胃癌转移相关miRNA的差异表达谱及miR-218的生物学分析

目的 探讨胃癌转移相关微小RNA（miRNA）的差异表达情况并进行miR-218的生物学分析。方法 采用实时荧光定量PCR（qPCR）及miRNA芯片法检测低转移潜能的胃癌细胞亚系（SGC7901-NM、MKN28-NM）与高转移潜能的胃癌细胞亚系（SGC7901-M、MKN28-M）间miRNA的差异表达。提取不同转移潜能胃癌细胞系和10例胃癌冰冻组织及相应的转移淋巴结中的总RNA,利用qPCR检测miR-218在不同细胞及组织中的表达情况。结果 对不同转移潜能的胃癌细胞亚系进行芯片检测发现,与SGC7901-NM细胞比较,SGC7901-M 细胞有47个分子表达下调,15个分子表达上调。与MKN28-NM细胞比较,MKN28-M细胞有41个分子表达下调,83个分子表达上调。在SGC7901-M及MKN28-M细胞中,34个分子表达均出现下降,11个分子表达均出现上升。对不同转移潜能的胃癌细胞亚系以及人永生化正常胃黏膜细胞系GES进行检测可以发现,4种不同转移潜能的胃癌细胞亚系中miR-218的表达均低于正常胃黏膜细胞系GES,差异有统计学意义（P＜0.05）,且在高转移潜能胃癌细胞亚系中miR-218的表达均低于低转移潜能胃癌细胞系,差异有统计学意义（P＜0.05）。胃癌转移淋巴结中miR-218的表达水平为0.23±0.02,低于胃癌原发灶的1.09±0.05,差异有统计学意义（P＜0.05）。结论 胃癌转移相关miRNA会出现差异表达情况,高转移潜能胃癌细胞中的miR-218表达水平上调可能与胃癌转移存在一定关系。     

miR-486-5p对胃癌细胞株SGC7901生物学行为的影响

背景与目的：既往研究表明微小RNA-486-5p(miR-486-5p)在多种肿瘤的进展中起重要作用,但其在胃癌中作用的研究较少,本研究旨在探讨miR-486-5p对胃癌细胞株SGC7901增殖、凋亡及迁移能力的影响。方法：使用实时定量PCR(quantification real-time PCR,qRT-PCR)检测胃癌细胞株SGC7901及胃黏膜上皮细胞GES-1中miR-486-5p的表达,构建miR-486-5p过表达质粒,使用脂质体法瞬时转染胃癌细胞株SGC7901,qRT-PCR检测转染细胞后miR-486-5p的表达丰度,噻唑蓝(MTT)法及流式细胞仪检测细胞的增殖及凋亡情况,Transwell小室迁移实验检测细胞的迁移能力。结果：miR-486-5p在SGC7901细胞中表达明显下调,SGC7901细胞转染miR-486-5p过表达质粒后,miR-486-5p表达明显上调,细胞增殖、迁移能力降低,凋亡率增高,差异均有统计学意义(P<0.05)。结论：miR-486-5p可抑制胃癌细胞株SGC7901的增殖和迁移。     

miR-204在胃癌生长中的作用及机制

目的:探讨microRNA-204(miR-204)在胃癌中的表达,研究miR-204在胃癌细胞增殖中的作用和机制。方法:采用RT-PCR方法检测胃癌组织、胃癌细胞中的miR-204相对表达量;分析miR-204的表达与临床病理参数的关系;瞬时转染上调胃癌SGC7901细胞中miR-204的表达量,CCK8检测转染前后细胞增殖能力的变化;Western blot检测转染前后SGC7901细胞中Bcl-2表达的变化。结果:胃癌组织中miR-204相对表达量（1.94±0.78）明显低于正常胃组织（4.01±1.47）（P＜0.01）;同样,人胃癌细胞株中miR-204表达水平明显低于正常胃上皮细胞（P＜0.01）。胃癌组织中miR-204的表达水平与肿瘤的大小、远处转移和TNM分期明显相关（P＜0.05）。CCK8结果显示,miR-204 mimics转染后SCG7901细胞的增殖率较转染前明显下降（P＜0.05）,Western blot结果显示胃癌细胞中Bcl-2的表达水平较转染前明显下调（P＜0.05）。结论:miR-204在胃癌组织中低表达且与其恶性生物学行为相关,上调miR-204可通过下调Bcl-2的表达抑制胃癌细胞的增殖。     

miR-103与胃癌多药耐药作用机制探讨

目的 既往研究肿瘤耐药均集中在DNA水平,而DNA又影响mRNA及蛋白质表达.但是mRNA与编码蛋白质的表达并不成比例,而非编码RNA恰好能解释两者之间的不平衡.非编码RNA即微小RNA(microRNA,miRNA),是一类内源性短链非编码小分子核糖核苷酸,长度约18~25个核糖核苷酸,是转录后基因表达调节的关键分子,参与胃癌的发生发展.本研究旨在探讨miR-103在胃癌多药耐药中作用及其分子机制.方法 miRNA芯片筛选SGC7901/ADR及SGC7901细胞差异表达miRNA,应用qRT-PCR验证miR-103表达;将miR-103的拟似物及抑制物分别转染SGC7901/ADR及SGC7901细胞,MTT法检测转染前后对多柔比星敏感性变化;蛋白质印迹法检测miR-103对caveolin-1表达的影响.结果 miR-103在SGC7901/ADR细胞中表达(0.32±0.04)显著低于SGC7901细胞.miR-103拟似物转染SGC7901/ADR细胞后对多柔比星的敏感性较对照组显著提高,IC50由(18.83±0.32) μg/mL下降到(4.54±0.29) μg/mL,t=1.04,P<0.05;而miR-103抑制物转染SGC7901细胞后对多柔比星的敏感性显著降低,IC50由(1.65±0.03) μg/mL上升到(15.27±0.26) μg/mL,t=1.25,P<0.05.miR-103靶向作用于caveolin-1的3'-UTR,并在转录后水平负向调控caveolin-1表达.结论 miR-103通过靶向负调控caveolin-1表达,增加SGC7901/ADR细胞对多柔比星敏感性,从而逆转胃癌多药耐药.     

Methylation of miR-129-5p CpG island modulates multi-drug resistance in gastric cancer by targeting ABC transporters

Recent studies have reported that hyper-methylation in the promoter region of miRNAs could silence the expression of tumor suppressive miRNAs and might play significant roles in the process of tumor development. However, the potential mechanisms regarding how methylation of miRNA CpG Island could regulate cancer cell chemo-resistance have not yet been studied. Using microarray and BSP (Bisulfate Sequencing PCR) assays, we found that compared with the parent SGC7901/VCR cells, expression of miR-129-5p was restored in SGC7901/VCR gastric cancer multi-drug resistant cell line treated by de-methylation reagent (5-AZA-dC). Using gain or loss of function assays, we found the over-expressed miR-129-5p reduced the chemo-resistance of SGC7901/VCR and SGC7901/ADR cells, while down-regulation of miR-129-5p had an opposite effect. Furthermore, three members of multi-drug resistance (MDR) related ABC transporters (ABCB1, ABCC5 and ABCG1) were found to be direct targets of miR-129-5p using bioinformatics analysis and report gene assays. The present study indicated that hyper-methylation of miR-129-5p CpG island might play important roles in the development of gastric cancer chemo-resistance by targeting MDR related ABC transporters and might be used as a potential therapeutic target in preventing the chemo-resistance of gastric cancer.     

miR-9-5p靶向FGF9抑制胃癌细胞迁移侵袭的作用机制

目的:探讨miR-9-5p在胃癌组织中的表达及对胃癌细胞株SGC7901、AGS细胞迁移和侵袭影响的作用机制。方法:real-time PCR和Western blot检测癌旁组织、胃癌组织及其细胞系中miR-9-5p和FGF9的表达；Transwell小室检测过表达miR-9-5p或敲除FGF9对SGC7901和AGS细胞迁移和侵袭能力的影响；TargetScan在线分析、双荧光素酶报告基因和Western blot实验验证miR-9-5p和FGF9的靶向关系；将转染后的SGC7901细胞分为对照（NC）组和实验（miR-9-5p）组接种于裸鼠右侧腋窝皮下，观察记录裸鼠成瘤情况并绘制生长曲线。结果:与癌旁组织相比，胃癌组织及其细胞系中miR-9-5p表达下调、FGF9表达上调（P＜0.05）；过表达miR-9-5p或敲除FGF9能抑制SGC7901、AGS细胞迁移和侵袭；TargetScan在线分析、双荧光素酶报告基因和Western blot实验表明miR-9-5p能调控FGF9表达；miR-9-5p组细胞成瘤速度较NC组慢（P＜0.05），肿瘤体积及重量小（P＜0.05）。结论:miR-9-5p在胃癌组织中表达下调，过表达miR-9-5p可抑制FGF9表达，从而抑制胃癌细胞的迁移和侵袭，减缓肿瘤生长。     

Identification of new aberrantly expressed miRNAs in intestinal-type gastric cancer and its clinical significance

miRNAs are small 19 to 22 nucleotide sequences of RNA that negatively regulate gene expression. miRNA expression profiles may become useful biomarkers for diagnostics, prognosis and prediction of response to treat, and it could be a powerful tool for cancer prevention and therapeutics. Several miRNA expression profiles of miRNAs in gastric cancer have been reported, but these studies screened only few miRNAs and samples used in experiments include several different subtypes of gastric cancers, which decrease the sensitivity to identify new aberrant miRNAs. In this study, a miRNA expression profile was identified by miRCURY LNA Array (v.14.0) between intestinal-type gastric cancers and normal tissues. Forty miRNA precursors were up-regulated and thirty-six miRNA were down-regulated in intestinal-type gastric cancers (p<0.01). Sixteen new miRNAs were found in intestinal-type gastric cancers. Seventeen new miRNAs were found in intestinal-type gastric cancers. miR-145, miR-27a, miR-494 are differently expressed between intestinal-type and diffuse-type gastric cancers. miR-32, miR-182 and miR-143 dysregulated expression levels are related with different pathological stages of intestinal-type gastric cancers (p<0.01). Taken together, aberrantly expressed miRNAs may offer new clues to tumorigenesis of gastric cancers. miR-32, miR-182 and miR-143 may be potential diagnostic biomarkers for intestinal-type gastric cancers.     

miR-124在胃癌中的表达及临床意义

背景与目的：miR-124在多种肿瘤中发挥抑癌基因样功能,如肺癌、前列腺癌、膀胱癌和乳腺癌,但是其在胃癌中的表达及临床意义尚不清楚。该研究旨在研究miR-124在正常胃黏膜上皮细胞与不同胃癌细胞及胃癌组织及正常胃黏膜组织中的表达,分析其表达与胃癌患者性别、年龄、组织学分级、T分期、TNM分期、淋巴结转移及预后之间的相关性。方法：采用实时荧光定量聚合酶链反应(real-time fluorescent quantitative polymerase chain-reaction,RTFQ-PCR)检测miR-124在人胃黏膜上皮细胞及胃癌细胞中的表达,采用原位杂交法检测miR-124在胃癌及癌旁正常组织中的表达。结果：RTFQ-PCR结果显示,miR-124在胃癌MKN-74、MKN-28、MKN-45、MGC-803、SGC-7901及AGS细胞中的表达均低于GES-1细胞;原位杂交实验结果显示,miR-124在正常胃黏膜中呈强阳性表达,在胃腺癌组织中表达下降、局灶阳性或缺失;统计分析显示,miR-124与胃腺癌患者组织学分级、TNM分期及淋巴结转移密切相关,与患者的年龄、性别及肿瘤大小无关;Kaplan-Meier生存曲线统计分析显示,miR-124低表达患者的总生存时间和无病生存时间显明低于miR-124高表达患者;多因素分析结果提示,miR-124表达下调是影响患者生存的独立预后因素。结论：miR-124在胃癌细胞及组织中表达下调,并且与患者的组织学分级、TNM分期、淋巴结转移及预后密切相关。     

剪接因子SF3b6通过MAPK信号通路促进胃癌细胞的增殖和迁移

目的:探讨剪接因子3b亚基6(splicing factor 3b subunit6,SF3b6)对胃癌细胞增殖、凋亡、侵袭和迁移等的影响及其作用机制.方法:通过组织芯片检测SF3b6在胃癌和癌旁组织中的表达,采用WB和qPCR检测SF3b6在正常永生化胃上皮细胞(GES-1)和胃癌细胞系(HGC27、AGS、BGC8...     

宫颈癌及癌前病变组织中microRNAs的差异表达

目的 寻找与宫颈癌及宫颈癌前病变相关的microRNA。 方法 利用miRNA芯片,筛查宫颈 癌组织、宫颈上皮内瘤变及正常宫颈组织中差异表达的miRNA,并用实时定量RT-PCR在60份宫颈组 织标本中对4个miRNA进行验证。利用生物信息学对部分差异表达的miRNA的靶基因进行功能分析。 结果 与正常宫颈组织比较,宫颈癌及高级别宫颈病变（HSIL）中存差异表达的miRNAs,其中在宫 颈癌中下调最明显的是miR-218（下调倍数为0.175）,上调最明显的是miR-21（上调倍数为5.68）。 实时定量RT-PCR验证结果与miRNA芯片结果基本一致。功能分析显示预测的miR-218及miR-21的靶基 因与肿瘤的生长、侵袭转移有关。结论 宫颈癌及癌前病变中存在异常表达的miRNA,它们在宫颈癌 发生过程中可能起癌基因或抑癌基因的作用。     

长链非编码RNA HOTAIR 在胃癌中的表达及意义

目的:探讨长链非编码RNA HOX 转录反义RNA（HOTAIR）在胃癌组织及胃癌细胞株中的表达及与临床病理关系,并进一步研究其对胃癌细胞增殖的影响。方法:收集2010 年1月至 2012 年 1月我院40例胃癌手术切除标本（包括癌组织及对应的正常胃上皮组织）,qRT-PCR检测40例胃癌中HOTAIR的表达,并分析其与临床病理关系。qRT-PCR检测胃癌细胞株和正常胃上皮细胞株中的HOTAIR的表达差异,利用siRNA抑制HOTAIR表达后,分别用MTT法和流式细胞仪（FCM）检测对细胞增殖和凋亡的影响。结果:胃癌组织中的HOTAIR的表达水平（6.32±2.56）显著高于正常胃上皮组织（4.61±1.81）（P=0.001）。同时,HOTAIR在人胃癌细胞株MKN28、SGC7901、BGC823中的表达水平明显高于正常胃上皮细胞GES-1（P＜0.05）。胃癌肿瘤组织中HOTAIR的表达水平与肿瘤的大小和临床分期显著相关（P＜0.05）。利用siRNA干扰HOTAIR的表达后,SGC7901细胞增殖明显降低,凋亡增加（P＜0.01）。结论:HOTAIR在胃癌中显著高表达,并可促进胃癌细胞增殖,可能成为胃癌的诊断和治疗提供新的分子标记物。     

miR-93-5p和miR-27a-3p在直肠癌组织中的表达及其意义

目的 探讨在直肠癌组织中呈现出特异性表达的miRNA与临床病理分期、肿瘤浸润深度、淋巴结转移等参数之间的关系及其可能的意义。方法 用微阵列基因芯片技术分析未经任何术前放化疗的71例直肠癌患者癌组织与癌旁组织间miRNA表达的区别,筛选出上调的miR-93-5p和下调的miR-27a-3p,扩大样本量后进行qRT-PCR验证,随后进行多种临床病理参数分析并探讨其可能存在的意义。结果 miR-27a-3p的表达在芯片检测中呈现出低表达,但在PCR验证时呈现出了高表达,且数据较为离散;miR-93-5p在两种检测方法中均显示出高表达的特性(癌组织表达量是癌旁组织的3.165倍,P=0.006),并与肿瘤体积(P=0.004)、治疗前癌胚抗原水平(P=0.001)及淋巴结转移数目(r=0.534,P=0.005)具有相关性,其中与治疗前癌胚抗原水平及淋巴结转移阳性组受侵数目存在正相关。结论 在直肠癌组织中存在特异性表达的miRNA。根据miR-93-5p和miR-27a-3p在直肠癌组织中的表达特点,miR-93-5p有望作为新型生物标记物,为直肠癌的临床诊疗提供参考价值。     

胃癌细胞中高表达hnRNP K蛋白上调miR-20a的表达

目的:探索胃癌细胞中高表达hnRNP K蛋白直接调控的miRNA。方法:通过制备正常胃黏膜细胞GES-1和胃癌细胞SGC-7901的细胞芯片初筛高表达hnRNP K胃癌细胞miRNA表达谱；查询TCGA数据库得到胃癌大样本mRNA转录组和miRNA数据，分析处理得到hnRNP K以2倍差异高表达对应的miRNA差异表达谱；对芯片和TCGA数据库结果交互分析得到上调共表达的miRNA；过表达和敲除hnRNP K，通过Western Blot和Real Time q-PCR验证筛查的结果；利用TCGA大数据对hnRNP K和miRNA进行归一化处理，验证筛选的miRNA与hnRNP K和胃癌的相关性。结果:通过芯片初筛miRNA表达谱与TCGA查询结果交互分析得到胃癌上调miRNA共表达谱（miR-17/20a/24/182）；Western Blot和Real Time q-PCR验证结果显示hnRNP K可直接调控miR-20a的表达；TCGA数据分析表明miR-20a与hnRNP K正相关，且在胃癌中高表达。结论:胃癌细胞中高表达hnRNP K蛋白上调miR-20a的表达。     

miR-106a靶向调控TIMP2对人胃癌细胞增殖、转移及EMT的影响

目的 探讨微小RNA-106a(miR-106a)在人胃癌组织中的表达及其与癌细胞增殖、转移的关系。方法 收集人胃癌和配对癌旁福尔马林固定-石蜡包埋样本共50对,Real-time PCR法检测miR-106a在人胃癌组织中的表达;培养人低分化胃癌细胞系SGC-7901、BGC-823、MKN-45和永生化人胃黏膜上皮细胞GES-1,Real-time PCR法检测miR-106a在人胃癌细胞中的表达;MTT法检测细胞增殖,Transwell法检测细胞迁移和侵袭,生物信息学和双荧光素酶法鉴定miR-106a靶基因,Western blot检测靶蛋白TIMP2、MMP2、MMP9、E-cadherin、N-cadherin表达。结果 Real-time PCR检测显示,与癌旁组织比较,miR-106a在人胃癌组织中高表达,差异有统计学意义(P＜0.001);与GES-1细胞比较,miR-106a在人胃癌细胞SGC-7901、BGC-823、MKN-45中普遍高表达,差异有统计学意义(P＜0.001)。MTT检测显示抑制miR-106a后胃癌细胞SGC-7901、BGC-823增殖能力下降(P＜0.01)。Transwell显示胃癌细胞BGC-823迁移、侵袭能力下降(P＜0.001)。双荧光素酶法显示TIMP2野生型报告基因与miR-106a mimic共转后,其荧光素酶活性较miR-106a NC组明显下降(P＜0.001),但TIMP2突变型报告基因无明显变化。Western blot显示抑制miR-106a后TIMP2表达升高,MMP2、MMP9表达下降,E-cadherin表达升高,N-cadherin表达下降。结论 miR-106a在人胃癌中的高表达可能通过靶向TIMP2而影响癌细胞的增殖、转移和上皮-间质转化。     

Clinical significance and correlation of miR-200c and P-gp expression in gastric cancer and the effects on multidrug resistance

BackgroundPoor prognosis is common in gastric cancer patients due to multidrug resistance (MDR)-induced recurrence and metastasis. In the present study, we investigated the expression of microRNA (miR)-200c in gastric cancer tissues and cell lines and its relationship with the expression of the drug resistant gene ABCB1, which encodes P-glycoprotein (P-gp).MethodsThe basic characteristics of 102 patients with gastric cancer were reviewed. Real time-polymerase chain reaction (PCR), immunohistochemistry, and Western blot were employed to detect the expression levels of miR-200c and P-gp in gastric carcinoma tissues and cell lines. The correlation of miR-200c messenger RNA (mRNA) level with clinicopathological characteristics and P-gp protein expression were analyzed. SGC7901/vincristine (VCR) cells were transfected with miR-200c mimics or a specific small interfering RNA (siRNA) targeting the ABCB1 gene. The methyl thiazolyl tetrazolium (MTT) assay and flow cytometry were used to determine the role of miR-200c and ABCB1 on the viability and apoptosis of gastric carcinoma cell lines.ResultsThe level of miR-200c in carcinoma tissues was significantly lower than that in adjacent tissues, and the expression level of P-gp in carcinoma tissues was obviously higher than that in adjacent tissues (P<0.01, P=0.029). The expression levels of miR-200c and P-gp were associated with the malignant characteristics of gastric cancer, and patients with high expression of miR-200c or negative expression of P-gp had a better prognosis (P=0.006, P=0.022). MiR-200c negatively regulated the ABCB1 gene in gastric cancer cell lines. MiR-200c overexpression and ABCB1 down-regulation increased the sensitivity of SGC7901/VCR cells to VCR and reversed MDR by promoting cell apoptosis.ConclusionsThe expression level of miR-200c decreases in gastric carcinoma tissues and drug-resistant gastric cancer SGC7901/VCR cells. Overexpression of miR-200c may enhance the sensitivity of SGC7901/VCR cells to VCR by regulating the expression of P-gp.     

MicroRNA sequence and expression analysis in breast tumors by deep sequencing

MicroRNAs (miRNA) regulate many genes critical for tumorigenesis. We profiled miRNAs from 11 normal breast tissues, 17 noninvasive, 151 invasive breast carcinomas, and 6 cell lines by in-house-developed barcoded Solexa sequencing. miRNAs were organized in genomic clusters representing promoter-controlled miRNA expression and sequence families representing seed sequence-dependent miRNA target regulation. Unsupervised clustering of samples by miRNA sequence families best reflected the clustering based on mRNA expression available for this sample set. Clustering and comparative analysis of miRNA read frequencies showed that normal breast samples were separated from most noninvasive ductal carcinoma in situ and invasive carcinomas by increased miR-21 (the most abundant miRNA in carcinomas) and multiple decreased miRNA families (including miR-98/let-7), with most miRNA changes apparent already in the noninvasive carcinomas. In addition, patients that went on to develop metastasis showed increased expression of mir-423, and triple-negative breast carcinomas were most distinct from other tumor subtypes due to upregulation of the mir~17-92 cluster. However, absolute miRNA levels between normal breast and carcinomas did not reveal any significant differences. We also discovered two polymorphic nucleotide variations among the more abundant miRNAs miR-181a (T19G) and miR-185 (T16G), but we did not identify nucleotide variations expected for classical tumor suppressor function associated with miRNAs. The differentiation of tumor subtypes and prediction of metastasis based on miRNA levels is statistically possible but is not driven by deregulation of abundant miRNAs, implicating far fewer miRNAs in tumorigenic processes than previously suggested.     

EGFR对胃癌细胞SGC7901化疗敏感性及细胞中STAT3磷酸化水平的影响

目的:探讨表皮生长因子受体(epidermal growth factor receptor,EGFR)对胃癌细胞SGC7901化疗敏感性及细胞中信号转导和转录因子3(STAT3)磷酸化水平的影响.方法:收集胃癌组织及对应的癌旁组织,体外培养胃癌细胞MKM28、SGC7901、BGC823和胃黏膜上皮细胞GES-1,Western blot检测胃癌组织、癌旁组织及胃癌细胞MKM28、SGC7901、BGC823和胃黏膜上皮细胞GES-1中EGFR的表达水平.细胞转染小干扰RNA对照序列(siRNA control组)和EGFR小干扰RNA(EGFR siRNA组),同时设置对照组(只加入转染试剂)、化疗组(细胞培养液中加入8 μmol/L 5-氟尿嘧啶)、联合组(转染EGFR siRNA后的细胞,细胞培养液中加入8 μmol/L 5-氟尿嘧啶),培养48 h后,Western blot检测细胞中活化的含半胱氨酸的天冬氨酸蛋白水解酶3(Cleaved Caspase-3)、信号转导和转录因子3(STAT3)、磷酸化STAT3(p-STAT3)、EGFR表达水平,噻唑蓝(MTT)检测细胞增殖情况,流式细胞术检测细胞凋亡情况.结果:EGFR在胃癌组织中表达水平明显高于癌旁组织,在胃癌细胞中的表达水平明显高于胃黏膜上皮细胞.EGFR siRNA组细胞中EGFR水平明显降低.EGFR siRNA组、化疗组、联合组细胞存活率及p-STAT3表达水平明显低于对照组,而凋亡率及细胞中Cleaved Caspase-3水平明显高于对照组。联合组细胞存活率及p-STAT3表达水平明显低于化疗组,而凋亡率及细胞中Cleaved Caspase-3水平明显高于化疗组。结论:EGFR在胃癌中过表达.抑制EGFR表达后,胃癌细胞增殖受到抑制,凋亡增多,化疗敏感性增加,作用机制可能与STAT3磷酸化水平有关.