Transcriptome analysis reveals the link between lncRNA-mRNA co-expression network and tumor immune microenvironment and overall survival in head and neck squamous cell carcinoma.
转录组分析揭示了 lncRNA-mRNA 共表达网络与头颈部鳞状细胞癌肿瘤免疫微环境和总生存期之间的联系。
- 作者列表："Zhong Z","Hong M","Chen X","Xi Y","Xu Y","Kong D","Deng J","Li Y","Hu R","Sun C","Liang J
BACKGROUND:As the sixth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) develops visceral metastases during the advanced stage of the disease and exhibits a low five-year survival rate. The importance of tumor microenvironment (TME) in tumor initiation and metastasis is widely recognized. In addition, accumulating evidence indicates that long non-coding RNA (lncRNA) is involved in crosstalk between TME and tumor cells. However, the lncRNA-associated regulators modulating the HNSCC microenvironment and progression remain largely unknown. METHODS:The publicly available transcriptome data and matched clinical HNSCC data were collected from The Cancer Genome Atlas (TCGA). Immune scores (ISs) and stromal scores (SSs) of HNSCC TME were calculated using ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) was conducted to determine the co-expressed lncRNAs and protein-coding mRNAs. RESULTS:Results showed that the high IS HNSCC male patient subgroup exhibited improved survival. Additionally, we identified 169 lncRNAs and 825 protein-coding mRNAs that were differentially expressed in high IS HNSCC samples, with the up-regulated mRNAs displaying enrichment in immune-related biological processes. Notably, we identified a high co-expression lncRNA-mRNA module (i.e., purple module) that showed strong correlation with ISs. This module contained 79 lncRNAs and 442 mRNAs, including 26 lncRNAs and 215 mRNAs showing association between expression and male HNSCC survival. Consistently, 207 of the 215 mRNAs were up-regulated in high IS HNSCC group and were enriched in immune-related signaling pathways. Based on bioinformatics analyses and previous functional assays, certain lncRNAs (e.g., AL365361.1 and PCED1B-AS1) in the purple module likely contributed to the modification of tumor immune microenvironment (TIME) in the high IS HNSCC patients, achieved by regulating transcription of abundant immune-related genes (e.g., CCR7 and TLR8). CONCLUSIONS:In summary, we ascertained a HNSCC male patient subgroup that displayed high ISs and good survival probability. We identified hundreds of genes with specific expression patterns in this HNSCC subgroup as well as a highly co-expressed lncRNA-mRNA module with great potential for the modulation of TIME of HNSCC. Our study provides evidence of a link between the lncRNA-associated gene network, TIME, and HNSCC progression, and highlights potential therapeutic targets for this disease.
背景: 头颈部鳞状细胞癌 (HNSCC) 是全球第六大常见恶性肿瘤，在疾病晚期发生内脏转移，五年生存率较低。肿瘤微环境 (TME) 在肿瘤发生和转移中的重要性被广泛认可。此外，越来越多的证据表明，长链非编码 RNA (lncRNA) 参与了 TME 和肿瘤细胞之间的串扰。然而，调节 HNSCC 微环境和进展的 lncRNA 相关调控因子在很大程度上仍然未知。 方法: 从癌症基因组图谱 (TCGA) 中收集公开的转录组数据和匹配的临床 HNSCC 数据。使用估计算法计算 HNSCC TME 的免疫评分 (ISs) 和基质评分 (SSs)。进行加权基因共表达网络分析 (WGCNA)，确定共表达的 lncRNAs 和蛋白编码 mrna。 结果: 结果显示高 IS HNSCC 男性患者亚组表现出生存改善。此外，我们鉴定了 169 个 lncRNAs 和 825 个蛋白编码 mRNAs 在高 IS HNSCC 样本中差异表达，上调的 mRNAs 在免疫相关生物学过程中显示富集。值得注意的是，我们发现了一个高共表达的 lncRNA-mRNA 模块 (即紫色模块)，它与 ISs 表现出很强的相关性。该模块包含 79 个 lncRNAs 和 442 个 mRNAs，包括 26 个 lncRNAs 和 215 个 mRNAs，显示表达与男性 HNSCC 生存之间的关联。一致地，207 个 mrna 中的 215 个在 high IS HNSCC 组中上调，并富集在免疫相关信号通路中。基于生物信息学分析和以前的功能测定，某些 lncRNAs (e.g., AL365361.1 和 PCED1B-AS1) 中的紫色模块可能有助于高 IS HNSCC 患者肿瘤免疫微环境 (TIME) 的修饰，通过调节丰富的免疫相关基因 (e.g., CCR7 和 TLR8)。 结论: 总之，我们确定了一个显示高 ISs 和良好生存概率的 HNSCC 男性患者亚组。我们在这个 HNSCC 亚组中鉴定了数百个具有特异性表达模式的基因，以及一个高度共表达的 lncRNA-mRNA 模块，具有调节 HNSCC 时间的巨大潜力。我们的研究提供了 lncRNA 相关基因网络、时间和 HNSCC 进展之间联系的证据，并强调了这种疾病的潜在治疗靶点。
METHODS:INTRODUCTION:Human papillomavirus (HPV) is the most common sexually transmitted infection and is associated with several types of cancer. The number of cases of HPV-associated head and neck squamous cell carcinomas (HNSCCs), especially oropharyngeal carcinomas, has increased significantly in recent years despite decreased tobacco smoking rates. Currently, no data concerning the risk factors and prevalence of HPV in HNSCC patients in all regions of Brazil are available, making it difficult to promote advances in this field of public health. Therefore, our goal is to determine the impact of infection by HPV, including HPVs with different genotypes, on head and neck cancer and the risk factors associated with the development of head and neck cancer in all regions of Brazil. METHODS AND ANALYSIS:This is a case-control study that will include 622 patients and 622 controls from all regions of Brazil. A questionnaire will be applied to gather information on sociodemographic, behavioural and health factors. Oral, cervical or penile/scrotal, and anal specimens and serum samples will be collected from all participants. Formalin-fixed paraffin-embedded tissue from tumour biopsies will be analysed only in the case group. Molecular and serological analyses will be performed to evaluate the presence and role of HPV in the development of head and neck cancer. ETHICS AND DISSEMINATION:This project was approved by the research ethical committee of the proposing institution (Hospital Moinhos de Vento, number 2.852.060). Ethical approval from the collaborators is currently under evaluation and is not yet complete. The results of this study will be presented at meetings with the Brazilian Ministry of Health through technical reports and to the scientific community at national and international events, with subsequent publication of scientific articles.
METHODS:BACKGROUND:Factors related to head and neck cancer and the treatment of the disease can affect quality of life. The aim of this study was to determine factors associated with the severity of impact on oral health-related quality of life (OHRQoL) in survivors of head and neck cancer using a multivariate analysis. METHODS:This cross-sectional study evaluated 90 volunteers who had completed radiotherapy at least 3 months earlier. OHRQoL was assessed using oral health impact profile (OHIP-14) and the data were analyzed using robust variance poisson regression models. RESULTS:The mean total OHIP-14 score was 23.98 ± 12.55. Patients with hyposalivation had 56% higher (worse) mean OHIP-14 total scores (CI:1.11-2.18) and patients with advanced stage tumors had 31% higher mean OHIP-14 total scores (CI:1.03-1.66) in multivariate analyses. CONCLUSION:OHRQoL of survivors of head and neck cancer experienced a negative impact following radiotherapy. The impact was associated with hyposalivation and advanced stage tumors.
METHODS:BACKGROUND:To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. MATERIAL AND METHODS:A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. RESULTS:Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. CONCLUSIONS:The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN.