IMP3、RFP、HER-2蛋白在Ⅱ型子宮內(nèi)膜癌中的表達(dá)及意義
發(fā)布時(shí)間：2018-08-06 14:49
【摘要】：目的：子宮內(nèi)膜癌是常見的婦科腫瘤之一，分為兩型:雌激素依賴型（Ⅰ型），即子宮內(nèi)膜樣癌（enodmetrioid adenocarcinoma，EC)，與雌激素刺激有關(guān)。非雌激素依賴型（Ⅱ型），即非子宮內(nèi)膜樣癌(nonendometrioidadenocarcinoma， NEC)，主要包括子宮內(nèi)膜漿液性癌(uterine serouscarcinoma，USC)、透明細(xì)胞癌（clear cell carcinoma，CCC），多見于絕經(jīng)后婦女，與雌激素?zé)o關(guān)。這兩種亞型子宮內(nèi)膜癌的生物學(xué)行為截然相反，I型預(yù)后較好，惡性程度低，Ⅱ型具有侵襲性的生物學(xué)行為和差的臨床預(yù)后，且手術(shù)范圍更大，術(shù)后輔助治療手段不盡相同。因此術(shù)前正確的鑒別出此兩種亞型子宮內(nèi)膜癌，對(duì)指導(dǎo)臨床治療、評(píng)估預(yù)后有重要意義。目前子宮內(nèi)膜癌的術(shù)前診斷主要依賴診刮，由于診刮在非可視條件下操作，誤診率較高，且獲取標(biāo)本量較少或存在反應(yīng)性或化生性改變，而難做出正確的病理診斷。因此，新的腫瘤標(biāo)記物和治療靶點(diǎn)已成為基礎(chǔ)研究者和臨床醫(yī)師關(guān)注的焦點(diǎn)。IMP3（insulinlike growth factor II mRNA-binding protein3）基因?qū)儆谝葝u素樣生長因子Ⅱ-mRNA結(jié)合蛋白家族中的成員之一，是一種新識(shí)別的癌胚蛋白，在胎兒和癌組織中高表達(dá)，而在成人良性組織中呈低表達(dá)或不表達(dá)。研究表明IMP3可通過增強(qiáng)胰島素樣生長因子-2的表達(dá)增進(jìn)腫瘤細(xì)胞增殖，并可能間接通過CD44、基質(zhì)金屬蛋白酶等多種途徑參與子宮內(nèi)膜癌的浸潤和轉(zhuǎn)移。因此，有學(xué)者認(rèn)為IMP3是子宮內(nèi)膜癌的一個(gè)特異性標(biāo)記物，能促進(jìn)腫瘤細(xì)胞增殖和侵襲。RFP（ret finger protein）蛋白屬于巨B盒戒指蛋白家族，具有三分體結(jié)構(gòu)特點(diǎn)，結(jié)構(gòu)域包括一個(gè)環(huán)指結(jié)構(gòu)、一個(gè)B-盒式結(jié)構(gòu)、一個(gè)卷曲結(jié)構(gòu)位點(diǎn)。在人類腫瘤和和雄鼠生殖細(xì)胞中均檢測到高表達(dá)，參與細(xì)胞的生長、轉(zhuǎn)化及癌變。RFP蛋白可以激活原癌基因Ret導(dǎo)致腫瘤的發(fā)生。有研究表明RFP與子宮內(nèi)膜癌的發(fā)生相關(guān)。HER-2（C-erbB-2）是跨膜受體酪氨酸激酶家族的重要成員之一，作為跨膜糖蛋白，其細(xì)胞膜部分可以轉(zhuǎn)導(dǎo)細(xì)胞增殖、凋亡信號(hào)，通過多種途徑調(diào)節(jié)cox-2的表達(dá)，從而刺激子宮內(nèi)膜癌增殖和血管生成。本研究通過免疫組織化學(xué)的方法檢測了IMP3、RFP、HER-2蛋白在子宮內(nèi)膜癌組織中的表達(dá)，旨在探討三者在子宮內(nèi)膜癌發(fā)生發(fā)展過程中的作用以及對(duì)兩種亞型子宮內(nèi)膜癌的鑒別意義。 方法： 選取2008年1月至2013年1月在河北醫(yī)科大學(xué)附屬第四醫(yī)院住院治療的子宮內(nèi)膜癌患者55例，均為首次手術(shù)切除，所有病例術(shù)前均未接受放療、化療或激素治療，且不合并其它腫瘤。根據(jù)組織形態(tài)分為：Ⅰ型癌30例，Ⅱ型癌25例，采用鏈霉菌抗生物素蛋白-過氧化物酶連結(jié)法（streptavidin-perosidase，SP法）行免疫組化檢測。 結(jié)果： 1Ⅰ、Ⅱ型子宮內(nèi)膜癌臨床特點(diǎn)的比較 Ⅰ型癌平均年齡55.6±1.67歲，Ⅱ型癌平均年齡59.68±1.34歲，包括USC共15例，CCC共10例。根據(jù)WHO分級(jí)：Ⅰ型癌中高分化(G1)9例，中分化(G2)11例，低分化(G3)10例。Ⅱ型癌目前尚無統(tǒng)一的病理分級(jí)標(biāo)準(zhǔn)，未進(jìn)行分級(jí)。根據(jù)2009年國際婦產(chǎn)科聯(lián)合會(huì)(FIGO)子宮內(nèi)膜癌手術(shù)-病理分期， I型癌中I～I(xiàn)I期20例，III～Ⅳ期10例；Ⅱ型癌中I～I(xiàn)I期14例，III～Ⅳ期11例。所有病例都進(jìn)行了淋巴清掃，Ⅰ型癌中淋巴轉(zhuǎn)移者8例，未轉(zhuǎn)移者22例；Ⅱ型癌中淋巴轉(zhuǎn)移者8例，未轉(zhuǎn)移者17例。Ⅰ型癌中ER陰性表達(dá)3例，PR陰性表達(dá)4例，Ⅱ型癌中ER陰性表達(dá)15例，PR陰性表達(dá)17例，陽性者多為弱陽性表達(dá) 2IMP3、RFP、HER-2蛋白表達(dá)與臨床資料間的關(guān)系 IMP3、RFP、HER-2蛋白在Ⅱ型子宮內(nèi)膜癌中的陽性表達(dá)率分別為68％、84%、60%，，明顯高于子宮內(nèi)膜腺癌（P0.05）。IMP3，RFP蛋白在有、無淋巴結(jié)轉(zhuǎn)移組中的陽性表達(dá)率分別為50%（8/16）、8%（3/39）及44%（7/16）、13%（5/39），差異均有統(tǒng)計(jì)學(xué)意義（P0.05，P0.05）�？梢奍MP3、RFP蛋白的表達(dá)隨淋巴結(jié)的轉(zhuǎn)移而增加，說明IMP3、RFP陽性表達(dá)的患者更容易發(fā)生淋巴結(jié)轉(zhuǎn)移。而HER-2蛋白的表達(dá)與淋巴結(jié)轉(zhuǎn)移無關(guān)。IMP3、RFP、HER-2蛋白表達(dá)與腫瘤的臨床分期、腫瘤細(xì)胞分化級(jí)別無明顯相關(guān)性（P0.05）。 3IMP3、RFP、HER-2蛋白對(duì)Ⅰ、Ⅱ型子宮內(nèi)膜癌的鑒別意義 各單一腫瘤標(biāo)記物中，RFP的靈敏度最高為84%，但其特異度最低為80%，為彌補(bǔ)這一缺憾，對(duì)各腫瘤標(biāo)記物進(jìn)行組合，發(fā)現(xiàn)組合后的腫瘤標(biāo)記物中，IMP3+/RFP+的靈敏度和特異度、陽性預(yù)測值均最高，分別為64%、93.3%、88.9%。用logistic回歸分析IMP3、RFP、HER-2蛋白鑒別兩種類型子宮內(nèi)膜癌的價(jià)值，RFP的診斷價(jià)值最高（OR=10.826，95%可信區(qū)間為2.398～48.878），其次是IMP3（OR=5.261，95%可信區(qū)間為1.109～24.957），HER-2最差（OR=1.021，95%可信區(qū)間為0.218～4.775）。IMP3、RFP蛋白在鑒別Ⅰ型和Ⅱ型子宮內(nèi)膜腺癌方面具有診斷價(jià)值，結(jié)合所查臨床病理資料中ER、PR的表達(dá)情況，組合各指標(biāo)，采用logistic回歸分析發(fā)現(xiàn)，最佳診斷模式為IMP3+/RFP+（OR值為24.889，95%可信區(qū)間為4.777～129.688）。 結(jié)論： 1IMP3、RFP蛋白作為一種特異性很高的腫瘤標(biāo)記物主要表達(dá)于Ⅱ型子宮內(nèi)膜癌中，可用于區(qū)分兩種類型的子宮內(nèi)膜癌。 2HER-2蛋白在Ⅰ、Ⅱ型內(nèi)膜癌中的表達(dá)無明顯差異，但在子宮內(nèi)膜癌中的總表達(dá)率較高，提示其可能參與子宮內(nèi)膜癌的發(fā)生，為子宮內(nèi)膜癌的靶向治療提供新的靶點(diǎn)。 3IMP3、RFP蛋白的表達(dá)隨淋巴結(jié)的轉(zhuǎn)移而增加，說明IMP3、RFP陽性表達(dá)與淋巴結(jié)轉(zhuǎn)移有關(guān)。 4IMP3+/RFP+是診斷II型子宮內(nèi)膜癌最佳輔助診斷指標(biāo)，當(dāng)診斷出現(xiàn)困難時(shí)，有助于正確鑒別出II型子宮內(nèi)膜癌，為患者的臨床治療提供準(zhǔn)確的臨床依據(jù)。
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R737.33
本文編號(hào)：2168069
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R737.33
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