Connecting METTL3 and intratumoural CD33(+) MDSCs in predicting clinical outcome in cervical cancer.
Connecting METTL3 and intratumoural CD33(+) MDSCs in predicting clinical outcome in cervical cancer.
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连接 METTL3 和瘤内 CD33( ) MDSC 预测宫颈癌的临床结果
DOI：
10.1186/s12967-020-02553-z
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发表时间：
2020-10-15
影响因子：
7.4
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Ni HH;Zhang L;Huang H;Dai SQ;Li J
甲基转移酶样3(METTL3)是m6A甲基转移酶家族的成员，在癌症中起癌基因的作用。最近的研究表明，宿主的先天性免疫是由控制m6A表位转录变化的酶来调节的。在这里，我们旨在探讨肿瘤组织中METTL3和CD33+髓系衍生抑制细胞(MDSCs)水平与宫颈癌(CC)患者生存的关系。收集197例CC患者的石蜡包埋肿瘤标本。免疫组化(IHC)法检测METTL3和CD33的表达水平。采用皮尔逊或斯皮尔曼卡方检验分析IHC变异的临床关联性。总生存期(OS)和无病生存期(DFS)采用Kaplan-Meier法和LOG-RANK检验。通过COX比例风险模型进行多因素分析，得到危险比(HR)和独立显著性。用METTL3特异性siRNA抑制CD33+细胞或CC来源的细胞中的METTL3，并与相应的对照组比较，在METTL3-siRNA和METTL3-Knokdown-CC来源的细胞共培养体系中进行MDSC的诱导。我们发现，与来自同一CC患者的肿瘤旁组织相比，肿瘤组织中METTL3和CD33+MDSCs的水平增加。重要的是，METTL3的表达与肿瘤组织中CD33+细胞密度呈正相关(P = 0.011)。我们进一步发现，在缺乏−的情况下，CD33+CD11b+人类白细胞抗原-DR MDSC的直接诱导和肿瘤来源的MDSC的体外诱导都会减少。肿瘤微环境中METTL3水平与肿瘤分期密切相关。肿瘤组织中METTL3和CD33+MDSCs水平与DFS或OS减少显著相关。COX模型分析显示，肿瘤细胞中METTL3水平是影响患者生存的独立因素，尤其是DFS(HR = 3.157，P = 0.022)和OS(HR = 3.271，P = 0.012)，而CD33+MDSC数量是DFS的独立预测因素(HR：3.958，P = 0.031)。有趣的是，在疾病晚期(II-IV)患者中，肿瘤细胞中的METTL3是DFS(HR = 6.725，P = 0.010)和OS(HR = 5.140，P = 0.021)的独立因素，而CD33+MDSC密度是OS(HR = 8.802，P = 0.037)的独立因素。我们的研究结果提示CD33+MDSC的扩增与高水平的METTL3有关，并且METTL3和CD33+MDSC是CC的独立预后因素。
Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC). Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson’s or Spearman’s chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls. We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR− MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II–IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037). Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.
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