本文選題：淋巴瘤 + MALT1　； 參考：《貴州醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:通過觀察粘膜相關(guān)淋巴組織淋巴瘤易位基因1(mucosa-associated lymphoid tissue lymphoma translocation gene 1,MALT1)抑制劑Z-VRPR-FMK對(duì)彌漫大B細(xì)胞淋巴瘤(Diffuse large B cell lymphoma,DLBCL)裸鼠移植瘤生長(zhǎng)的影響和核因子κB(Nuclear factor kappa B,NF-κB)通路相關(guān)的信號(hào)分子異常,探討MALT1在DLBCL生長(zhǎng)中的作用,為發(fā)現(xiàn)DLBCL治療的新靶點(diǎn)提供理論依據(jù)。方法:培養(yǎng)生發(fā)中心細(xì)胞樣彌漫大B細(xì)胞淋巴瘤(germinal center B cell like-Diffuse large B cell lymphoma,GCB-DLBCL)和活化后B細(xì)胞樣彌漫大B細(xì)胞淋巴瘤(Activated B cell like-Diffuse large B cell lymphoma,ABC-DLBCL)細(xì)胞株OCI-LY1和OCI-LY10,建立DLBCL裸鼠移植瘤模型;將成瘤裸鼠隨機(jī)分為對(duì)照組和抑制劑組。抑制劑組用Z-VRPR-FMK、對(duì)照組用等量生理鹽水腹腔注射。定期測(cè)量并記錄裸鼠體重和腫瘤體積,繪制移植瘤生長(zhǎng)曲線圖;實(shí)時(shí)熒光定量PCR(Real time PCR)檢測(cè)p65基因在核酸水平的表達(dá),免疫組化染色檢測(cè)P65蛋白表達(dá),蛋白印記和免疫組織化學(xué)染色檢測(cè)MALT1、A20、MMP2和MMP9蛋白的表達(dá)。對(duì)上述檢查結(jié)果進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果:1.裸鼠成瘤:DLBCL細(xì)胞總成瘤率68%(17/25),其中OCI-LY1細(xì)胞株成瘤率為60%(9/15),成瘤的時(shí)間為18.16±3.36天,OCI-LY10細(xì)胞株成瘤率為80%(8/10),成瘤的時(shí)間為13.63±3.02天。2.裸鼠和移植瘤的生長(zhǎng):OCI-LY1細(xì)胞株荷瘤鼠對(duì)照組和抑制劑組之間體重和瘤塊體積變化都沒有統(tǒng)計(jì)學(xué)差異,(P均大于0.05)。兩組OCI-LY10細(xì)胞移植瘤鼠體重在處理后逐漸上升,對(duì)照組在第9天開始逐漸下降,而抑制劑組體重則持續(xù)上升,在第11天和第13天兩組體重有統(tǒng)計(jì)學(xué)差異,P分別為0.028和0.016。3.P65表達(dá):OCI-LY1細(xì)胞移植瘤中,抑制劑組p65的mRNA和蛋白核表達(dá)均低于對(duì)照組,但差異無統(tǒng)計(jì)學(xué)意義(P=0.060),OCI-LY10細(xì)胞移植瘤中p65核酸和蛋白表達(dá)水平都較對(duì)照組顯著降低(P=0.000,P=0.028)。4.MALT1、A20、MMP2和MMP9蛋白表達(dá):免疫組化染色顯示MALT1,A20,MMP2和MMP9陽性信號(hào)均定位于細(xì)胞質(zhì)。兩種DLBCL移植瘤的抑制劑處理組MALT1,MMP2,MMP9蛋白陽性表達(dá)信號(hào)較對(duì)照組強(qiáng),A20表達(dá)則相反。Western blot檢測(cè)和分析顯示:兩組OCI-LY1細(xì)胞株移植瘤比較:在抑制劑組MALT1蛋白表達(dá)顯著降低(P=0.013),而A20蛋白表達(dá)則升高(P=0.005),兩組間MMP9、MMP2表達(dá)水平無明顯差異(P=0.234,P=0.071);兩組OCI-LY10細(xì)胞移植瘤相比:在抑制劑組MALT1、MMP2、MMP9蛋白表達(dá)水平均顯著較低(P依次為0.042,0.002,0.006),A20蛋白表達(dá)顯著升高(P=0.000)。結(jié)論:1.ABC樣DLBCL中存在MALT1蛋白的異常表達(dá),并與腫瘤中NF-κB的持續(xù)活化密切相關(guān),MALT1可能成為ABC樣DLBCL治療的有效靶點(diǎn)。2.Z-VRPR-FMK能有效地抑制DLBCL中MALT1蛋白的表達(dá),可能通過解除其對(duì)A20蛋白的裂解作用,從而抑制NF-κB的活化。3.ABC樣DLBC中,MMP2和MMP9是NF-κB活化后上調(diào)表達(dá)的靶分子,其表達(dá)影響腫瘤的生長(zhǎng)。
[Abstract]:Objective: to investigate the effects of Z-VRPR-FMK, a translocation gene 1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1) -MALT1 inhibitor, on the growth of diffuse large B cell lymphomatous lymphoma (DLBCL) xenografts in nude mice and the correlation between nuclear factor kappa B (NF- 魏 B) pathway and nuclear factor 魏 B (NF- 魏 B) pathway. Abnormal signal molecules, To explore the role of MALT1 in the growth of DLBCL and to provide theoretical basis for finding new targets for DLBCL therapy. Methods: OCI-LY1 and OCI-LY10 were cultured from germinal center cell-like diffuse large B-cell lymphoma (germinal center B cell like-Diffuse large B cell lymphoma1) and Activated B cell like-Diffuse large B cell lymphoma1 (OCI-LY1) and OCI-LY10. Nude mice were randomly divided into control group and inhibitor group. The inhibitor group was treated with Z-VRPR- FMK and the control group with the same amount of normal saline intraperitoneal injection. The body weight and tumor volume of nude mice were measured and recorded regularly, the growth curve of transplanted tumor was drawn, the expression of p65 gene at nucleic acid level was detected by Real time PCR, and the expression of p65 protein was detected by immunohistochemical staining. Protein imprinting and immunohistochemical staining were used to detect the expression of MMP2 and MMP9. The results were statistically analyzed. The result is 1: 1. The tumorigenic rate of OCI-LY1 cell line was 60% (9 / 15), the tumorigenesis time of OCI-LY10 cell line was 18.16 鹵3.36 days (80%, 8 / 10), and the tumorigenic time of OCI-LY10 cell line was 13.63 鹵3.02 days, and the tumorigenic rate of OCI-LY10 cell line was 68% (17 / 25). The tumorigenic rate of OCI-LY1 cell line was 60% (9 / 15), and the tumorigenic time was 18.16 鹵3.36 days. There was no significant difference in body weight and tumor volume between the control group and the inhibitor group (P > 0.05). The weight of OCI-LY10 transplanted tumor mice gradually increased after treatment, the control group began to decrease gradually on the 9th day, while the weight of the inhibitor group continued to increase. On the 11th and 13th days, there were significant differences in body weight between the two groups (P = 0.028 and 0.016.3.P65, respectively). The expression of p65 mRNA and protein in the inhibitor group was lower than that in the control group. The expression of p65 nucleic acid and protein in OCI-LY10 cells was significantly lower than that in the control group (P0. 000). 4. The expression of MMP2 and MMP9 protein in MALT1A20 MMP2 and MMP9 protein: the positive signals of MALT1A20 MMP2 and MMP9 were localized in cytoplasm by immunohistochemical staining. The positive expression of MALT1 mMP2mMP9 protein in the two DLBCL transplanted tumor groups was significantly lower than that in the control group. Western blot analysis showed that the expression of MALT1 protein was significantly lower in the inhibitor group than that in the control group (Pn0.013), and the expression of MALT1 protein in the two groups was significantly lower than that in the OCI-LY1 cell line. However, the expression of A20 protein increased (P0. 005), and there was no significant difference between the two groups in the expression of MMP9 and MMP2 (P0. 234, P0. 071). The expression of A20 protein in OCI-LY10 cells was significantly lower than that in the inhibitor group (P = 0. 042, 0. 002, 0. 006, P = 0. 0000), and the expression of A20 protein in OCI-LY10 cells was significantly lower than that in the control group (P = 0. 042, 0. 002P = 0. 0000). Conclusion: 1. There is abnormal expression of MALT1 protein in ABC-like DLBCL, and it is closely related to the continued activation of NF- 魏 B in tumor. MALT1 may be an effective target for ABC-like DLBCL treatment. Z-2.VRPR-FMK can effectively inhibit the expression of MALT1 protein in DLBCL. It is possible to inhibit the activation of NF- 魏 B by removing the cleavage of A20 protein. 3. MMP2 and MMP9 in ABC-like DLBC are the target molecules that up-regulate the expression of NF- 魏 B, and their expression affects the growth of tumor.
【學(xué)位授予單位】：貴州醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.1

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