【摘要】：第一部分LncRNA UCA1在胃癌的發(fā)生發(fā)展中的作用研究目的:LncRNAUCA1在胃癌的發(fā)生發(fā)展中的作用研究方法:診斷為原發(fā)性胃癌且未進行化療或放療的56位患者行胃切除術,取胃癌組織和癌旁正常組織切除后立即用液氮進行冰凍,然后保存于-80℃以備用。首先把由4%多聚甲醛浸泡了 48小時以后的由手術切除的胃粘膜組織,用石蠟進行包埋,再經(jīng)4μm連續(xù)切片以后的用石蠟包埋好的組織再行HE染色,染色以后再由病理學專業(yè)的專家對上述切片給予分析和評價。再經(jīng)免疫組化染色后提取胃癌樣本總RNA,抽提細胞總RNA并進行變性瓊脂糖電泳檢測以及RNA逆轉錄反應。在進行反轉錄反應之后,應用Real-time PCR技術對lnc RNA、mRNA的表達豐度分別進行檢測。結果:1 HE及免疫組化染色胃癌組織和癌旁正常組織的石蠟標本經(jīng)HE染色,病理學復查示診斷和實驗前診斷一致;免疫組織化學染色表明,胃癌組織標本呈現(xiàn)出高度度表達,而癌旁正常組織基本上不作出表達。2 胃癌組織中的lnc RNA表達水平明顯上調采用Real-time PCR方法對病理采集(癌組織和癌旁胃組織)中,lnc RNA UCA1的表達進行檢測,采集標本共56對。lnc RNA UCA1在癌旁組織中的相對含量(1.29 ± 0.26)低于癌組組織(2.85±0.74),Wilcoxon matched pairs test 有顯著統(tǒng)計學意義(p0.01)。表明lnc RNA UCA1極有可能是一種存在于胃癌組織中的促癌基基因。3 lnc RNA UCA1在胃癌和7癌旁胃正常組織中相對含量的比值同胃癌的臨床病理特征、臨床預后相關進一步研究。分析在56例胃癌以及胃癌旁組織內(nèi)的lnc RNA表達出的相對含量的C/P比值與性別、年齡、癌腫大小、分期、浸潤程度、分化情況、淋巴結侵襲之間的關系。結果發(fā)現(xiàn):C/P比值與腫瘤大小、腫瘤的分化程度有明顯關聯(lián);其于低分化的胃癌病人中的表達有增加趨勢,分析差異具有統(tǒng)計學意義;與性別、年齡無明顯相關,分析差異沒有統(tǒng)計學意義,但其和癌腫的浸潤程度、淋巴結轉移、TNM分期及遠處轉移亦無明顯相關,分析差異沒有統(tǒng)汁學意義,懷疑此結果可能與樣本量偏少有關。在此過程中我們把56例標本平均分成兩組,分別為C/PC/P平均值組和C/PC/P平均值組,對術后生存時間(hour)進行統(tǒng)計學分析。發(fā)現(xiàn)C/PC/P平均值組患者術后生存時間長于C/PC/P平均值組,且差異沒有統(tǒng)計學意義,究其原因可能受隨訪時間過短及胃癌術后5年生存率較高等因素影響。結論:lncRNAUCA1與胃癌的發(fā)生、發(fā)展及分化程度相關,在胃癌中起到促癌基因的作用。第二部分LncRNA UCA1通過下調miR-27b表達增強胃癌多藥耐藥性研究目的:探索UCA1和miR-27b在胃癌的發(fā)生發(fā)展中的聯(lián)系,并進一步研究其在胃癌的多藥耐藥性中的作用。探討lncRNAUCA1通過下調miR-27b的表達強度和胃癌的多藥耐藥性的關系。篩選和驗證胃癌耐藥相關lnc RNA分子。通過實驗驗證lnc RNA UCA1在胃癌的多藥耐藥性發(fā)生中所起的作用;并驗證lnc RNA UCA1能夠調節(jié)胃癌多藥耐藥性的分子機理。方法:異常表達的lncRNA的基因芯片數(shù)據(jù)來源于GEO數(shù)據(jù)庫。采用實時熒光定量 PCR的方法對28組癌癥和癌旁的正常組織樣本給予分析以評估lncRNAUCA1和miR27b的表達情況。采用人類胃胃癌細胞系SGC-7901細胞和SGC-7901衍生的具有阿霉素抗性的SGC-7901/ADR細胞,順鉑耐藥的SGC-7901/DDP細胞和5-氟尿嘧啶耐藥的SGC-7901/FU細胞作為體外細胞模型來評估UCA1和miR-27b在胃癌多藥耐藥性中的作用。診斷為原發(fā)性胃癌且未進行化療或放療的28位患者行胃切除術,取胃癌組織和癌旁正常組織切除后立即用液氮進行冰凍,然后保存于-80℃以備用。細胞培養(yǎng)和轉染癌癥細胞培養(yǎng)在RPMI-1640培養(yǎng)基內(nèi),并加入10%FBS,100μg/mL青霉素,及100U/mL鏈霉素。通過采用Ribobio試劑盒采用75 nM UCA1 siRNA或混合陰性對照(Ribobio)對 SGC-7901/ADR,SGC-7901/DDP 和 SGC-7901/FU 細胞進行轉染,而采用 100 nMmiR-27b模擬物或陰性對照(Ribobio)對SGC-7901/ADR細胞進行轉染,使用的試劑盒為Lipofectamine 2000 48小時后,收集siRNA轉染的細胞,并用qRT-PCR測定其抑制的程度。對與UCA1基因互補的DNA進行擴增,并插入到pcDNA3.1的BamhI/XhoI位點之間。采用pcDNA3.1-UCA1表達載體或50 nM miR-27b抑制劑(Ribobio)SGC-7901細胞進行轉染。胃癌組織和相應的癌旁正常組織的lncRNA表達譜的基因芯片數(shù)據(jù)調采用DIANA工其對UCA1和miR-27b的結合位點進行預測。采用TRIzol試劑提取組織及細胞樣品的總RNA。進行反轉錄以獲得一鏈cDNA。采用TaqMan MicroRNA Assay Kit進行實時熒光定量PCR分析。結果采用2-AACT法進行計算。采用線性回歸分析對UCA1表達的水平和miR-27b表達的水平的相關性進行評估。采用Cy3標記的抗生物素抗體在37℃反應30min時檢測信號。采用DAPI來復染細胞核,然后用FV1000熒光顯微鏡檢測免疫熒光。采用UCA1 siRNA或miR-27b模擬物對SGC-7901/ADR細胞進行轉染,而采用UCA1表達載體或miR-27b抑制劑對SGC-7901細胞進行轉染。轉染24小時后,在96孔板上接種細胞。24小時后,用不同濃度的ADR,DDP或5-FU對細胞進行處理48小時。采用傳統(tǒng)MTT芯片來對細胞活性進行測量。采用酶標儀來記錄490 nm的吸光度情況。通過繪制劑量-反應曲線計算 IC50 值。采用 Annexin V-FITC Apoptosis Detection Kit 來檢測細胞的凋亡情況,采用流式細胞儀計算凋亡率。將含有30μg總蛋白的樣品被置于每一條帶上,然后用10%SDS-PAGE進行分離。之后,電泳使蛋白樣品轉移至硝酸纖維膜上。對硝酸纖維膜進行封閉、洗滌并用抗BCL-2一抗(ab32124,Abeam)和裂解的半胱天冬蛋門酶-3(#9661.Cell Signaling.Danvers,MA,USA)以及β-肌動蛋白(ab8227,Abcam)孵育過夜。洗滌之后,用HRP共軛的二抗對硝酸纖維膜進行孵育。采用化學發(fā)光超敏顯色試劑盒super ECL detection reagent對蛋白條帶進行視覺化。采用GraphPad Prism 6.0進行數(shù)據(jù)分析。采用非配對雙側t檢驗方法來進行組間差異評估。p0.05表示差異具有統(tǒng)計顯著性。結果:1胃癌中UCA1和miR-27b呈負相關在本部分中,我們首先通過提取GEO數(shù)據(jù)庫的基因芯片數(shù)據(jù)研究了胃癌組織中異常表達的lncRNA。有一項近期的研究基于6個癌癥組織樣品和6個配對的癌旁組織樣品對lncRNA的表達譜進行了分析。通過回顧他們的基因芯片數(shù)據(jù)(accession No.GSE53137),我們觀察到UCA1是胃癌組織樣品中被最大程度上調表達的lncRNA之一。為了進一步驗證這種異常表達情況,我們進一步基于28對癌癥組織和癌旁正常組織樣品進行了實時熒光定量PCR分析(qRT-PCR)。結果表明,UCA1在癌癥組織中被顯著上調(圖2-1B)。與此同時,我們的qRT-PCR結果表明miR-27b,一種對胃癌細胞具有抑制多藥耐藥性的miRNA,在癌癥組織中顯著下降。通過線性回歸分析,我們進一步確認了 UCA1和miR-27b的負相關關系(R2=0.23.p=0.01)。然后,我們決定進一步調查它們之間是否存在什么關聯(lián),以及它們在胃癌細胞多藥耐藥性形成中的影響。2抑制UCA1可恢復MDR 胃癌細胞中miR-27b的表達水平通過qRT-PCR,我們發(fā)現(xiàn)MDR胃癌細胞,包括SGC-7901/ADR,SGC-7901/DDP和SGC-7901/5-FU細胞有進一步增加UCA1表達和降低miR-27b表達。很明顯,生物信息分析表明UCA1有兩個與miR-27b結合的可能位點。因此,我們決定調查看看UCA1是否對miR-27b的表達具有調控作用。FISH分析結果表明,UCA1和miR-27b在SGC7901和SGC-7901/ADR細胞的細胞核和細胞質中都有分布。UCA1在SGC-7901/ADR細胞中的表達量明顯要更高,而miR-27b表達量則在SGC7901細胞中更高(圖22-D)。接著,用UCA siRNA對 SGC-7901/ADR,SGC-7901/DDP 和 SGC-7901/5-FU 細胞進行轉染。具有較高抑制作用的Si-UCAl-1被用于后續(xù)研究。QRT-PCR結果表明,對UCA1的抑制能夠顯著恢復miR-27b在MDR 胃癌細胞內(nèi)的表達。3 UCA1抑制和miR-27b過量表達使MDR 胃癌細胞對化療試劑變得更加敏感為了進一步調查UCA1和miR-27b在胃癌細胞MDR形成中的作用,我們采用MTT芯片對UCAlsiRNA或miR-27b模擬物轉染后的SGC-7901/ADR細胞中的ADR.DDP和5-FU的IC50進行檢測。結果表明,UCA1抑制和miR-27b過量表達都會降低SGC-7901/ADR細胞中的ADR,DDP和5-FU的IC50。接著,我們采用流式細胞儀檢驗用20μg/ml ADR處理后的SGC-7901/ADR細胞中ADR誘導的細胞凋亡。結果表明,UCA1抑制和miR-27b的增強表達的細胞能夠顯著增加ADR處理后的細胞凋亡。因為想要進一步驗證這些細胞中由ADR誘導的細胞凋亡,本課題組運用免疫印跡分析以檢測抗凋亡蛋白BCL-2和凋亡蛋白裂解的半胱天冬蛋白酶-3的變化情況。結果表明,UCA1抑制和miR-27b過量表達在20μg/mlADR處理后的SGC-7901/ADR細胞內(nèi)顯著降低了 BCL-2農(nóng)達并增加了半胱天冬蛋白酶-3的表達。上述結果顯示UCA1抑制和miR-27b過量表達使MDR胃癌細胞對化療試劑變得更敏感。4 UCA1過量表達和miR-27b抑制使胃癌細胞產(chǎn)生了 MDR為了進一步調查UCA1和miR-27b對胃癌細胞的多藥耐藥性的調控作用,首先采用UCA1表達載體或miR-27b抑制劑對SGC-7901細胞進行轉染。MTT芯片結果證實UCA1過量表達和miR-27b抑制增加了SGC-7901細胞的ADR,DDP和5-FU的IC50。后續(xù)的流式細胞儀分析表明UCA1過量表達和miR-27b抑制顯著降低了 ADR(10μ/ml)誘導的細胞凋亡。LncRNAUCA1是胃癌細胞中的促癌因子；LncRNAUCA1能夠下調miR-27b表達從而增強胃癌多藥耐藥性,本論文通過競爭內(nèi)源性 RNA理論為基礎,從而把胃癌細胞多藥耐藥性相關的lnc RNA表達譜和mi RNA農(nóng)達譜的數(shù)據(jù)進行統(tǒng)一合并分析,在ncRNA相互作用的層面表明了UCA1-mi RNA通路在胃癌MDR中的調節(jié)作用,結論:在胃癌中,UCA1與miR-27b表達呈負相關關系。抑制UCA1可恢復miR-27b在癌癥細胞中的表達。UCA1-miR-27b通路參與了癌癥細胞的化學敏感性調節(jié)。
[Abstract]:Part I research on the role of LncRNA UCA1 in the development of gastric cancer: the study of the role of LncRNAUCA1 in the development of gastric cancer: 56 patients diagnosed as primary gastric cancer without chemotherapy or radiotherapy were treated with gastrectomy, and the gastric tissue and normal tissue were removed and frozen immediately after the resection of normal tissues and then preserved. At -80 C for reserve. First, the surgical excised gastric mucosa was soaked by 4% polyformaldehyde for 48 hours, and paraffin was embedded with paraffin. After 4 mu m, the paraffin embedded tissues were then stained with HE. After the staining, the pathology professional experts analyzed and evaluated the above sections. After staining, the total RNA of gastric cancer samples was extracted, the total RNA of the cells was extracted and the agarose electrophoresis and RNA reverse transcription were performed. After the reaction, the expression of LNC RNA and mRNA was detected by Real-time PCR. Results: 1 HE and immunohistochemical staining of gastric cancer tissue and paraffin paraffin specimens of the normal tissues adjacent to cancer After HE staining, the pathological examination showed that the diagnosis was consistent with the diagnosis before and before the experiment. The immunohistochemical staining showed that the tissue specimens of gastric cancer showed a high degree of expression, while the normal tissues beside the carcinoma basically did not express the expression of LNC RNA in the.2 gastric carcinoma tissue, and the Real-time PCR method was used for pathological collection (cancer tissue and paracancerous stomach group). In the fabric, the expression of LNC RNA UCA1 was detected. The relative content of 56 pairs of.Lnc RNA UCA1 in the adjacent tissues (1.29 + 0.26) was lower than that of the cancer group (2.85 + 0.74), and the Wilcoxon matched pairs test had significant statistical significance (P0.01). The relative ratio of C RNA UCA1 in gastric carcinoma and 7 paracancerous normal gastric tissues is related to the clinicopathological features of gastric cancer and the clinical prognosis. The ratio of C/P to the relative content of LNC RNA expressed in 56 cases of gastric cancer and paracathal tissue, age, tumor size, stage, infiltration, differentiation, and lymph node invasion are analyzed. The results showed that the ratio of C/P was significantly associated with the size of tumor and the degree of differentiation of the tumor; the expression in the patients with low differentiated gastric cancer had an increasing trend, and the difference was statistically significant; there was no significant correlation with sex and age, and the analysis of differences was not significant, but it was associated with the degree of cancer and lymph node metastasis. There was no significant correlation between TNM staging and distant metastasis. There was no statistical significance in analysis. The results were suspected to be related to less sample size. In this process, we divided 56 specimens into two groups, which were the average value group of C/PC/P and the C/PC/P average group, and the postoperative survival time (hour) was statistically analyzed. The mean value group of C/PC/P was found. The survival time of the patients was longer than the C/PC/P average group, and the difference was not statistically significant. The reason may be influenced by the short follow-up time and the 5 year survival rate of gastric cancer. Conclusion: lncRNAUCA1 is related to the occurrence, development and differentiation of gastric cancer, and the role of the oncogene in gastric cancer. The second part of LncRNA UCA1 The aim of the study of miR-27b expression to enhance the multidrug resistance of gastric cancer: To explore the relationship between UCA1 and miR-27b in the development of gastric cancer and to further study its role in the multidrug resistance of gastric cancer. To explore the relationship between the expression intensity of miR-27b and the multidrug resistance of gastric cancer, and to screen and verify the drug resistance phase of gastric cancer. LNC RNA molecules. The role of LNC RNA UCA1 in the occurrence of multidrug resistance in gastric cancer was tested and the molecular mechanism of LNC RNA UCA1 to regulate the multidrug resistance of gastric cancer. Method: the abnormal expression of lncRNA gene chip data was derived from GEO database. 28 groups of cancer and cancer were used by real time fluorescence quantitative PCR. Analysis of the normal tissue samples was given to evaluate the expression of lncRNAUCA1 and miR27b. SGC-7901/ADR cells with adriamycin resistance derived from human gastric cancer cell line SGC-7901 cells and SGC-7901 were used to evaluate UCA, the cisplatin resistant SGC-7901/DDP cells and the 5- fluorouracil resistant SGC-7901/FU cells were used as an in vitro cell model to evaluate the UCA The role of 1 and miR-27b in the multidrug resistance of gastric cancer. 28 patients who were diagnosed as primary gastric cancer without chemotherapy or radiotherapy were treated with gastrectomy and frozen immediately after the resection of gastric cancer tissues and normal tissues, and then stored at -80 C for reserve. Cell culture and transfected cancer cells were cultured in the RPMI-1640 culture base, 10%FBS, 100 g/mL penicillin, and 100U/mL streptomycin were transfected by Ribobio kit with 75 nM UCA1 siRNA or mixed negative control (Ribobio) for SGC-7901/ADR, SGC-7901/DDP and SGC-7901/FU cells, and transfected with 100 nMmiR-27b simulants or negative controls. After the kit was Lipofectamine 200048 hours, the cells transfected with siRNA were collected and the degree of inhibition was measured by qRT-PCR. The DNA which complemented the UCA1 gene was amplified and inserted between the BamhI/XhoI loci of pcDNA3.1. The pcDNA3.1-UCA1 expression vector or the 50 nM miR-27b inhibitor (Ribobio) SGC-7901 cells were transfected. The gene chip data of the lncRNA expression profiles of the corresponding normal tissues adjacent to the carcinoma were adjusted by DIANA to predict the binding sites of UCA1 and miR-27b. TRIzol reagent was used to extract the total RNA. of tissue and cell samples for reverse transcription in order to obtain a chain cDNA. using TaqMan MicroRNA Assay Kit for real time fluorescence quantitative PCR analysis. The 2-AACT method was used to calculate the correlation between the level of UCA1 expression and the level of miR-27b expression. The Cy3 labeled anti biotin antibody was used to detect the signal at 37 C for 30min. DAPI was used to restain the nucleus, and then the immunofluorescence was detected by the FV1000 fluorescence microscope. UCA1 siRNA or miR-27b modules were used. The SGC-7901/ADR cells were transfected by the pseudo substance, and the SGC-7901 cells were transfected with the UCA1 expression vector or miR-27b inhibitor. After 24 hours transfection, the cells were treated with different concentrations of ADR, DDP or 5-FU for 48 hours after transfection for 48 hours. The cell activity was measured by traditional MTT chip. The absorbance of 490 nm was recorded. The IC50 value was calculated by plotting the dose response curve. The apoptosis of cells was detected by Annexin V-FITC Apoptosis Detection Kit. The apoptosis rate was calculated by flow cytometry. The samples containing 30 mu g protein were placed on each band and then separated with 10%SDS-PAGE. The protein samples were transferred to the nitric acid fiber membrane. The nitric acid fiber membrane was closed, washed and incubated for the night with the anti BCL-2 ab32124 (Abeam) and the lysed caspase -3 (#9661.Cell Signaling.Danvers, MA, USA) and the beta actin (ab8227, Abcam). After washing, the two anti nitric acid fiber membrane was incubated with the HRP conjugate. Super ECL detection reagent, a chemiluminescence hypersensitive reagent box, was used to visualize the protein bands. The data were analyzed with GraphPad Prism 6. The discrepancy was statistically significant by non paired bilateral t test, and the difference between the groups was statistically significant. Results: in 1 gastric cancer, UCA1 and miR-27b were negatively correlated in this department In the division, we first studied the abnormal expression of lncRNA. in gastric cancer by extracting the gene chip data from the GEO database. A recent study was based on the analysis of the expression profiles of lncRNA based on 6 cancer tissue samples and 6 paired paracancerous tissue samples. By reviewing their gene chip data (accession No.GSE53137), I have reviewed their gene chip data (accession No.GSE53137). We observed that UCA1 was one of the most up-regulated lncRNA expressions in gastric cancer tissue samples. To further verify this abnormal expression, we further conducted real-time quantitative PCR analysis (qRT-PCR) based on 28 cancerous tissues and normal tissue samples (qRT-PCR). The results showed that UCA1 was significantly up-regulated in cancer tissues (Figure 2-1B). At the same time, our qRT-PCR results showed that miR-27b, a miRNA with inhibition of multidrug resistance to gastric cancer cells, was significantly reduced in cancer tissue. We further confirmed the negative correlation between UCA1 and miR-27b by linear regression analysis (R2=0.23.p=0.01). Then, we decided to further investigate whether there was anything between them. We found that MDR gastric cancer cells, including SGC-7901/ADR, SGC-7901/DDP and SGC-7901/5-FU cells, can further increase the expression of UCA1 and reduce miR-27b expression in MDR gastric cancer cells, including SGC-7901/ADR, SGC-7901/DDP, and SGC-7901/5-FU cells. It is obvious that the bioinformatics of the MDR gastric cancer cells, including SGC-7901/ADR, SGC-7901/DDP and SGC-7901/5-FU cells, are obvious, biologically,.2. The analysis showed that UCA1 had two possible sites for binding with miR-27b. Therefore, we decided to investigate whether UCA1 had a regulatory effect on the expression of miR-27b..FISH analysis showed that UCA1 and miR-27b were distributed in both SGC7901 and SGC-7901/ADR cells in the nuclei and cytoplasm of the cytoplasm, and the expression of.UCA1 in SGC-7901/ADR cells was significantly more. The expression of miR-27b was higher in SGC7901 cells (Figure 22-D). Then, SGC-7901/ADR, SGC-7901/DDP and SGC-7901/5-FU cells were transfected with UCA siRNA. The high inhibitory Si-UCAl-1 was used for follow-up study of.QRT-PCR. The inhibition of UCA1 could significantly restore the expression of miR-27b in gastric cancer cells. UCA1 inhibition and overexpression of miR-27b make MDR gastric cancer cells more sensitive to chemotherapeutic agents in order to further investigate the role of UCA1 and miR-27b in the formation of MDR in gastric cancer cells. We used MTT chips to detect ADR.DDP and 5-FU in SGC-7901/ADR cells transfected by UCAlsiRNA or miR-27b analogue. The overexpression of ADR, DDP and 5-FU in SGC-7901/ADR cells could decrease the IC50. of ADR, DDP and 5-FU. We used flow cytometry to test the apoptosis induced by ADR in the SGC-7901/ADR cells treated with 20 mu g/ml ADR. The results showed that the cells with UCA1 inhibition and enhanced miR-27b expression could significantly increase the apoptosis after treatment. In order to further verify the apoptosis induced by ADR in these cells, the group used Western blot analysis to detect the changes in caspase -3 of anti apoptotic protein BCL-2 and apoptotic protein lysis. The results showed that UCA1 inhibition and miR-27b overexpression were significantly reduced in SGC-7901/ADR cells treated with 20 uh g /mlADR. The results showed that UCA1 inhibition and excessive expression of miR-27b made MDR gastric cancer cells more sensitive to chemotherapeutic agents,.4 UCA1 overexpression and miR-27b inhibition, so that gastric cancer cells produced MDR in order to further investigate the multidrug resistance of UCA1 and miR-27b on gastric cancer cells, the above results showed that UCA1 inhibition and miR-27b overexpression made the MDR gastric cancer cells more sensitive to.4 UCA1 overexpression and miR-27b inhibition. The UCA1 expression vector or miR-27b inhibitor was first transfected to SGC-7901 cells by.MTT chip. The results of UCA1 overexpression and miR-27b inhibition increased the ADR of SGC-7901 cells. The IC50. follow up flow cytometer analysis of DDP and 5-FU showed that the excess expression of UCA1 and inhibition significantly reduced the cells induced by 10 micron. Apoptotic.LncRNAUCA1 is a cancer promoting factor in gastric cancer cells; LncRNAUCA1 can down regulate the expression of miR-27b to enhance the multidrug resistance of gastric cancer. This paper is based on competitive endogenous RNA theory, so as to combine the LNC RNA expression profiles associated with multidrug resistance of gastric cancer cells and the data of MI RNA agricultural Da spectrum to analyze each other in ncRNA. The functional level indicates the regulatory role of UCA1-mi RNA pathway in gastric cancer MDR. Conclusion: in gastric cancer, the expression of UCA1 and miR-27b is negatively correlated. Inhibition of UCA1 can restore the expression of miR-27b in cancer cells and participate in the chemical sensitivity regulation of cancer cells.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.2

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