IMP3、RFP、HER-2蛋白在Ⅱ型子宫内膜癌中的表达及意义

发布时间：2018-08-06 14:49

【摘要】：目的：子宫内膜癌是常见的妇科肿瘤之一，分为两型:雌激素依赖型（Ⅰ型），即子宫内膜样癌（enodmetrioid adenocarcinoma，EC)，与雌激素刺激有关。非雌激素依赖型（Ⅱ型），即非子宫内膜样癌(nonendometrioidadenocarcinoma， NEC)，主要包括子宫内膜浆液性癌(uterine serouscarcinoma，USC)、透明细胞癌（clear cell carcinoma，CCC），多见于绝经后妇女，与雌激素无关。这两种亚型子宫内膜癌的生物学行为截然相反，I型预后较好，恶性程度低，Ⅱ型具有侵袭性的生物学行为和差的临床预后，且手术范围更大，术后辅助治疗手段不尽相同。因此术前正确的鉴别出此两种亚型子宫内膜癌，对指导临床治疗、评估预后有重要意义。目前子宫内膜癌的术前诊断主要依赖诊刮，由于诊刮在非可视条件下操作，误诊率较高，且获取标本量较少或存在反应性或化生性改变，而难做出正确的病理诊断。因此，新的肿瘤标记物和治疗靶点已成为基础研究者和临床医师关注的焦点。IMP3（insulinlike growth factor II mRNA-binding protein3）基因属于胰岛素样生长因子Ⅱ-mRNA结合蛋白家族中的成员之一，是一种新识别的癌胚蛋白，在胎儿和癌组织中高表达，而在成人良性组织中呈低表达或不表达。研究表明IMP3可通过增强胰岛素样生长因子-2的表达增进肿瘤细胞增殖，并可能间接通过CD44、基质金属蛋白酶等多种途径参与子宫内膜癌的浸润和转移。因此，有学者认为IMP3是子宫内膜癌的一个特异性标记物，能促进肿瘤细胞增殖和侵袭。RFP（ret finger protein）蛋白属于巨B盒戒指蛋白家族，具有三分体结构特点，结构域包括一个环指结构、一个B-盒式结构、一个卷曲结构位点。在人类肿瘤和和雄鼠生殖细胞中均检测到高表达，参与细胞的生长、转化及癌变。RFP蛋白可以激活原癌基因Ret导致肿瘤的发生。有研究表明RFP与子宫内膜癌的发生相关。HER-2（C-erbB-2）是跨膜受体酪氨酸激酶家族的重要成员之一，作为跨膜糖蛋白，其细胞膜部分可以转导细胞增殖、凋亡信号，通过多种途径调节cox-2的表达，从而刺激子宫内膜癌增殖和血管生成。本研究通过免疫组织化学的方法检测了IMP3、RFP、HER-2蛋白在子宫内膜癌组织中的表达，旨在探讨三者在子宫内膜癌发生发展过程中的作用以及对两种亚型子宫内膜癌的鉴别意义。方法：选取2008年1月至2013年1月在河北医科大学附属第四医院住院治疗的子宫内膜癌患者55例，均为首次手术切除，所有病例术前均未接受放疗、化疗或激素治疗，且不合并其它肿瘤。根据组织形态分为：Ⅰ型癌30例，Ⅱ型癌25例，采用链霉菌抗生物素蛋白-过氧化物酶连结法（streptavidin-perosidase，SP法）行免疫组化检测。结果： 1Ⅰ、Ⅱ型子宫内膜癌临床特点的比较 Ⅰ型癌平均年龄55.6±1.67岁，Ⅱ型癌平均年龄59.68±1.34岁，包括USC共15例，CCC共10例。根据WHO分级：Ⅰ型癌中高分化(G1)9例，中分化(G2)11例，低分化(G3)10例。Ⅱ型癌目前尚无统一的病理分级标准，未进行分级。根据2009年国际妇产科联合会(FIGO)子宫内膜癌手术-病理分期， I型癌中I～II期20例，III～Ⅳ期10例；Ⅱ型癌中I～II期14例，III～Ⅳ期11例。所有病例都进行了淋巴清扫，Ⅰ型癌中淋巴转移者8例，未转移者22例；Ⅱ型癌中淋巴转移者8例，未转移者17例。Ⅰ型癌中ER阴性表达3例，PR阴性表达4例，Ⅱ型癌中ER阴性表达15例，PR阴性表达17例，阳性者多为弱阳性表达 2IMP3、RFP、HER-2蛋白表达与临床资料间的关系 IMP3、RFP、HER-2蛋白在Ⅱ型子宫内膜癌中的阳性表达率分别为68％、84%、60%，，明显高于子宫内膜腺癌（P0.05）。IMP3，RFP蛋白在有、无淋巴结转移组中的阳性表达率分别为50%（8/16）、8%（3/39）及44%（7/16）、13%（5/39），差异均有统计学意义（P0.05，P0.05）。可见IMP3、RFP蛋白的表达随淋巴结的转移而增加，说明IMP3、RFP阳性表达的患者更容易发生淋巴结转移。而HER-2蛋白的表达与淋巴结转移无关。IMP3、RFP、HER-2蛋白表达与肿瘤的临床分期、肿瘤细胞分化级别无明显相关性（P0.05）。 3IMP3、RFP、HER-2蛋白对Ⅰ、Ⅱ型子宫内膜癌的鉴别意义各单一肿瘤标记物中，RFP的灵敏度最高为84%，但其特异度最低为80%，为弥补这一缺憾，对各肿瘤标记物进行组合，发现组合后的肿瘤标记物中，IMP3+/RFP+的灵敏度和特异度、阳性预测值均最高，分别为64%、93.3%、88.9%。用logistic回归分析IMP3、RFP、HER-2蛋白鉴别两种类型子宫内膜癌的价值，RFP的诊断价值最高（OR=10.826，95%可信区间为2.398～48.878），其次是IMP3（OR=5.261，95%可信区间为1.109～24.957），HER-2最差（OR=1.021，95%可信区间为0.218～4.775）。IMP3、RFP蛋白在鉴别Ⅰ型和Ⅱ型子宫内膜腺癌方面具有诊断价值，结合所查临床病理资料中ER、PR的表达情况，组合各指标，采用logistic回归分析发现，最佳诊断模式为IMP3+/RFP+（OR值为24.889，95%可信区间为4.777～129.688）。结论： 1IMP3、RFP蛋白作为一种特异性很高的肿瘤标记物主要表达于Ⅱ型子宫内膜癌中，可用于区分两种类型的子宫内膜癌。 2HER-2蛋白在Ⅰ、Ⅱ型内膜癌中的表达无明显差异，但在子宫内膜癌中的总表达率较高，提示其可能参与子宫内膜癌的发生，为子宫内膜癌的靶向治疗提供新的靶点。 3IMP3、RFP蛋白的表达随淋巴结的转移而增加，说明IMP3、RFP阳性表达与淋巴结转移有关。 4IMP3+/RFP+是诊断II型子宫内膜癌最佳辅助诊断指标，当诊断出现困难时，有助于正确鉴别出II型子宫内膜癌，为患者的临床治疗提供准确的临床依据。
[Abstract]:Objective: endometrial carcinoma is one of the common gynecologic tumors and is divided into two types: estrogen dependent (type I), enodmetrioid adenocarcinoma (EC), related to estrogen stimulation. Non estrogen dependent (type II), that is, non endometrioid carcinoma (nonendometrioidadenocarcinoma, NEC), mainly including endometrium serous Cancer (uterine serouscarcinoma, USC), clear cell carcinoma (CCC), more common in postmenopausal women, is not related to estrogen. These two subtypes of endometrial cancer have the opposite biological behavior, a better prognosis, a lower malignancy, an invasive biological behavior and poor clinical prognosis, and a wider operation. It is important to identify these two subtypes of endometrium cancer correctly before operation. It is important to guide clinical treatment and evaluate the prognosis. The preoperative diagnosis of endometrial carcinoma is mainly dependent on the diagnosis of curettage, because of the high misdiagnosis rate, and less or reactivity. The.IMP3 (insulinlike growth factor II mRNA-binding protein3) gene is one of the members of the insulin like growth factor II -mRNA binding protein family, which is one of the members of the insulin-like growth factor II -mRNA binding protein family. The newly identified carcinoembryonic proteins are highly expressed in fetal and cancer tissues and are low expression or non expression in adult benign tissues. The study shows that IMP3 can enhance the proliferation of tumor cells by enhancing the expression of insulin-like growth factor -2, and may be involved in endometrial cancer infiltration through a variety of pathways, such as CD44, matrix metalloproteinase, and so on. Therefore, some scholars believe that IMP3 is a specific marker for endometrial carcinoma, which promotes the proliferation and invasion of tumor cells and the invasion of.RFP (RET finger protein) protein belongs to the giant B box ring protein family, which has three body structure characteristics, the domain includes a ring finger structure, a B- box structure, a curly structural site. High expression is detected in both tumor and male rat germ cells, and participates in cell growth. Transformation and cancerous.RFP protein can activate the oncogene Ret to lead to the occurrence of tumor. Some studies have shown that.HER-2 (C-erbB-2) associated with the occurrence of endometrial carcinoma (C-erbB-2) is one of the important members of the transmembrane receptor tyrosine kinase family, as a transmembrane glycoprotein. The cell membrane part can transduce cell proliferation, apoptosis signal and regulate the expression of COX-2 through a variety of pathways, thus stimulating the proliferation and angiogenesis of endometrial carcinoma. This study detected the expression of IMP3, RFP, and HER-2 protein in endometrial carcinoma by immunohistochemical method. The aim of this study was to explore the development of endometrial cancer in three cases. The role of the process and its significance in the identification of two subtypes of endometrial carcinoma.
Method:
55 patients with endometrial cancer hospitalized at the Fourth Affiliated Hospital of Hebei Medical University from January 2008 to January 2013 were all excised for the first time. All cases were not treated with radiotherapy, chemotherapy or hormone therapy before operation, and no other tumors were combined. According to tissue morphology, 30 cases of type I carcinoma, 25 cases of type II cancer, and Streptomyces resistance were used. Immunohistochemistry (streptavidin-perosidase, SP) was used for immunohistochemistry.
Result:
Comparison of clinical characteristics of 1 I, type II endometrial carcinoma
The average age of type I carcinoma was 55.6 + 1.67 years, and the average age of type II carcinoma was 59.68 + 1.34 years old, including 15 cases of USC and 10 cases of CCC. According to WHO classification, 9 cases of high differentiation (G1) in type I carcinoma, 11 cases of middle differentiation (G2) and 10 cases of low differentiation (G3). Endometrial carcinoma operation - pathological stage, 20 cases of I to II in type I carcinoma, 10 cases in III to IV stage, 14 cases in I to II stage in type II carcinoma and 11 cases in III to IV stage. All cases were dissection of lymph, 8 cases of lymphatic metastasis in type I carcinoma, 22 cases of non metastasis, 8 cases of lymph metastasis in type II carcinoma, 17 cases without metastasis, 3 cases negative ER in type I carcinoma and PR Yin in type I carcinoma. PR Yin There were 4 cases of sexual expression, 15 cases of ER negative expression, 17 cases of PR negative expression, and most of them were weakly positive expression.
Relationship between 2IMP3, RFP and HER-2 protein expression and clinical data
The positive expression rates of IMP3, RFP and HER-2 protein in type II endometrial carcinoma were 68%, 84%, 60% respectively, which were significantly higher than that of endometrial adenocarcinoma (P0.05).IMP3. The positive rates of RFP protein were 50% (8/16), 8% (3/39) and 44% (7/16) and 13% (5/39) in no lymph node metastasis group (P0.05, P0.05). The expression of white was increased with the metastasis of lymph nodes, indicating that IMP3, RFP positive patients were more likely to have lymph node metastasis, but the expression of HER-2 protein was not related to.IMP3, RFP, HER-2 protein expression was not significantly related to the clinical stage of tumor, and there was no significant correlation between the differentiation grade of tumor cells (P0.05).
Differential diagnostic significance of 3IMP3, RFP and HER-2 protein in type I and type II endometrial carcinoma
Among the single tumor markers, the highest sensitivity of RFP was 84%, but the lowest specificity was 80%. In order to make up for this defect, the tumor markers were combined, and the sensitivity and specificity of IMP3+/RFP+ were found in the tumor markers after combination, and the positive predictive values were the highest, 64%, 93.3% respectively, and 88.9%. was analyzed by logistic regression, IMP3, RFP, HER-2. The value of protein identification of two types of endometrial carcinoma was found. The diagnostic value of RFP was the highest (OR=10.826,95% confidence interval was 2.398 to 48.878), followed by IMP3 (OR=5.261,95% confidence interval from 1.109 to 24.957), HER-2 was the worst (OR=1.021,95% confidence interval 0.218 to 4.775).IMP3, RFP protein was found in the identification of type I and type II endometrial adenocarcinoma. The value of diagnosis was combined with the expression of ER and PR in the clinicopathological data and combined with each index. The best diagnostic model was found to be IMP3+/RFP+ by logistic regression analysis (OR value was 4.777 to 129.688 of 24.889,95% confidence interval).
Conclusion:
1IMP3, RFP protein, as a highly specific tumor marker, is mainly expressed in type II endometrial carcinoma and can be used to distinguish two types of endometrial carcinoma.
There is no significant difference in the expression of 2HER-2 protein in type I and type II endometrial carcinoma, but the total expression rate in endometrial carcinoma is high, suggesting that it may participate in the occurrence of endometrial cancer and provide a new target for the targeting therapy of endometrial cancer.
The expression of 3IMP3 and RFP protein increased with lymph node metastasis, indicating that IMP3 and RFP positive expression were related to lymph node metastasis.
4IMP3+/RFP+ is the best diagnostic marker for the diagnosis of II type endometrial carcinoma. When the diagnosis is difficult, it is helpful to identify the II type endometrial carcinoma correctly and provide the accurate clinical basis for the clinical treatment of the patients.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.33

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