阿仙姑·哈斯木,努尔满古力·肉孜,徐丽秀,哈提拉·吐尔逊,马俊旗

• 1:新疆医科大学基础医学院病理学教研室
• 2:新疆维吾尔自治区人民医院妇科
• 3:新疆医科大学第一附属医院妇科

摘要(Abstract)：

目的探讨子宫颈癌发生与肿瘤组织代谢物及代谢途径关键酶表达变化的关系。方法收集子宫颈鳞癌、宫颈上皮内瘤变(CIN)及慢性宫颈炎(正常对照)新鲜及石蜡包埋组织标本,采用超高效液相色谱联合三重四级杆串联质谱(UHPLC-MS/MS)技术检测宫颈组织代谢组分,应用正交偏最小二乘判别分析法(OPLS-DA)对UHPLC-MS/MS数据进行模式识别分析,确定3种宫颈组织差异性代谢物组分,并应用代谢通路分析软件(Metabo Analyst和KEGG)综合分析,预测关键代谢通路。采用定量RT-PCR方法和免疫组织化学SP法检测关键代谢通路关键酶谷氨酸脱羧酶1(GAD1)、糖原合成激酶3(GSK-3)、丙酮酸激酶(PKM2)和肉毒碱棕榈酰基转移酶(CPT 1)的转录及蛋白表达情况。结果 3种宫颈组织之间有34种差异性小分子代谢物;代谢通路分析预测出18条关键代谢通路,其中能量代谢与宫颈癌发生可能最为密切;定量RT-PCR方法结果显示,宫颈癌组织内GAD1及GSK-3β表达水平明显降低(P<0.05),而PKM2及CPT1表达水平明显升高(P<0.05);免疫组织化学结果显示,从正常对照组织到CIN和宫颈癌,GAD1和GSK-3β表达水平明显下降(P<0.05),从强阳性和中等阳性逐渐向弱阳性和阴性变化,而PKM2和CPT1蛋白质表达水平明显上升(P<0.05),进一步验证了定量RT-PCR结果。结论宫颈癌发生伴有肿瘤组织内糖和脂肪酸分解代谢加剧,能量代谢增强,处于物质代谢紊乱的病理状态,其可能与关键代谢途径的限速酶表达调控存在密切关系。

关键词(KeyWords)： 宫颈癌;能量代谢;组织代谢组分;关键酶

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金(81360332)

作者(Author): 阿仙姑·哈斯木,努尔满古力·肉孜,徐丽秀,哈提拉·吐尔逊,马俊旗

参考文献(References)：

• [1]JAIN M,NILSSON R,SHARMA S,et al.Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation[J].Science,2012,336(6084):1040-1044.
• [2]WALKER H,BURRELL M,FLATLEY J,et al.A metabolite profiling method for diagnosis of precancerous cervical lesions and HPV persistence[J].Bioanalysis,2017,9(8):601-608.
• [3]YANG K,XIA B,WANG W,et al.Comprehensive analysis of metabolomics and transcriptomics in cervical cancer[J].Sci Rep,2017,7:43353.
• [4]AYSHAMGUL H,JUN QI M,BATUR M,et al.Metabonomic signature analysis of cervical carcinoma and precancerous diseases in Uighur women by 1 H-NMR spectroscopy[J].Exp Ther Med,2012,3(6):945-951.
• [5]马俊旗,阿仙姑·哈斯木,巴吐尔·买买提明,等.基于核磁共振代谢技术研究宫颈上皮内瘤样变患者血浆代谢物[J].科技导报,2010,28(12):36-40.
• [6]AYSHAMGUL H,AIXINGZI A,AMINIGUL M,et al.Plasma-free amino acid profiling of cervical cancer and cervical intraepithelial neoplasia patients and its application for early detection[J].Mol Biol Rep,2013,40(10):5853-5859.
• [7]阿仙姑·哈斯木,艾尼·赛买提,沙吉代·库尔班,等.高效液相色谱法分析宫颈癌及宫颈上皮内瘤变患者的血浆氨基酸变化[J].科技导报,2014,32(6):80-83.
• [8]夏米西努尔·阿不力米提,古扎努尔·阿不都许库尔,古扎丽努尔·阿不力孜,等.维吾尔族妇女对宫颈癌及HPV感染的认知程度调查[J].新疆医科大学学报,2009,32(5):522-525.
• [9]CAIRNS R A,HARRIS I S,MAK T W.Regulation of cancer cell metabolism[J].Nat Rev Cancer,2011,11(2):85-95.
• [10]SCHUIZE A.HARRIS A L.How cancer metabolism is tuned for proliferation and vulnerable to disruption[J].Nature,2012,491(7424):364-373.
• [11]FINLEY L W,ZHANG J,YE J,et al.Snap Shot:cancer metabolism pathways[J].Cell Metab,2013,17(3):466.
• [12]LEVINEA J,PUZI K A M.The contro1of the metabolic swftch in cancers by oncogenes and tumorsuppressor genes[J].Science,2010,330(6009):1340-1344.
• [13]ZENG J,LIU D,QIU Z,et al.GSK3beta overexpression indicates poor prognosis and its inhibition reduces cell proliferation and survival of non-small cell lung cancer cells[J].PloSOne,2014,9(3):e91231.
• [14]PACCEZ J D,DUNCAN K,VAYA A,et al.Inactivation of GSK3beta and activation of NF-kappa B pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma[J].Mol Biol Cell,2015,26(5):821-831.
• [15]CHUNLIANG S H,WEI W,YUANDONG L,et al.LNMICCpromotes nodal metastasis of cervical cancer by yeprogramming fatty acid metabolism[J].Cancer Res,2018,78(4):877-890.