本文選題：乳腺癌 + 腫瘤異質(zhì)性　； 參考：《吉林大學(xué)》2015年博士論文

【摘要】：研究背景： 乳腺癌是一種嚴(yán)重威脅女性健康的惡性腫瘤，占女性全部惡性腫瘤的18%，已經(jīng)成為35-65歲婦女第一位死亡原因。盡管個(gè)體化的靶向治療和其他治療手段的快速發(fā)展顯著地延長了乳腺癌的生存期，但是我們?nèi)匀粚θ橄侔┲委熤邪邢蛑委熌退幖叭幮匀橄侔o有效治療藥物等問題束手無策。這主要是由于乳腺癌本身具有高度異質(zhì)性，發(fā)病因子、疾病演進(jìn)、治療反應(yīng)和器官轉(zhuǎn)移傾向等互異。要想徹底地戰(zhàn)勝乳腺癌，需要更深入地研究乳腺癌發(fā)生、發(fā)展相關(guān)的信號(hào)通路，尋找新的個(gè)體化治療靶點(diǎn)。鑒于PI3K/AKT/mTOR通路的上游成員例如ER、PR和HER2在乳腺癌的重要地位，同為上游成員的胰島素樣生長因子1受體（insulin-like growth factor1receptor，IGF-1R）引起研究者們的極大興趣。IGF-1R是一種異四倍體的細(xì)胞質(zhì)膜糖蛋白，為一種跨膜的酪氨酸蛋白受體。在結(jié)合胰島素樣生長因子配體后，通過自身磷酸化，激活PI3K以及MAPK信號(hào)通路，調(diào)控細(xì)胞的增殖、分化和衰老。該通路在乳腺癌中的高頻率失調(diào),并證實(shí)其介導(dǎo)的信號(hào)在乳腺癌的生長、演變、侵襲以及腫瘤血管生成、轉(zhuǎn)移中均扮演著重要的角色。作為腫瘤靶向治療最有前景的靶點(diǎn)之一，針對IGF-1R的靶向治療藥物也逐漸問世。早期的試驗(yàn)結(jié)果非常令人鼓舞，遺憾的是隨后進(jìn)行的試驗(yàn)中有很多結(jié)果是失敗的，這說明我們對信號(hào)通路的認(rèn)識(shí)并不充分,使得我們有必要更深層次地探討其調(diào)控機(jī)制，并進(jìn)一步尋找能夠預(yù)測抗IGF-1R治療效果的生物標(biāo)志物，，進(jìn)而選擇潛在獲益的正確的目標(biāo)人群。新近研究發(fā)現(xiàn)，曾經(jīng)被認(rèn)為是基因轉(zhuǎn)錄“副產(chǎn)品”或“暗物質(zhì)”的長鏈非編碼RNA（long non-codingRNA,LncRNA）能夠通過多種作用方式調(diào)控腫瘤細(xì)胞的基因表達(dá)，從而廣泛參與腫瘤的發(fā)生及轉(zhuǎn)移。LncRNA是指一類長度超過200個(gè)核苷酸的RNA分子的總稱，已經(jīng)成為當(dāng)今分子生物學(xué)最熱門的前沿研究領(lǐng)域之一。雖然在人類基因組中已經(jīng)發(fā)現(xiàn)了一些LncRNA，但關(guān)于其對基因組的調(diào)控及具體機(jī)制尚不清楚，國際上亦沒有任何關(guān)于LncRNA調(diào)控IGF-1R表達(dá)的報(bào)道。本課題客座導(dǎo)師胡繼繁教授前期采用他在《Science》上發(fā)表的研究染色質(zhì)空間結(jié)構(gòu)方法，尋找參與IGF-1R啟動(dòng)子區(qū)域的調(diào)控因子時(shí)在IGF-1R基因區(qū)發(fā)現(xiàn)一條全新的lnRNA，命名為IRAIN。依據(jù)IGF-1R通路在乳腺癌中的重要地位及IRAIN處于IGF-1R基因區(qū)這一事實(shí)，我們推測IRAIN在乳腺癌的發(fā)生、發(fā)展中扮演一定的角色，然而IRAIN在乳腺癌領(lǐng)域的研究仍處于完全空白狀態(tài)。 研究目的： 闡明一種全新的長鏈非編碼RNA IRAIN在正常乳腺組織及各分子亞型乳腺癌組織的的表達(dá)水平、表達(dá)特點(diǎn)及其與IGF-1R基因表達(dá)的相關(guān)性；進(jìn)一步明確調(diào)控IGF-1R信號(hào)通路的關(guān)鍵分子及其作用機(jī)制；揭示IRAIN與乳腺癌臨床病理因素和預(yù)后的相關(guān)性。為乳腺癌尋找有預(yù)測、預(yù)后價(jià)值的生物標(biāo)記物及個(gè)體化的乳腺癌治療靶點(diǎn)提供全新的思路和實(shí)驗(yàn)依據(jù)。 研究方法： 1.半定量逆轉(zhuǎn)錄聚合酶鏈反應(yīng)（RT-PCR）確定IRAIN mRNA是否表達(dá)于乳腺癌組織中。2.應(yīng)用實(shí)時(shí)熒光定量逆轉(zhuǎn)錄聚合酶鏈反應(yīng)(qRT-PCR)方法檢測IRAIN mRNA和IGF-1R mRNA在正常乳腺組織及不同分子亞型乳腺癌組織的表達(dá)水平、表達(dá)特點(diǎn)。3.應(yīng)用鏈方向特異性RT-PCR（Strand-Specific RT-PCR,SSRT-PCR）繪制IRAIN轉(zhuǎn)錄方向。4.用聚合酶鏈反應(yīng)-限制性酶切片段長度多態(tài)性分析法(PCR-RELP)及DNA測序方法分析乳腺細(xì)胞系及冰凍人乳腺癌組織中IRAIN SNP位點(diǎn)（rs8034564）雜合狀態(tài)及等位基因表達(dá)特點(diǎn)，明確該基因是否呈單等位印記表達(dá)。5. DNA測序方法追蹤印記親本來源，分析正常組織與乳腺癌組織以及乳腺癌原發(fā)部位與轉(zhuǎn)移部位印記的變化情況。6.結(jié)合重亞硫酸鹽的測序法（Bisulfite Genomic Sequence，BSP）分析IRAIN啟動(dòng)子DNA甲基化狀態(tài)，初探單等位印記表達(dá)及發(fā)生印記轉(zhuǎn)換的機(jī)制。7.統(tǒng)計(jì)學(xué)分析IRAIN mRNA和IGF-1R mRNA表達(dá)與乳腺癌臨床病理特征及預(yù)后之間的關(guān)系。 研究結(jié)果： 1．半定量分析表明IRAIN在乳腺癌中廣泛表達(dá)，表達(dá)水平各異。進(jìn)一步應(yīng)用實(shí)時(shí)熒光定量PCR方法對各分子分型乳腺癌及正常乳腺組織中IRAIN mRNA表達(dá)進(jìn)行定量分析，實(shí)驗(yàn)結(jié)果顯示，與正常乳腺組織相比,各分子亞型乳腺癌中IRAIN表達(dá)均降低,其中以三陰性乳腺癌降低最為明顯，HER2陽性型乳腺癌IRAIN表達(dá)也明顯低于正常乳腺組織，兩者差異均有統(tǒng)計(jì)學(xué)意義（P＜0.05）。Luminal型同樣低于正常乳腺組織，但無統(tǒng)計(jì)學(xué)意義。而對后三者做兩兩比較，無統(tǒng)計(jì)學(xué)意義（P＞0.05）。IGF-1R在預(yù)后最好的Luminal型中表達(dá)最高，與正常乳腺組織接近，而在預(yù)后差的TNB型和HER2+型表達(dá)明顯低于正常乳腺組織及Luminal型，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。對TNB型和HER2+型兩者做比較，無統(tǒng)計(jì)學(xué)意義（P＞0.05）。 2.選取IRAIN基因上兩個(gè)不同位置，在多個(gè)乳腺癌患者組織上應(yīng)用SSRT-PCR方法確定IRAIN轉(zhuǎn)錄方向，其結(jié)果均是一致的，IRAIN轉(zhuǎn)錄方向與IGF-1R mRNA的方向相反，闡明IRAIN為IGF-1R的反義長鏈非編碼RNA。 3．IRAIN在人正常乳腺組織中呈單等位基因表達(dá)，在乳腺癌組織中仍呈單等位基因表達(dá)。有趣的是，單等位基因呈不均衡表達(dá)，等位基因‘A’優(yōu)勢表達(dá)，18例SNP位點(diǎn)為雜合子的患者中，16例表達(dá)等位基因“A”，占89%，只有2例表達(dá)等位基因“G”占11%，目前還不清楚等位基因“A”的優(yōu)勢表達(dá)是否與這種非編碼RNA的功能相關(guān)。 4．為了確定IRAIN親本來源即是父源等位基因表達(dá)還是母源等位基因表達(dá)，我們進(jìn)行了家系追蹤篩查，結(jié)果表明IRAIN是父源等位基因表達(dá)、母源印記的基因。 5．首次發(fā)現(xiàn)乳腺癌組織中發(fā)生了異常的IRAIN等位基因印記轉(zhuǎn)換（allele-switch）現(xiàn)象，即同一患者的正常組織與乳腺癌組織IRAIN呈現(xiàn)不同父母來源的單等位基因表達(dá)，也見到乳腺癌原發(fā)部位與轉(zhuǎn)移部位印記轉(zhuǎn)換現(xiàn)象。 6．BSP方法分析富含CpG島的IRAIN基因啟動(dòng)子區(qū)DNA甲基化狀態(tài)，發(fā)現(xiàn)乳腺癌中IRAIN啟動(dòng)子區(qū)域甲基化異常，提示DNA甲基化可能參與調(diào)控IRAIN基因單等位印記表達(dá)及發(fā)生印記轉(zhuǎn)換。 7．IRAIN在正常乳腺組織中表達(dá)最高，在惡性程度高的三陰性乳腺癌及HER2陽性型乳腺癌顯著低表達(dá)，提示IRAIN可能作為抑癌基因，調(diào)控腫瘤細(xì)胞生長。IRAIN表達(dá)高低與患者月經(jīng)狀態(tài)、腫瘤直徑、淋巴結(jié)轉(zhuǎn)移情況、組織學(xué)分級(jí)、脈管癌栓及增殖指數(shù)無顯著相關(guān)性。 研究結(jié)論： 1．本研究發(fā)現(xiàn)全新的位于IGF-1R基因區(qū)的長鏈非編碼RNA IRAIN在乳腺癌中廣泛表達(dá)，IRAIN在正常乳腺組織中表達(dá)最高，在惡性程度高的三陰性乳腺癌及HER2陽性型乳腺癌顯著低表達(dá)，提示IRAIN可能作為抑癌基因，調(diào)控腫瘤細(xì)胞生長。 2．IRAIN轉(zhuǎn)錄方向與IGF-1R mRNA的方向相反，是IGF-1R基因的反義長鏈非編碼RNA。 3．IRAIN在人正常乳腺組織及乳腺癌組織中呈單等位基因表達(dá)，單等位基因呈不均衡表達(dá)，優(yōu)勢表達(dá)其中一條等位基因。是父源等位基因表達(dá)、母源印記的基因，與其啟動(dòng)子區(qū)DNA甲基化異常有關(guān)，是人類基因組為數(shù)不多印記基因中新發(fā)現(xiàn)的成員之一。 4．首次發(fā)現(xiàn)乳腺癌中存在IRAIN等位基因印記轉(zhuǎn)換（allele-switch）現(xiàn)象，這在乳腺癌和其他惡性腫瘤中國內(nèi)外均未見報(bào)道，如果像我們推測的IRAIN作為抑癌基因，那么印記轉(zhuǎn)換很可能是抑癌基因失活的一種全新的方式，正如印記丟失(LOI)在腫瘤中的地位一樣，是一種標(biāo)志性的事件。 5．IRAIN有望成為對乳腺癌有預(yù)測、預(yù)后價(jià)值的生物標(biāo)記物及個(gè)體化的乳腺癌治療靶點(diǎn)。 6．IRAIN的研究得到了權(quán)威機(jī)構(gòu)的認(rèn)可，在2014年末IRAIN被世界最權(quán)威的美國國立生物信息中心基因庫（gene bank）驗(yàn)證通過，將它收錄入庫，Gene ID:104472848。
[Abstract]:Research background:
Breast cancer is a malignant tumor that is a serious threat to women's health, which accounts for 18% of all women's malignant tumors. It has become the first cause of death for women at the age of 35-65. Although the rapid development of individual targeted therapy and other treatment means significantly prolongs the survival period of breast cancer, it is still a target treatment for breast cancer treatment. Drug resistance and three negative breast cancer have no effective drug treatment. This is mainly due to the high heterogeneity of breast cancer itself, the pathogenesis, the evolution of the disease, the treatment response and the tendency of the organ metastasis. To overcome breast cancer thoroughly, it is necessary to study breast cancer in depth, develop related signaling pathways, and seek for the development of related signaling pathways. New individualized therapeutic targets. In view of the importance of the upstream members of the PI3K/AKT/mTOR pathway such as ER, PR and HER2 in breast cancer, and the upstream members of the insulin like growth factor 1 receptor (insulin-like growth factor1receptor, IGF-1R), the great interest of the researchers is that.IGF-1R is an isotetraploid cytoplasmic membrane glycoprotein. A transmembrane tyrosine receptor. After binding to the IGF ligand, the PI3K and MAPK signaling pathways are activated by autophosphorylation to regulate cell proliferation, differentiation and senescence. The high frequency of this pathway in breast cancer is high, and its mediated signal is demonstrated in the growth, evolution, invasion, and angiogenesis of breast cancer. As one of the most promising targets for tumor targeting therapy, the targeting therapy for IGF-1R is also coming out. Early results were very encouraging. Unfortunately, many results were failed in subsequent trials, which indicated that we were not fully aware of the signaling pathways. It makes it necessary for us to further explore its regulatory mechanism, and to further explore biomarkers that can predict the effectiveness of anti IGF-1R therapy, and then select the right target population with potential benefits. Recently, the new study found that the long chain non coded RNA (long non-codingRNA), which was once considered as a "by-product" or "dark matter", was considered to be a gene transcription. LncRNA) can regulate the gene expression of tumor cells through a variety of ways of action, so it is widely involved in the occurrence and metastasis of tumor..LncRNA is the general name of a class of RNA molecules with a length of more than 200 nucleotides. It has become one of the most popular frontiers in molecular biology. Although a number of human genome has been found in the human genome, it has been found in the human genome. Some LncRNA, but it is not clear about its regulation of the genome and its specific mechanism, and there are no reports on the LncRNA regulation of IGF-1R expression in the world. Professor Hu Jifan, the guest tutor of the subject, used his previous study on chromatin spatial structure, published on , to find the regulatory factors involved in the IGF-1R promoter region in I The GF-1R gene region found a new lnRNA, named as IRAIN. based on the IGF-1R pathway in breast cancer and the fact that IRAIN is in the IGF-1R gene region. We speculate that IRAIN plays a role in the development of breast cancer and the development of IRAIN in the field of breast cancer is still completely blank.
The purpose of the study is:
To clarify the expression level, expression of a new long chain non coding RNA IRAIN in normal breast tissue and the subtype of subtype breast cancer, and the correlation with IGF-1R gene expression; further clarify the key molecules of the IGF-1R signaling pathway and its mechanism of action, and reveal the clinicopathological factors and prognosis of IRAIN and breast cancer. It provides a new idea and experimental basis for breast cancer to find biomarkers with prognostic value and individualized target for breast cancer treatment.
Research methods:
1. semi quantitative reverse transcriptase polymerase chain reaction (RT-PCR) determination of the expression of IRAIN mRNA in breast cancer tissues by.2. application real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) method to detect the expression of IRAIN mRNA and IGF-1R mRNA in normal mammary tissues and different molecular subtypes of breast cancer tissues, and to express the direction of.3. application chain. Specific RT-PCR (Strand-Specific RT-PCR, SSRT-PCR) plotted IRAIN transcriptional direction.4. using polymerase chain reaction restriction fragment length polymorphism analysis (PCR-RELP) and DNA sequencing method to analyze the heterozygous state and allele expression characteristics of IRAIN SNP loci (rs8034564) in breast cell lines and frozen human breast cancer tissues. The.5. DNA sequencing method was used to trace the source of the imprinted parent, and to analyze the changes of the normal tissue and breast cancer tissue, the original site of the breast cancer and the imprint of the metastatic site..6. binding heavy sulfite sequencing method (Bisulfite Genomic Sequence, BSP) was used to analyze the DNA methylation status of IRAIN promoter, and the single allele was first explored. The mechanism of imprinting expression and imprinting transformation.7. statistical analysis of the relationship between IRAIN mRNA and IGF-1R mRNA expression and clinicopathological features and prognosis of breast cancer.
The results of the study:
1. semi quantitative analysis showed that IRAIN was widely expressed in breast cancer and the expression level was different. The quantitative analysis of IRAIN mRNA expression in all molecular types of breast cancer and normal breast tissue was analyzed by real-time fluorescence quantitative PCR. The results showed that the expression of IRAIN in the subtypes of breast cancer was lower than that of normal mammary tissues. The expression of three negative breast cancer was the most obvious, and the expression of IRAIN in HER2 positive breast cancer was significantly lower than that of normal breast tissue. The difference was statistically significant (P < 0.05).Luminal type was also lower than that of normal breast tissue, but no statistical significance was found. There was no statistical significance (P > 0.05).IGF-1R at the most prognosis (P > 0.05).IGF-1R in the prognosis. The highest expression in the good Luminal type was close to the normal breast tissue, but the expression of TNB and HER2+ in the poor prognosis was significantly lower than that of the normal breast tissue and the Luminal type (P < 0.05). There was no statistically significant difference between the TNB and the HER2+ type (P > 0.05).
2. select the two different positions of IRAIN gene and determine the IRAIN transcriptional direction by SSRT-PCR method in the tissues of multiple breast cancer patients. The results are all consistent. The IRAIN direction is opposite to the direction of IGF-1R mRNA, and the antisense long chain uncoded RNA. IRAIN is IGF-1R.
The expression of single allele in human normal mammary tissues and single allele are still expressed in breast cancer tissues. It is interesting that the single allele is unevenly expressed and the allele 'A' superiority is expressed. In 18 SNP loci as heterozygotes, 16 alleles are "A", accounting for 89%, and only 2 expression alleles "G" "11%", it is unclear whether the dominant expression of allele "A" is related to the function of this non coding RNA.
4. in order to determine whether the parent source of IRAIN is the parent allele or the mother source allele, we carried out a family tracking screening. The results showed that IRAIN was the parent allele expression and the parent imprinted gene.
5. the abnormal IRAIN allelic imprint conversion (allele-switch) phenomenon was found in the breast cancer tissue for the first time. That is, the normal tissue of the same patient and the breast cancer tissue IRAIN present the single allele expression of different parent sources, and also the original location of the breast cancer and the transfer part of the breast cancer.
The 6.BSP method analyzed the DNA methylation status of the IRAIN gene promoter region of the rich CpG Island, and found the abnormal methylation in the IRAIN promoter region of the breast cancer, suggesting that DNA methylation may be involved in the regulation of the single allelic expression of the IRAIN gene and the alteration of the imprinting of the IRAIN gene.
The expression of 7.IRAIN is the highest in normal breast tissue, which is significantly lower in three negative breast cancer and HER2 positive breast cancer, suggesting that IRAIN may be used as a tumor suppressor gene to regulate the level of.IRAIN expression in tumor cell growth and the patient's menstrual state, tumor diameter, lymph node metastasis, histological grading, vascular tumor thrombus and proliferation. There was no significant correlation between the index and the index.
The conclusions are as follows:
1. we found that the new long chain non coded RNA IRAIN located in the IGF-1R gene region is widely expressed in breast cancer. IRAIN is expressed in the normal breast tissue, and the high level of malignant breast cancer and HER2 positive breast cancer are significantly lower, suggesting that IRAIN may act as a tumor suppressor gene and regulate the growth of tumor cells.
The direction of 2.IRAIN transcription is opposite to that of IGF-1R mRNA, which is an antisense long chain non coding RNA. of IGF-1R gene.
3.IRAIN is one of the single alleles expressed in human normal breast tissue and breast cancer tissue. The single allele is unevenly expressed, and one of the alleles is expressed. It is the expression of the allele of the parent source. The gene of the parent imprint is related to the abnormal DNA methylation in the promoter region. It is a new discovery in the few imprinted genes of the human genome. One of the members.
4. the IRAIN allele imprinted conversion (allele-switch) phenomenon is found in breast cancer for the first time, which is not reported in both breast and other malignant tumors. If we speculate that IRAIN is a tumor suppressor gene, imprint conversion is likely to be a new way of inactivation of the tumor suppressor gene, as the loss of LOI (LOI) is swollen. The same position in the tumor is a landmark event.
5.IRAIN is expected to become a biomarker for predicting and prognostic value of breast cancer and an individualized target for breast cancer therapy.
6.IRAIN's research was approved by authoritative institutions, and at the end of 2014, IRAIN was approved by the world's most authoritative US National bioinformation center gene library (gene bank) to include it in the library, Gene ID:104472848..
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R737.9

【共引文獻(xiàn)】

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1 李世超;姜軍;楊新華;張毅;范林軍;張帆;劉靜;孫鵬;王明浩;;乳腺癌分子分型與外周血循環(huán)腫瘤細(xì)胞相關(guān)性探討[J];第三軍醫(yī)大學(xué)學(xué)報(bào);2012年10期

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