本文選題：碘難治 + 甲狀腺癌��； 參考：《山東大學》2017年碩士論文

【摘要】：目的甲狀腺癌是內(nèi)分泌系統(tǒng)發(fā)病率最高的惡性腫瘤,雖然分化型甲狀腺癌患者大部分都有良好的預后,但是依然有5%的分化型甲狀腺癌的患者出現(xiàn)了遠處轉(zhuǎn)移,2/3的遠處轉(zhuǎn)移的患者和未分化型甲狀腺癌一樣,失去了對碘的攝取能力,這部分發(fā)生遠處轉(zhuǎn)移失去攝碘能力的分化型甲狀腺癌被稱為碘難治性分化型甲狀腺癌(Radioiodine Refractory Thyroid Cancer,RAI-R DTC)。碘難治性分化型甲狀腺癌患者預后較差,和大部分預后良好的分化型甲狀腺癌區(qū)別巨大。本研究對碘難治性甲狀腺癌患者病理組織進行搜集,對山東省齊魯醫(yī)院2002-2015年間行131I治療,并符合《美國甲狀腺協(xié)會2015年(American Thyroid Association,ATA)成人甲狀腺結(jié)節(jié)和分化型甲狀腺癌管理指南》中對于碘難治性甲狀腺癌診斷的患者,對這部分患者的病理組織進行NIS、OCT4和CD133的免疫組化表達分析。探索碘難治型分化型甲狀腺癌對放射碘治療不敏感的分子病理機制,為碘難治分化型甲狀腺癌的進一步治療提供新的思路。方法搜集山東大學齊魯醫(yī)院2002-2015年間進行131I治療的病人資料,選取符合《美國甲狀腺協(xié)會2015年(American Thyroid Association,ATA)成人甲狀腺結(jié)節(jié)和分化型甲狀腺管理指南》中對于碘難治性分化型甲狀腺癌的診斷標準,搜集這部分患者的病理組織標本。根據(jù)文獻報導,NIS可能是造成碘難治患者對放射治療不敏感的原因,選取NIS為目標蛋白進行研究。有證據(jù)顯示,OCT4基因?qū)τ诰S持細胞多能性具有重要作用,與腫瘤細胞的惡性生物學特點和傳統(tǒng)治療抵抗性之間有一定關(guān)系,因此在本研究中把OCT4蛋白作為研究的目標之一。腫瘤干細胞學說的提出,讓人們對腫瘤發(fā)生和發(fā)展有了新的認識,有研究指出,CD133為生物學標志的腫瘤干細胞對傳統(tǒng)的化療和放療具有抵抗作用,因此在本研究中,選取CD133為研究目標。對患者的病理組織行目標蛋白的免疫組化染色分析,探究與同位素碘治療不敏感之間的相關(guān)性。結(jié)果1.NIS在碘難治遠處轉(zhuǎn)移DTC中和對照組中的表達NIS表達在甲狀腺濾泡的胞漿,細胞核未見表達(圖1)。RAI-RDTC組NIS的陽性表達率為57.14%,RAIDTC組和正常對照組NIS的陽性表達率都達到了100%。最終的免疫組化評分顯示,RAI-RDTC組為4.29±1.77,RAIDTC組為9.57±1.57,正常對照組10.14±0.94,RAI-RDTC組中NIS的陽性表達率明顯低于RAIDTC組和正常對照組。免疫組化評分結(jié)果顯示,RAI-RDTC組NIS表達明顯少于RAI DTC組和正常對照組,RAI DTC組和正常對照組之間則無明顯差異(表2)。2.0CT4在碘難治遠處轉(zhuǎn)移DTC和對照組中的表達在正常對照組沒有觀察到OCT4蛋白的表達,在RAI-R DTC和RAI DTC組,OCT4表達在甲狀腺濾泡細胞和癌灶細胞的細胞核,胞漿不表達(圖1)。在RAI-R DTC和RAI DTC組,OCT4的陽性表達率都高達100%,且最終的免疫組化評分組間沒有統(tǒng)計學差異。3,CD133在碘難治遠處轉(zhuǎn)移DTC中和對照組中的表達在RAI-RDTC組中CD133散在表達在甲狀腺濾泡細胞和癌灶細胞的胞漿和膜上。在RAI-RDTC組CD133的陽性表達率為71.43%,在RAI DTC組CD133的陽性表達率為42.85%,正常(陰性)對照組,未觀察到CD133表達。最終的免疫組化評分 RAI-RDTC組為6.86±2.14,RAIDTC 組為 1.71 ±0.92(表1),RAI-R DTC組CD133的陽性表達率和免疫組化評分分都較RAI DTC組和正常對照組明顯升高(圖1.P0.05)。結(jié)論1.碘難治性分化型甲狀腺癌背后的可能原因之一是NIS的表達降低,從而導致細胞從血液向細胞內(nèi)轉(zhuǎn)運的碘減少,對碘的攝取和蓄積能力降低;2.CD133在碘難治性DTC患者的病理組織中相對于對照組表達明顯升高。3.OCT4雖然在正常甲狀腺結(jié)節(jié)組織中的未檢測到表達,但是在RAI-R DTC組和RAI DTC組中都顯示高表達,提示OCT4可能不是造成碘同位素治療不敏感的主要原因,但是對于甲狀腺癌的發(fā)生發(fā)展有一定意義。
[Abstract]:Objective thyroid cancer is the highest incidence of malignant neoplasm in the endocrine system. Although most of the patients with differentiated thyroid cancer have good prognosis, 5% of the patients with differentiated thyroid cancer still have distant metastasis. The patients with distant metastases of 2/3 and undifferentiated thyroid cancer have lost the ability to absorb iodine. Differentiated thyroid carcinoma that partially metastases and loses iodine uptake is called Radioiodine Refractory Thyroid Cancer (RAI-R DTC). The prognosis of patients with iodized differentiated thyroid cancer is poor and is very different from that of most well differentiated thyroid cancers. The pathological tissue of patients with adenocarcinoma was collected and treated with 131I in Qilu Hospital of Shandong province for 2002-2015 years. It was in line with < 2015 (American Thyroid Association, ATA) adult thyroid nodule and differentiated thyroid cancer management guide > for the diagnosis of iodine refractory thyroid cancer, and the pathology of this part of the patients. The immunohistochemical expression analysis of NIS, OCT4 and CD133 was carried out to explore the molecular pathological mechanism of iodine refractory differentiated thyroid carcinoma which was insensitive to radioiodine treatment, providing a new idea for further treatment of iodine refractory differentiated thyroid cancer. Methods the data of patients with 131I treatment in Qilu Hospital of Shandong University were collected for 2002-2015 years. Select the diagnostic criteria for iodine refractory differentiated thyroid carcinoma in accordance with the American Thyroid Association (ATA) Association (ATA) adult thyroid nodule and differentiated thyroid management guide, and collect the pathological tissue specimens of this part of the patients. According to the literature, NIS may be a radiation therapy for patients with iodine refractory. The cause of insensitivity is to select NIS as the target protein. There is evidence that the OCT4 gene plays an important role in maintaining cell pluriability, and has a certain relationship with the malignant biological characteristics of the tumor cells and the traditional treatment resistance. Therefore, the OCT4 protein is one of the research goals in this study. It is suggested that people have a new understanding of the occurrence and development of tumor. It is pointed out that the tumor stem cells with CD133 as a biological marker are resistant to traditional chemotherapy and radiotherapy. Therefore, in this study, CD133 is selected as the research target. The immunohistochemical staining analysis of the target protein of the pathological tissue of the patients is used to explore and explore the isotope iodine. The correlation between treatment insensitivity. Results 1.NIS expression in DTC and control group was expressed in the cytoplasm of thyroid follicular, the nucleus was not expressed in the nucleus of thyroid follicular, and the positive expression rate of NIS in group.RAI-RDTC was 57.14%. The positive expression rate of NIS in group RAIDTC and normal control group reached the final immunohistochemical score of 100%.. The results showed that the RAI-RDTC group was 4.29 + 1.77, the RAIDTC group was 9.57 + 1.57 and the normal control group was 10.14 0.94. The positive expression rate of NIS in the RAI-RDTC group was significantly lower than that in the RAIDTC group and the normal control group. The immunohistochemical score showed that the NIS expression in the RAI-RDTC group was significantly less than that in the RAI DTC group and the normal control group, and there was no significant difference between the RAI DTC group and the normal control group. The expression of.2.0CT4 in DTC and control group was not observed in normal control group. In the normal control group, the expression of OCT4 protein was not observed. In the group of RAI-R DTC and RAI DTC, OCT4 was expressed in the nuclei of the thyroid follicle cells and cancer cells, and the cytoplasm was not expressed (Fig. 1). In RAI-R DTC and RAI DTC groups, the positive expression rate was up to 100%, and the most of them were in the RAI-R DTC and RAI DTC groups. There was no statistical difference between the final immunohistochemical score groups.3, the expression of CD133 in DTC and the control group in the iodine refractory distant metastasis, CD133 scattered in the cytoplasm and membrane of the thyroid follicle cells and cancer cells in the RAI-RDTC group. The positive expression rate of CD133 in the RAI-RDTC group was 71.43%, and the positive expression rate of CD133 in RAI DTC group was 42.85%, In the normal (negative) control group, the expression of CD133 was not observed. The final immunohistochemical score in the RAI-RDTC group was 6.86 + 2.14, the RAIDTC group was 1.71 + 0.92 (Table 1). The positive and immunohistochemical scores of CD133 in the RAI-R DTC group were significantly higher than those in the RAI DTC group and the normal control group (Fig. 1.P0.05). Conclusion behind the conclusion of 1. iodine refractory differentiated thyroid carcinoma One of the possible reasons is the decrease in the expression of NIS, which leads to the decrease of the iodized iodine from the blood to the cell and the decrease in the uptake and accumulation of iodine; the expression of 2.CD133 in the pathological tissue of the iodized DTC patients is significantly higher than that of the control group, although the expression in the normal thyroid gland nodules is not detected, but the expression of.3.OCT4 is not detected, but the expression of the cells is not detected in the normal thyroid nodule tissue. High expression in both RAI-R DTC and RAI DTC groups suggests that OCT4 may not be the main cause of insensitivity to iodine isotopes, but it is of certain significance for the development of thyroid cancer.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R736.1

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