本文選題：結(jié)腸癌 + Musashi1��； 參考：《河北醫(yī)科大學(xué)》2016年博士論文

【摘要】：結(jié)腸癌是全球范圍內(nèi)消化道最常見的惡性腫瘤之一,其發(fā)病率在我國(guó)僅次于胃癌和食道癌,位居第三,且近年來(lái)發(fā)病率持續(xù)升高,預(yù)后差。有關(guān)其發(fā)病機(jī)制及防治措施的研究是生物醫(yī)學(xué)領(lǐng)域研究的熱點(diǎn)之一。結(jié)腸癌的發(fā)生是在不同遺傳背景下由致癌基因的激活和抑癌基因的失活共同作用的結(jié)果。轉(zhuǎn)錄后調(diào)控是基因表達(dá)的關(guān)鍵部分,這一過(guò)程主要受RNA結(jié)合蛋白(RNA-Binding Proteins,RBPs)的調(diào)節(jié)。業(yè)已證實(shí),人體基因組中包含有800多種RBPs,其中的幾種被發(fā)現(xiàn)控制著與癌變過(guò)程相關(guān)的基因網(wǎng)絡(luò)。對(duì)RBPs深入的研究逐步揭示,它們與轉(zhuǎn)錄因子類似,具有抑癌和促癌作用。Musashi1(Msi1)作為一種進(jìn)化保守的RNA結(jié)合蛋白家族成員,對(duì)于維持自我更新與分化之間的平衡具有重要作用。眾多研究表明,Msi1可作為一種致癌基因,也是多種腫瘤干細(xì)胞和(或)祖細(xì)胞的重要標(biāo)記物,能刺激腫瘤干、祖細(xì)胞的形成和發(fā)展。過(guò)度表達(dá)Msi1的腸上皮祖細(xì)胞可通過(guò)激活Wnt、Notch信號(hào)通路及調(diào)節(jié)p21這三個(gè)作用靶點(diǎn),使細(xì)胞增殖旺盛,促進(jìn)祖細(xì)胞的致瘤性,增加移植瘤的致瘤性。一般認(rèn)為,腫瘤干細(xì)胞對(duì)放化療抗拒,是腫瘤發(fā)生、發(fā)展和復(fù)發(fā)、轉(zhuǎn)移的根源。Msi1可能通過(guò)促進(jìn)β-鏈蛋白(β-catenin)的核內(nèi)聚,增加結(jié)腸癌放療的不敏感性,促進(jìn)侵襲性腫瘤發(fā)展。此外Msi1位于多個(gè)信號(hào)通路的交匯點(diǎn),是細(xì)胞基因表達(dá)的關(guān)鍵調(diào)節(jié)器,在細(xì)胞發(fā)育和內(nèi)環(huán)境穩(wěn)態(tài)中發(fā)揮重要作用。同時(shí),Msi1也可作為多種癌變的關(guān)鍵調(diào)節(jié)劑,參與腫瘤的發(fā)生和發(fā)展。Msi1有望成為防治癌癥的一個(gè)分子靶點(diǎn)。因此,確定Msi1在結(jié)腸癌中的作用及其機(jī)制具有重要的理論意義和潛在的應(yīng)用價(jià)值。但目前有關(guān)Msi1對(duì)結(jié)腸癌細(xì)胞的作用及其機(jī)制尚不明確。本研究旨在探討Msi1在結(jié)腸癌發(fā)生、發(fā)展中的作用及其機(jī)制,以及對(duì)放療敏感性的影響。本課題研究將分四部分進(jìn)行。1.首先在結(jié)腸癌患者的癌組織和結(jié)腸癌細(xì)胞系證實(shí)Msi1的高表達(dá),通過(guò)RNA干擾技術(shù)構(gòu)建沉默msi1穩(wěn)轉(zhuǎn)細(xì)胞系;2.探討沉默msi1對(duì)結(jié)腸癌細(xì)胞生物學(xué)特性的影響;3.探討沉默msi1對(duì)結(jié)腸癌細(xì)胞生長(zhǎng)影響的分子機(jī)制;4.探討沉默msi1對(duì)結(jié)腸癌細(xì)胞放療敏感性的影響。第一部分結(jié)腸癌組織和細(xì)胞中musashi1蛋白表達(dá)及musashi1穩(wěn)定低表達(dá)結(jié)腸癌細(xì)胞系構(gòu)建目的:檢測(cè)musashi1在結(jié)腸癌組織和結(jié)腸癌細(xì)胞系的表達(dá)水平;構(gòu)建msi1穩(wěn)定低表達(dá)結(jié)腸癌細(xì)胞系。方法:采用westernblot方法檢測(cè)結(jié)腸癌患者癌組織、癌周正常組織、以及hct116、sw480和sw620三種結(jié)腸癌細(xì)胞系中msi1的蛋白表達(dá),挑選msi1表達(dá)水平最高的結(jié)腸癌細(xì)胞系進(jìn)行后續(xù)研究。應(yīng)用rna干擾技術(shù)設(shè)計(jì)沉默msi1的基因序列及陰性對(duì)照序列,通過(guò)與質(zhì)粒連接后感染工具細(xì)胞,將干擾質(zhì)粒及陰性對(duì)照質(zhì)粒植入慢病毒載體,隨后感染結(jié)腸癌細(xì)胞;經(jīng)過(guò)抗生素篩選獲得穩(wěn)定低表達(dá)細(xì)胞株,并運(yùn)用real-timepcr及westernblot的方法從rna水平和蛋白水平檢測(cè)空白組(blank)、陰性對(duì)照組(negativecontrol,nc)和敲低組(knockdown,kd)hct116結(jié)腸癌細(xì)胞基因沉默的效果。結(jié)果:通過(guò)westernblot方法檢測(cè),發(fā)現(xiàn)與正常腸粘膜相比,結(jié)腸癌組織及三種結(jié)腸癌細(xì)胞株中msi1蛋白均特異性高表達(dá);在hct116、sw480、sw620三種結(jié)腸癌細(xì)胞株中,hct116細(xì)胞msi1蛋白的表達(dá)量最高,因此選取hct116細(xì)胞作為后續(xù)研究的目的細(xì)胞。本研究中,成功構(gòu)建了帶有干擾msi1基因序列g(shù)v248-msi1-shrna的慢病毒及陰性對(duì)照慢病毒gv248-nc-shrna,將干擾慢病毒及陰性對(duì)照慢病毒感染結(jié)腸癌hct116細(xì)胞,利用嘌呤霉素篩選出穩(wěn)定的表達(dá)株。同時(shí)real-timepcr和westernblot結(jié)果顯示,感染msi1干擾慢病毒載體后結(jié)腸癌hct116細(xì)胞msi1在rna水平和蛋白水平分別下降了73.85%和59.01%。小結(jié):結(jié)腸癌組織及結(jié)腸癌細(xì)胞株中msi1蛋白均特異性高表達(dá)。利用結(jié)腸癌hct116細(xì)胞株可成功構(gòu)建穩(wěn)定低表達(dá)msi1細(xì)胞系。第二部分沉默musashi1對(duì)結(jié)腸癌hct116細(xì)胞生物學(xué)特性的影響目的:探討沉默musashi1對(duì)結(jié)腸癌hct116細(xì)胞生物學(xué)特性的影響。方法:利用構(gòu)建穩(wěn)定低表達(dá)msi1的結(jié)腸癌hct116細(xì)胞,應(yīng)用mts法檢測(cè)沉默msi1后結(jié)腸癌細(xì)胞增殖情況,應(yīng)用流式細(xì)胞儀檢測(cè)細(xì)胞周期及凋亡的變化,transwell小室檢測(cè)其體外侵襲能力,腫瘤球?qū)嶒?yàn)檢測(cè)腫瘤細(xì)胞干性。并通過(guò)建立裸鼠移植瘤模型,觀察沉默msi1對(duì)裸鼠成瘤的影響。結(jié)果:mts法及transwell小室檢測(cè)結(jié)果顯示,沉默msi1后,結(jié)腸癌hct116細(xì)胞體外增殖及侵襲能力顯著下降。流式細(xì)胞檢測(cè)結(jié)果顯示,沉默msi1后腫瘤細(xì)胞的凋亡明顯增加,g0/g1期細(xì)胞增多。腫瘤球?qū)嶒?yàn)結(jié)果顯示,沉默msi1可明顯降低腫瘤球形成的數(shù)量。結(jié)腸癌hct116細(xì)胞裸鼠皮下移植瘤結(jié)果顯示,降低msi1表達(dá)可明顯抑制移植瘤的生長(zhǎng)。小結(jié):沉默msi1能抑制結(jié)腸癌hct116細(xì)胞體外增殖能力和侵襲能力,導(dǎo)致細(xì)胞g0/g1期阻滯,誘導(dǎo)細(xì)胞凋亡。沉默msi1可明顯降低結(jié)腸癌hct116細(xì)胞的干性,抑制移植瘤的生長(zhǎng)。第三部分沉默musashi1對(duì)結(jié)腸癌hct116細(xì)胞生長(zhǎng)抑制的分子機(jī)制目的:探討沉默musashi1抑制結(jié)腸癌hct116細(xì)胞生長(zhǎng)的分子機(jī)制。方法:利用real-timepcr和westernblot技術(shù)檢測(cè)沉默msi1基因后細(xì)胞周期蛋白依賴性激酶抑制物p21(抑癌基因)mrna和蛋白的表達(dá)水平,并構(gòu)建p213’-utr熒光素酶報(bào)告基因載體(p21wt)及其突變體(p21mu),將報(bào)告基因載體轉(zhuǎn)染沉默msi1的細(xì)胞和對(duì)照組細(xì)胞株,計(jì)算msi1敲低組細(xì)胞與對(duì)照組細(xì)胞的熒光比值,并進(jìn)行比較以判斷p213’-utr區(qū)活性。結(jié)果:westernblot方法檢測(cè)發(fā)現(xiàn),與空白組及陰性對(duì)照組相比較,沉默msi1后結(jié)腸癌hct116細(xì)胞的p21蛋白表達(dá)明顯上調(diào);real-timepcr結(jié)果顯示,3組細(xì)胞p21mrna水平的表達(dá)未見明顯變化。進(jìn)一步熒光素酶報(bào)告實(shí)驗(yàn)結(jié)果顯示,與空白組、陰性對(duì)照組相比,敲低組p21wt的熒光素酶活性明顯上升,msi1反應(yīng)位點(diǎn)突變體p21mu的熒光素酶活性則沒有明顯變化。小結(jié):結(jié)腸癌hct116細(xì)胞中,msi1能夠與其靶基因p21mrna的3’-utr區(qū)特異性的結(jié)合,并抑制其翻譯,下調(diào)p21蛋白表達(dá),進(jìn)而促進(jìn)腫瘤細(xì)胞生長(zhǎng)。沉默msi1后可通過(guò)上調(diào)p21蛋白的表達(dá),發(fā)揮抑制腫瘤生長(zhǎng)作用。第四部分沉默musashi1對(duì)結(jié)腸癌hct116細(xì)胞放療敏感性的影響目的:探討沉默musashi1對(duì)結(jié)腸癌hct116細(xì)胞放療敏感性的影響。方法:采用慢病毒介導(dǎo)的Msi1干擾表達(dá)質(zhì)粒感染HCT116細(xì)胞;對(duì)感染的HCT116細(xì)胞進(jìn)行X線照射;運(yùn)用克隆實(shí)驗(yàn)檢測(cè)沉默Msi1基因?qū)CT116細(xì)胞放射敏感性的影響。通過(guò)MTS法檢測(cè)照射后結(jié)腸癌細(xì)胞增殖情況,并計(jì)算其抑制率。運(yùn)用流式細(xì)胞術(shù)檢測(cè)照射后細(xì)胞周期及凋亡的變化。結(jié)果:克隆形成實(shí)驗(yàn)顯示,經(jīng)0~8Gy X線照射后,敲低組細(xì)胞存活曲線下降,D0、Dq、N和SF2值均明顯低于空白組和陰性對(duì)照組,相對(duì)于空白組和陰性對(duì)照組放射增敏比SER分別為1.56和1.47。MTS試驗(yàn)結(jié)果顯示,各時(shí)間段敲低組細(xì)胞的增殖活性均顯著低于空白組和陰性對(duì)照組,而且隨著時(shí)間和劑量的增加,各組抑制率逐漸增加。進(jìn)一步流式細(xì)胞術(shù)顯示,照射后各組細(xì)胞凋亡率明顯增加,并呈現(xiàn)時(shí)間依賴性,隨著時(shí)間延長(zhǎng),凋亡率逐漸增加。敲低組凋亡比例在各時(shí)間點(diǎn)增加的程度更加明顯。并且照射后敲低組細(xì)胞G2/M期比例較空白組和陰性對(duì)照組顯著下降。小結(jié):抑制結(jié)腸癌HCT116細(xì)胞Msi1基因表達(dá)具有放療增敏作用,其增敏機(jī)制可能是通過(guò)促進(jìn)細(xì)胞凋亡,解除放療后細(xì)胞G2/M期阻滯,從而增加結(jié)腸癌HCT116細(xì)胞的放療敏感性。結(jié)論:1結(jié)腸癌組織及結(jié)腸癌細(xì)胞株中Msi1蛋白均特異性高表達(dá),提示Msi1可能在結(jié)腸癌發(fā)生與發(fā)展中起重要作用;2利用結(jié)腸癌HCT116細(xì)胞可成功構(gòu)建穩(wěn)定低表達(dá)Msi1的細(xì)胞株;3沉默Msi1可抑制結(jié)腸癌HCT116細(xì)胞增殖和侵襲能力,導(dǎo)致細(xì)胞G0/G1期阻滯,誘導(dǎo)細(xì)胞凋亡,降低細(xì)胞干性,抑制移植瘤的生長(zhǎng);4沉默Msi1可上調(diào)結(jié)腸癌HCT116細(xì)胞Msi1的靶基因p21蛋白的表達(dá),發(fā)揮抑制腫瘤生長(zhǎng)的作用;5沉默Msi1可通過(guò)促進(jìn)結(jié)腸癌HCT116細(xì)胞凋亡,解除放療后細(xì)胞G2/M期阻滯,發(fā)揮放療增敏作用。
[Abstract]:Colon cancer is one of the most common malignant tumors in the digestive tract around the world. Its incidence is third only second to gastric cancer and esophagus cancer in our country. In recent years, the incidence of cancer is increasing and the prognosis is poor. The research on its pathogenesis and prevention measures is one of the hot spots in the field of biomedical research. The occurrence of colon cancer is in different heredity In the background, the result of the activation of the oncogene and the inactivation of the tumor suppressor gene. Post transcriptional regulation is the key part of gene expression. This process is mainly regulated by the RNA binding protein (RNA-Binding Proteins, RBPs). It has been confirmed that there are more than 800 kinds of RBPs in the human genome, several of which have been found to be controlled and cancerous. RBPs in-depth studies have gradually revealed that they are similar to transcriptional factors..Musashi1 (Msi1), a member of the conserved RNA binding protein family, has an important role in maintaining the balance between self renewal and differentiation. Many studies have shown that Msi1 can be used as a carcinogenic basis. Because it is also an important marker for a variety of cancer stem and / or progenitor cells, it can stimulate the formation and development of tumor stem and progenitor cells. Overexpression of Msi1's upper intestinal progenitor cells can stimulate the proliferation of cells by activating Wnt, Notch signaling pathway and regulating the three targets of p21, which can promote the tumorigenicity of the progenitor cells and increase the tumorigenicity of the transplanted tumor. It is generally believed that tumor stem cells are resistant to radiotherapy and chemotherapy, which is tumor occurrence, development and recurrence. The origin of metastasis,.Msi1, may increase the nuclear cohesion of beta chain protein (beta -catenin), increase the insensitivity of colon cancer radiotherapy, and promote the development of invasive tumor. In addition, Msi1 is the key point of cell gene expression at the intersection of multiple signal pathways. The node plays an important role in cell development and internal environment homeostasis. At the same time, Msi1 can also be a key regulator of multiple carcinogenesis..Msi1 is expected to be a molecular target for the prevention and control of cancer. Therefore, the role of Msi1 in colon cancer and its mechanism have important theoretical significance and potential application price. However, the effect of Msi1 on colon cancer cells and its mechanism are not yet clear. The purpose of this study is to explore the role and mechanism of Msi1 in the development of colon cancer and its effect on the sensitivity of radiotherapy. The study will be divided into four parts for.1., first of all, in cancer tissue and colon cancer cell lines in colon cancer patients to confirm the high table of Msi1 To construct silenced msi1 stable cell lines by RNA interference technique; 2. to investigate the effect of silent msi1 on the biological characteristics of colon cancer cells; 3. to explore the molecular mechanism of the effect of silent msi1 on the growth of colon cancer cells; 4. to explore the effect of silent msi1 on the sensitivity of colon cancer cells. Part one colon cancer tissue and cell musashi1 protein table Construction of musashi1 stable and low expression colon cancer cell lines: to detect the expression level of musashi1 in colon and colon cancer cell lines and to construct msi1 stable low expression colon cancer cell lines. Methods: Westernblot method was used to detect cancer tissue of colon cancer patients, cancer Zhou Zhengchang tissue, and HCT116, SW480 and SW620 three types of colon cancer The protein expression of msi1 in the cell line and the follow-up study of the colon cancer cell lines with the highest msi1 expression level were selected. The RNA interference technique was used to design the gene sequence and negative control sequence of the silent msi1. The plasmid and negative control particles were implanted into the lentivirus vector and then infected with the colon cancer cells after the infection of the plasmid with the plasmid. A stable low expression cell line was obtained by antibiotic screening, and the real-timepcr and Westernblot methods were used to detect the blank group (blank) from RNA level and protein level, and the effect of silence on the HCT116 colon cancer cell based on the negative control group (negativecontrol, NC) and the knockout group (knockdown, KD). Results: detection by Westernblot method was found. Msi1 protein was highly expressed in colon and three colon cancer cell lines in normal intestinal mucosa; the expression of msi1 protein in HCT116 cells was the highest in the three colon cancer cell lines of HCT116, SW480, and SW620. Therefore, HCT116 cells were selected as the purpose of the follow-up study. In this study, the msi1 gene was successfully constructed. The lentivirus and negative control lentivirus gv248-nc-shrna of sequence gv248-msi1-shrna will interfere with the HCT116 cells of colonic cancer infected by lentivirus and negative control lentivirus, and use purinamycin to screen out the stable expression strain. Meanwhile, real-timepcr and Westernblot results show that the HCT116 cell msi1 of colon cancer is in RNA after the infection of msi1 dry virus carrier. The level and protein level decreased by 73.85% and 59.01%., respectively: msi1 protein was highly expressed in colon and colon cancer cell lines. A stable low expression msi1 cell line was successfully constructed using HCT116 cell line of colon cancer. The effect of second partially silent musashi1 on the cell biological characteristics of colon cancer HCT116: To explore the silent Mu The effect of sashi1 on the biological characteristics of colon cancer HCT116 cells. Methods: using the construction of HCT116 cells with stable low expression of msi1, the proliferation of colon cancer cells after silent msi1 was detected by MTS method. The changes of cell cycle and apoptosis were detected by flow cytometry. The invasiveness of the cells in vitro was detected by the Transwell compartment and the tumor ball test was detected. The effect of silent msi1 on tumor formation in nude mice was observed through the establishment of a nude mouse model. Results: the results of MTS and Transwell cell detection showed that after silent msi1, the proliferation and invasion ability of HCT116 cells in colon cancer decreased significantly in vitro. Flow cytometry results showed that the apoptosis of tumor cells after silent msi1 increased obviously. The results of tumor ball test showed that silencing of msi1 could significantly reduce the number of tumor formation. The result of subcutaneous transplantation of HCT116 cells in HCT116 cells of colon cancer showed that the decrease of msi1 expression could obviously inhibit the growth of the transplanted tumor. The silence msi1 could inhibit the proliferation and invasion ability of HCT116 cells in colon cancer and lead to cell G 0/g1 phase arrest, inducing cell apoptosis. Silence msi1 can obviously reduce the stem of colon cancer HCT116 cells and inhibit the growth of xenografts. Third the molecular mechanism of silent musashi1 on the growth inhibition of colon cancer HCT116 cells: To explore the molecular mechanism of silence musashi1 to inhibit the growth of HCT116 cells in colon cancer. Methods: using real-timepcr and West Ernblot technique detected the expression level of mRNA and protein of cell cyclin dependent kinase inhibitor p21 (tumor suppressor gene) after silencing the msi1 gene, and constructed P213 '-utr luciferase reporter gene vector (p21wt) and its mutant (p21mu), and transfected the reporter gene vector into the cells of the silent msi1 and the control group, and calculated the cells of the msi1 knockout group. The fluorescence ratio of the cells in the control group was compared to determine the activity of P213 '-utr region. Results: the results of Westernblot method detection showed that the expression of p21 protein in HCT116 cells of colon cancer after silent msi1 was up to be up obviously compared with the blank group and negative control group. The results of real-timepcr showed that the expression of p21mrna level in the 3 groups did not change obviously. The results of further luciferase reporter assay showed that the luciferase activity of p21wt in the knockout group was significantly higher than that in the blank group and the negative control group, and the luciferase activity of the msi1 reaction site mutant p21mu was not significantly changed. Msi1, in colon cancer HCT116 cells, was enough to bind to the 3 '-utr region specific to the target gene p21mrna. And inhibit its translation, down regulate the expression of p21 protein, and then promote the growth of tumor cells. After silent msi1, the expression of p21 protein can be used to inhibit the growth of tumor. The effect of the fourth part of silence musashi1 on the radiotherapy sensitivity of colon cancer HCT116 cells: To explore the effect of silent musashi1 on the radiotherapy sensitivity of colon cancer HCT116 cells Methods: HCT116 cells were infected with lentivirus mediated Msi1 interference expression plasmid, the infected HCT116 cells were irradiated by X-ray, and the effect of silent Msi1 gene on the radiosensitivity of HCT116 cells was detected by cloning experiment. The proliferation of colon cancer cells after irradiation was detected by MTS method and the inhibition rate was calculated. Flow cytometry was used to detect the cell proliferation. Changes in cell cycle and apoptosis after irradiation. Results: the clone formation experiment showed that after 0~8Gy X-ray irradiation, the survival curve of the cells in the knock low group decreased, and the values of D0, Dq, N and SF2 were significantly lower than those in the blank group and the negative control group. The radiosensitivity ratio of the blank group and the negative control group was 1.56 and the 1.47.MTS test results showed, respectively, at each time period. The proliferation activity of the cells in the knockout group was significantly lower than that in the blank group and the negative control group, and the inhibition rate of each group increased gradually with the increase of time and dose. Further flow cytometry showed that the apoptosis rate of each group increased obviously after irradiation, and the apoptosis rate gradually increased with time. The proportion of the G2/M phase in the lower group after irradiation was significantly lower than that in the blank group and the negative control group. A summary: the inhibition of Msi1 gene expression in colon cancer HCT116 cells has the effect of radiation sensitization, and its sensitizing mechanism may be by promoting cell withering and relieving G2/M block after radiotherapy, thus increasing the growth of cells. Conclusion: the Msi1 protein in 1 colon and colon cancer cell lines is highly expressed, suggesting that Msi1 may play an important role in the development and development of colon cancer; 2 the cell lines with low expression of Msi1 can be successfully constructed by using colon cancer HCT116 cells, and 3 silenced Msi1 can inhibit the HCT116 fine of colon cancer. Cell proliferation and invasion can induce cell G0/G1 phase block, induce cell apoptosis, reduce cell stem and inhibit the growth of transplanted tumor. 4 silent Msi1 can up regulate the expression of p21 protein of Msi1 target gene of colon cancer HCT116 cells and play the role of inhibiting tumor growth; 5 silent Msi1 can promote apoptosis of colon cancer HCT116 cells and remove the fine after radiotherapy. Cell G2/M phase block, and play the sensitizing effect of radiotherapy.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.35

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