Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.
Faculty of Medicine, Center for Human Molecular Genetics & Pharmacogenomics, University of Maribor, Maribor, Slovenia.
J Oral Pathol Med. 2021 Oct;50(9):874-881. doi: 10.1111/jop.13174. Epub 2021 Mar 31.
Head and neck cancer (HNSCC) is one of the most lethal cancers characterized by high relapse and poor prognosis. Several miRNAs have been implicated in HNSCC, including the tumor suppressor miR-137. A large CpG island (CpG73) spans most of the miR-137 gene sequence and stretches 659-bp downstream, ending just upstream of miR-2682 in the same host gene. Here, we assessed the role of the MIR137/MIR2682 locus in HNSCC.
MiRNA expression was analyzed in paired cancerous and normal tissues from 77 HNSCC patients by Quantitative Reverse-Transcription PCR. CpG73 methylation in paired tissues from 48 patients was determined by combined bisulfite restriction analysis. Associations between expression and methylation levels and patient clinicopathological parameters were investigated.
Decreased expression of miR-137 (P<0.01) and miR-2682 (P<0.01) precursors was observed in cancerous tissues, most significantly in oropharyngeal tumors. Lower miR-137 levels correlated with increased perineural invasiveness (P = 0.04). Predicted common miRNA targets MTDH and Notch1 were upregulated in tumor tissues. The CpG73 region between miR-137 and miR-2682 was hypermethylated in tumors. Methylation was observed in 60.4% of cancerous compared to 31.6% of normal tissues, and methylation levels were significantly higher (P<0.01) in tumors. Increased methylation correlated with decreased disease-free patient survival (P = 0.024).
The MIR137/MIR2682 locus correlated with HNSCC perineural invasiveness. This is the first report showing miR-2682 downregulation in head and neck cancer. Our results support the tumor suppressive role of miR-137 and miR-2682. The inverse correlation between CpG73 hypermethylation and disease-free survival suggests this epigenetic mark may have prognostic value in HNSCC.
头颈部癌症（HNSCC）是最致命的癌症之一，其特点是复发率高，预后差。几种 miRNA 已被牵连到头颈部癌症中，包括肿瘤抑制因子 miR-137。一个大的 CpG 岛（CpG73）跨越了 miR-137 基因序列的大部分，延伸 659 个碱基对下游，就在同一宿主基因中的 miR-2682 上游结束。在这里，我们评估了 MIR137/MIR2682 基因座在 HNSCC 中的作用。
通过定量逆转录 PCR 分析了 77 例 HNSCC 患者配对癌组织和正常组织中的 miRNA 表达。通过联合亚硫酸氢盐限制性分析确定了 48 例患者配对组织中的 CpG73 甲基化。研究了表达和甲基化水平与患者临床病理参数之间的关系。
在癌组织中观察到 miR-137（P<0.01）和 miR-2682（P<0.01）前体的表达降低，在口咽肿瘤中最为显著。较低的 miR-137 水平与神经周围侵袭增加相关（P=0.04）。预测的共同 miRNA 靶标 MTDH 和 Notch1 在肿瘤组织中上调。miR-137 和 miR-2682 之间的 CpG73 区域在肿瘤中呈高甲基化状态。在癌组织中观察到 60.4%的甲基化，而在正常组织中为 31.6%，肿瘤组织中的甲基化水平显著更高（P<0.01）。甲基化程度增加与无病生存患者生存率降低相关（P=0.024）。
MIR137/MIR2682 基因座与 HNSCC 神经周围侵袭有关。这是第一个报道在头颈部癌症中下调 miR-2682 的报告。我们的结果支持 miR-137 和 miR-2682 的肿瘤抑制作用。CpG73 高甲基化与无病生存之间的负相关表明，这种表观遗传标记可能对头颈部癌症具有预后价值。
