糖酵解和线粒体氧化磷酸化在喉鳞状细胞癌中相关性的初步研究

发布时间：2018-05-15 13:20

本文选题：糖酵解 + 代谢重编　；参考：《河北医科大学》2017年硕士论文

【摘要】：目的:代谢重编是肿瘤发生的主要特征之一,肿瘤细胞通过重整代谢促进肿瘤增殖、侵袭和转移。因此,本文通过免疫组织化学染色分析不同代谢标记物的表达情况来阐明喉鳞状细胞癌(Laryngeal squamous cell carcinoma,LSCC)组织的代谢状态及不同代谢模式又是如何促进肿瘤存活与恶变。方法:收集2014年12月至2016年12月经手术切除的50例喉鳞状细胞癌组织及10例癌旁组织,并对临床资料进行整理分析。应用免疫组织化学方法检测不同代谢标记物在喉鳞状细胞癌组织及癌旁组织中的表达情况,评估不同代谢物之间的相关性及它们与临床病理学资料的关系。我们根据样本的特点采用卡方或者Fisher’s确切概率的检验方法通过SPSS21.0统计软件进行统计分析;不同代谢标记物之间的相关性则用Spearman等级相关来分析。通过双侧检验,所测结果以P0.05认为差异有统计学意义。结果:1单羧酸转运体4(Monocarboxylate transporter-4,MCT-4)几乎不在正常粘膜组织表达,而单羧酸转运体1(Monocarboxylate transporter-1,MCT-1)和F1-ATP合酶β亚单位(F1-ATPase beta-subunit,β-F1-ATPase)主要在正常组织中具有干细胞活性的基底细胞层表达。在喉鳞状细胞癌组织中MCT-1、MCT-4、线粒体外膜转位酶20(Translocase of outer mitochondrial membrane 20,TOMM20)、β-F1-ATPase、碳酸酐酶Ⅸ(Carbonic anhydraseⅨ,CAⅨ)和过氧化物氧化还原蛋白1(Peroxiredoxin-1,PRDX-1)的阳性表达率分别为74.0%、66.0%、70.0%、78.0%、64.0%、70.0%。通过统计分析,我们发现不同标记物的阳性表达率在喉鳞状细胞癌组织和癌旁组织中组间差异均有统计学意义(PMCT-1=0.007;PMCT-4=0.001;PTOMM20=0.017;Pβ-F1-ATPase=0.015;PCAⅨ=0.010;PPRDX-1=0.017)。2在50例喉鳞状细胞癌组织中mct-1,tomm20,β-f1-atpase和prdx-1阳性表达率在不同病理分级和临床分期的分组中组间差异均有统计学意义(pmct-1,病理分级=0.001,pmct-1,临床分期=0.003;ptomm20,病理分级=0.012,ptomm20,临床分期=0.021;pβ-f1-atpase,病理分级=0.031,pβ-f1-atpase,临床分期=0.046;pprdx-1,病理分级=0.012,pprdx-1,临床分期=0.021)。此外,mct-1和prdx-1阳性表达率在有无淋巴结转移的分组中组间差异有统计学意义(pmct-1,淋巴结转移=0.047;pprdx-1,淋巴结转移=0.043),tomm20阳性表达率在不同吸烟量分组中的组间差异有统计学意义(ptomm20,吸烟量=0.019)。同时,mct-4和caⅨ阳性表达率在不同病理分级分组中的阳性表达组间差异均有统计学意义(pmct-4,病理分级=0.003;pcaⅨ,病理分级=0.022)。3通过免疫组织化学染色,我们更直观地发现线粒体氧化磷酸化相关标记物主要在肿瘤实质表达,并且可以选择性进行扩增。而在相邻肿瘤间质中表达较低甚至缺失。肿瘤分化程度越差、恶性程度越高线粒体氧化磷酸化相关标记物的阳性表达水平就越高。在高分化的肿瘤中线粒体氧化磷酸化相关标记物主要在癌巢侵袭性的前端表达,在低分化的肿瘤中则呈成弥漫性高表达。相反,糖酵解标记物mct-4可以在肿瘤实质和肿瘤间质表达,在肿瘤实质中,糖酵解标记物mct-4主要在高分化的肿瘤组织和肥胖衰老退变的肿瘤组织中表达;在肿瘤间质中,mct-4始终在肿瘤相关成纤维细胞和炎症细胞中表达。4我们应用spearman等级相关来分析糖酵解和线粒体氧化磷酸化标记物在喉鳞状细胞癌中表达的相关性。其中,mct-1、tomm20、β-f1-atpase和prdx-1四者之间呈正相关,此外,mct-4、caⅨ和prdx-1三者之间呈正相关。结论:1在正常组织中,具有干细胞活性的基底细胞层与l-乳酸、酮类物质的高摄取和线粒体氧化磷酸化代谢相关:mct-1和β-f1-atpase是基底细胞层的标记物。2结果证实:在喉鳞状细胞癌组织中我们几乎未见mct-4(+)且tomm20(-)的传统“糖酵解”肿瘤细胞,表明喉鳞状细胞癌中可能不存在传统的“warburgeffect”。但是,肿瘤实质可以进行线粒体氧化磷酸化扩增,诱导相邻间质进行糖酵解。这意味着糖酵解和线粒体氧化磷酸化在喉鳞状细胞癌中同时存在,协同促进肿瘤增殖、侵袭和转移。3靶向线粒体氧化磷酸化和糖酵解相关蛋白可以为肿瘤学的诊断和治疗提供新的思路,应开发应用于肿瘤的个体化治疗中。这或许是延缓肿瘤进展、降低治疗抵抗和提高疗效的有效手段。
[Abstract]:Objective: metabolic rearrangement is one of the main characteristics of tumor occurrence. Tumor cells promote tumor proliferation, invasion and metastasis through renormalization. Therefore, the metabolic status of Laryngeal squamous cell carcinoma (LSCC) tissue is elucidated by immunohistochemical staining analysis of the expression of different metabolic markers. Different metabolic patterns promote tumor survival and malignancy. Methods: 50 cases of laryngeal squamous cell carcinoma (laryngeal squamous cell carcinoma) and 10 para cancerous tissues were collected from December 2014 to 2016, and the clinical data were collected and analyzed. Immunohistochemistry was used to detect different metabolic markers in the tissues of squamous cell carcinoma of the larynx and the para cancer group. The correlation between the different metabolites and their relationship with the clinicopathological data was evaluated. We used the statistical analysis of the chi square or Fisher 's's exact probabilities through the SPSS21.0 statistical software according to the characteristics of the samples; the correlation between the different metabolic markers was related to the Spearman level correlation. Analysis. Through bilateral tests, the results were found to be statistically significant with P0.05. Results: 1 mono carboxylic transporter 4 (Monocarboxylate transporter-4, MCT-4) was almost not expressed in normal mucous tissue, while mono carboxylic transporter 1 (Monocarboxylate transporter-1, MCT-1) and F1-ATP synthase beta subunit (F1-ATPase beta-subunit, beta -F1-ATPase) MCT-1, MCT-4, mitochondrial epicardial transposition enzyme 20 (Translocase of outer mitochondrial membrane 20, TOMM20), beta -F1-ATPase, carbonic anhydrase IX (Carbonic anhydrase IX, CA IX) and peroxide redox protein 1 in laryngeal squamous cell carcinoma tissue. The positive expression rates of n-1, PRDX-1) were 74%, 66%, 70%, 78%, 64%, and 64%. Through statistical analysis, we found that the positive rates of different markers were statistically significant (PMCT-1=0.007; PMCT-4=0.001; PTOMM20=0.017; P beta -F1-ATPase=0.015; PCA IX =0.010; PPRDX-1=0). .017) the positive expression rates of MCT-1, tomm20, beta -f1-atpase and prdx-1 in 50 cases of laryngeal squamous cell carcinoma were statistically significant in different pathological grades and clinical stages (pmct-1, pmct-1, pmct-1, clinical stage =0.003, ptomm20, pathogenesis, clinical staging, pathology, pathology, pathology, pathology, pathology, and pathology. =0.031, P beta -f1-atpase, clinical staging =0.046; pprdx-1, pathological grading =0.012, pprdx-1, clinical stage =0.021). Moreover, the positive rates of MCT-1 and prdx-1 were statistically significant (pmct-1, lymph node metastasis =0.047; lymph node metastasis). There were statistical significance (ptomm20, smoking =0.019) in the smoke volume group. At the same time, the positive expression rates of mct-4 and CA IX positive expression rates in different pathological classification groups were statistically significant (pmct-4, pathological grading =0.003; PCA IX, pathological grading =0.022).3 through immunohistochemical staining, we more intuitively found Mitochondrial oxidative phosphorylation related markers are mainly expressed in tumor substance and can be selectively amplified. The lower or even deletion in adjacent tumor interstitium. The worse the tumor differentiation, the higher the degree of malignancy the higher the positive expression level of mitochondrial oxidative phosphorylation related markers. Mitochondria in highly differentiated tumors Oxidative phosphorylation related markers are mainly expressed in the front-end of the invasion of cancer nests, and diffuse high expression in low differentiated tumors. On the contrary, glycolytic marker mct-4 can be expressed in tumor substance and tumor interstitium. In tumor substance, glycolytic marker mct-4 is mainly in highly differentiated tumor tissue and the swelling of obesity and senescence. Expression in tumor tissue; in the tumor interstitium, mct-4 is always expressed in tumor related fibroblasts and inflammatory cells. We use Spearman correlation to analyze the correlation between glycolysis and mitochondrial oxidative phosphorylation markers in laryngeal squamous cell carcinoma. Among them, there is a positive correlation between MCT-1, tomm20, beta -f1-atpase and prdx-1 four. In addition, there is a positive correlation between mct-4, CA IX and prdx-1 three. Conclusion: 1 in normal tissues, the basal cell layer with stem cell activity is related to the high uptake of l-, the high uptake of ketone substances and mitochondrial oxidative phosphorylation: MCT-1 and beta -f1-atpase are the markers of the basal cell layer,.2 results, which are confirmed in the laryngeal squamous cell carcinoma tissue. There is no traditional "glycolysis" tumor cells of mct-4 (+) and tomm20 (-), indicating that there may be no traditional "warburgeffect" in laryngeal squamous cell carcinoma. However, the tumor substance can be amplified by oxidative phosphorylation of mitochondria to induce glycolysis in adjacent stroma, which means glycolysis and mitochondrial oxidative phosphorylation in laryngeal squamous cells. The simultaneous existence of cancer, synergistic promotion of tumor proliferation, invasion and metastasis of.3 targeted mitochondrial oxidative phosphorylation and glycolysis related proteins can provide new ideas for the diagnosis and treatment of oncology, and should be developed in the individualized treatment of tumors. This may be an effective means of slowing down the progress of the tumor, reducing the resistance to treatment and improving the efficacy.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.65

【参考文献】