4Department of Pathology, Affiliated Hospital, Yanan Medical College, Yanan University, Yanan 716000, China【Abstract】 AIM: To study the expressions of P16 and P27 and its clinical significance in epithelial ovarian carcinoma. METHODS: Archival ovarian epithelial carcinoma (n=38), normal ovarian issues（n=18） and benign ovarian tumor (n=20) were detected for P16 and P27 expressions by immunohistochemistry streptavidinperoxidase staining (SP method). RESULTS: The positive rates of P16 expression in ovarian epithelial carcinoma, benign ovarian tumor and normal tissues were 39%, 70% and 83% respectively and the positive rates of P27 expression in ovarian epithelial carcinoma, benign ovarian tumor and normal tissues were 32%，65% and 78% respectively. The P16 and P27 expressions in ovarian epithelial carcinoma were obviously lower than those in benign ovarian tumor and in normal tissues. In histological grades of ovarian epithelial carcinoma, the rates of high P16 and P27 protein expressions in welldifferentiated samples were significantly higher than those in moderatelydifferentiated samples and poorlydifferentiated samples (P0.01). The rates of high P16 and P27 protein expressions in early clinical stage of ovarian epithelial carcinomas were significantly higher than those in late clinical stage (P0.01). The rates of high P16 and P27 protein expressions in ovarian epithelial carcinomas with lymph node metastasis were significantly lower than those without lymph node metastasis (P0.01). CONCLUSION: The expressions of P16 and P27 protein are correlated to the histological degree of cancer cells, clinical phase of the patients and lymph node metastasis. The detection of P16 and P27 protein expressions may be a valuable marker for the tumor malignant behavior and the prognosis of the patients with ovarian epithelial carcinoma.【Keywords】 ovarian neoplasms; P16; P27; immunohistochemistry【摘要】 目的：研究p16，p27基因在卵巢上皮性恶性肿瘤中的表达及其临床意义. 方法：用免疫组织化学方法检测18例卵巢正常组织、20例卵巢良性肿瘤及38例卵巢癌组织中p16，p27基因的表达情况，并与临床特征相比较. 结果： P16蛋白在卵巢上皮性恶、良性肿瘤和正常组织中的阳性表达率分别为39%,70%和83%；P27蛋白在卵巢上皮性恶、良性肿瘤和正常组织中阳性表达率分别为32%,65%和78%，P16和P27蛋白在卵巢上皮性恶性肿瘤中的表达明显低于卵巢正常组织和卵巢良性肿瘤. 在细胞分化程度级的肿瘤中，P16和P27蛋白表达阳性率明显高于分化程度级和级的肿瘤(P0.01); 在临床分期早期的肿瘤中，P16和P27蛋白的表达率明显高于临床分期晚期的肿瘤(P0.01). 不伴淋巴转移的P16和P27蛋白的表达率明显高于有淋巴转移的蛋白的表达率(P50%.统计学处理：应用SPSS 12.0统计学软件，进行2检验，以P0.05为有统计学意义.2结果2.1P16，P27蛋白在正常卵巢组织、良性卵巢肿瘤及卵巢癌组织中的表达P16与P27在卵巢癌组织的表达率分别为32%(12/38)，39%(15/38），多为弱表达. 在正常卵巢组织中的表达率分别为78%(14/18), 83%(15/18)； 在良性卵巢肿瘤中的表达率分别为70%(14/20), 65%(13/20). 卵巢恶性肿瘤中P16, P27蛋白阳性表达率与正常卵巢组织和良性卵巢肿瘤有显著性差异(P0.05).2.2P16，P27蛋白表达与卵巢癌临床病理指标的关系P16，P27蛋白在卵巢癌中的表达与卵巢癌组织细胞分化程度、临床分期及有无淋巴结转移显著相关. P16，P27蛋白在高分化组的表达阳性率明显高于中、低分化组. 随着分化程度的降低，P16，P27蛋白表达阳性率也逐渐降低. 无淋巴结转移组中的阳性表达率显著高于有淋巴结转移组（P0.05）. 临床分期中期 期的卵巢癌组织中P16，P27蛋白表达阳性率明显高于期期（P0.05，表1）.表1P16,P27蛋白的表达与卵巢癌临床病理指标的关系(略)2.3P16，P27在卵巢癌中表达的关系两者表达显著相关（kappa=0.387, 2=21.392, P=0.011）.表达程度一致率为66% (25/38，表2).表2P16在卵巢癌中的表达与P27表达的关系(n)3讨论p16基因是直接调控恶性肿瘤细胞周期的抑癌基因1. 通过与Cyclin D竞争结合CDK4，抑制Cyclin D/CDK4复合物的活性，从而抑制细胞的分裂和恶性转换3. 当p16由于突变或缺失而不能正常表达时，一方面不能竞争结合CDK4，导致CDK的过度作用，引起磷酸化而抑制作用被解除；另一方面增加Cyclin D与CDK4结合，进一步刺激细胞分裂，从而使细胞失去控制，趋于恶性化. p27也是参与恶性肿瘤细胞周期调控的抑癌基因. 其可阻止细胞通过G1/S期转化的限制点抑制细胞分裂增殖，使细胞有机会修复损坏的DNA或修复DNA复制中产生的错误，控制细胞的生长与分化 2. 研究4-5表明，p27对细胞周期的调控主要依赖于其蛋白的表达水平及活性的改变，蛋白水平低下或缺失，可导致细胞过度生长，引起肿瘤发生. 有研究 6-7证明,与正常组织相比，恶性肿瘤中p16, p27的表达显着下降. 并且提示p16, p27的表达与肿瘤的生物学行为有关. p16, p27阳性表达者的生物学行为较好,转移率低. 阴性者则相反. 本研究结果表明P16, P27蛋白表达与卵巢癌患者的病理分级、临床分期及淋巴结转移密切相关.与文献报道基本相符.本研究显示，卵巢恶性上皮性肿瘤中，P16,P27蛋白阳性表达降低，与正常卵巢组织和良性卵巢肿瘤P16,P27蛋白表达有显著性差异，提示P16,P27蛋白表达的下降与卵巢恶性上皮性肿瘤的发生有关. 随着卵巢恶性上皮性肿瘤分化程度的降低，P16,P27蛋白表达也降低；在临床晚期的卵巢上皮性肿瘤患者中，P16,P27蛋白表达率低于早期患者，不伴淋巴结转移的P27蛋白的表达率明显高于有淋巴结转移的表达率. 提示P16,P27蛋白表达的下降可能在卵巢恶性肿瘤的进展中起一定作用，并且与预后有密切关系. Shigemass等8和Zhang等9研究发现，P16, P27蛋白表达下降可导致卵巢恶性肿瘤细胞对化疗药物的敏感性降低，预后不佳. 而其蛋白的表达却与卵巢肿瘤细胞对化疗药物敏感性呈正相关. Alessandrini等10研究发现，P27蛋白的表达与卵巢恶性上皮性肿瘤患者的无瘤生存期和低生存率存在着正相关. 本研究采用同一组病例作了两种抑癌基因蛋白表达的检测，结果提示P16和P27蛋白在卵巢癌中两者表达有显著相关性，说明二者在卵巢癌的发生发展过程中可能存在一定的联系. 但P16，P27也有部分表达不同, 提示P16与P27可能有相关性又可能都是独立的预后因子.【参考文献】1 Kamb A, Gruis NA, WeaverFeldhans J, et al. A cell cycle regulator potentially involved in genesis of many tumor typesJ. Science，1994,264(5157): 436-440.2 Craig C，Weeersto R，Kim M，et al. A recombinant adenovirus expressing P27kip1 induces cellcycle arrest and loss cyclincdk activity in human breast cancer cells J. Oncogene, 1997，14(5): 2283-2289.3 Sui L, Masaki T, Masuyuki O, et al. The Concurrent expression of P27 kepl and cyclin D1 in edpithelial ovarian tumorsJ. Genecol Oncol, 1999, 73: 202-209.4 Motohiko S, Toshio N, Toshihiko T, et al. Clear cell carcinoma has an expression pattern of cell cyclin regulatory molencles that is unique anong ovarian adenocarcinmoas J. Cancer, 1999,85:669-676.5 Sui L, Dong Y, masaki J, et al. Implication of malignancy and prognosis of P27 kip1, cyclinE, and CDK2 expression in epithelial ovarian tumorJ. Gynecol Oncol, 2001，83:56-63.6 刘荣福,邵国兴,王禾,等. 前列腺癌基因P16的表达与肿瘤生物学行为的关系J. 第四军医大学学报, 1999，20(8): 692-695.7 薛兴欢,代志军,苏宝山, 等. P27蛋白在乳腺癌中的表达及其临床病理意义J. 第四军医大学学报, 2003， 24(13):1231-1233.8 Shigemass K, Shiroyama Y, Sawasaki T, et al. Underexpression of cyclindependent kinase inhibitor