Connecting METTL3 and intratumoural CD33 + MDSCs in predicting clinical outcome in cervical cancer
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Journal of Translational Medicine Open Access
RESEARCH
Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer Huan‑he Ni1,2†, Lin Zhang3†, He Huang1,4, Shu‑qin Dai3* and Jiang Li1,2*
Abstract Background: 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 D33+ m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and C myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC). Methods: 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 vari‑ ants 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 C D33+ 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 cor‑ responding controls. Results: We found that tumour tissues displayed increased levels of METTL3 and C D33+ 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 C D33+ 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
*Correspondence: [email protected]; [email protected] † Huan-he Ni and Lin Zhang contributed equally to this article 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Biotherapy, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, P. R. China 3 Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. Chin
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