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The tumor-suppressive role of microRNA-873 in nasopharyngeal carcinoma correlates with downregulation of ZIC2 and inhibition of AKT signaling pathway

MicroRNA-873 在鼻咽癌中的抑瘤作用与下调 ZIC2 和抑制 AKT 信号通路有关

  • 影响因子:4.15
  • DOI:10.1038/s41417-020-0185-8
  • 作者列表:"Lv, Baotao","Li, Fuzhou","Liu, Xiaoli","Lin, Liqiang
  • 发表时间:2020-06-18
Abstract

Cancer stem cells (CSCs) are responsible for tumor initiation, relapse, and metastasis. Thus, residual CSCs after chemotherapy may result in poor prognosis for nasopharyngeal carcinoma (NPC). Emerging evidence suggests that differentially expressed microRNAs (miRNAs) regulate genes that carry out important functions in CSCs. Here we investigate the interaction of microRNA-873 (miR-873) with the Zic family member 2 (ZIC2) and the effects on downstream serine–threonine protein kinase (AKT) signaling pathway in CSCs in the context of NPC. Initially, microarray-based gene expression profiling identified ZIC2 as a key differentially expressed gene in NPC, which was subsequently confirmed to be upregulated in clinical NPC tissue samples. NPC cells were subjected to sphere-formation conditions in low-attachment plates, followed by sorting of CD133^+ cells, which were selected as NPC stem cells after further characterization of stem cell biomarkers. ZIC2 was then shown to be enriched in NPC stem cells at both mRNA and protein levels. However, loss of ZIC2 was associated with the self-renewal, proliferative and tumorigenic properties of NPC stem cells. Next, miRNAs potentially able to target ZIC2 were predicted by the intersection of mirDIP and TargetScan database results, and miRNA miR-873 was found to be downregulated in NPC tissues in general but especially in NPC stem cells. Upregulation of miR-873 inhibited the stem-like properties and tumorigenicity of NPC stem cells, which was found to take place through downregulation of ZIC2 and disruption of the AKT signaling pathway. Collectively, the results obtained suggest that overexpression of miR-873 could aid NPC tumor suppression through reduction of the malignant potential of CSCs.

摘要

肿瘤干细胞 (CSCs) 负责肿瘤的启动、复发和转移。因此,化疗后残留的 CSCs 可能导致鼻咽癌 (NPC) 预后不良。新出现的证据表明,差异表达的 microRNAs (miRNAs) 调控着 CSCs 中执行重要功能的基因。在这里,我们研究了 microRNA-873 (miR-873) 与 Zic 家族成员 2 (ZIC2) 的相互作用以及对下游丝氨酸-苏氨酸蛋白激酶 (AKT) 的影响。NPC 背景下 CSCs 中的信号通路。最初,基于微阵列的基因表达谱确定了 ZIC2 是 NPC 中关键的差异表达基因,随后在临床 NPC 组织样本中证实其上调。NPC 细胞在低附着板中进行球形形成条件,然后分选 CD133 ^ + 细胞,在进一步表征干细胞生物标志物后,选择 CD133 ^ + 细胞作为 NPC 干细胞。然后在 mRNA 和蛋白水平上显示 ZIC2 在 NPC 干细胞中富集。然而,ZIC2 的缺失与 NPC 干细胞的自我更新、增殖和致瘤特性相关。接下来,通过 mirDIP 和 TargetScan 数据库结果的交叉预测了可能靶向 ZIC2 的 miRNAs,发现 miRNA miR-873 在鼻咽癌组织中普遍下调,尤其是在鼻咽癌干细胞中。MiR-873 的上调抑制了 NPC 干细胞的干细胞样特性和致瘤性,发现其通过下调 ZIC2 和破坏 AKT 信号通路而发生。总的来说,结果表明 miR-873 的过表达可以通过降低 CSCs 的恶性潜能来帮助抑制鼻咽癌。

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影响因子:2.65
发表时间:2020-01-29
来源期刊:BMJ open
DOI:10.1136/bmjopen-2019-031602
作者列表:["Wendland EM","Kops NL","Comerlato J","Horvath JDC","Bessel M","Sperb D","Pimenta C","de Souza FMA","Mendes Pereira GF","Falcetta FS"]

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.

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影响因子:2.60
发表时间:2020-01-21
来源期刊:Head & neck
DOI:10.1002/hed.26063
作者列表:["Soldera EB","Ortigara GB","Bonzanini LIL","Schulz RE","Danesi CC","Antoniazzi RP","Linhares Ferrazzo K"]

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.

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影响因子:1.62
发表时间:2020-01-22
DOI:10.4317/medoral.23335
作者列表:["Ramos-Vega V","Venegas Rojas B","Donoso Torres W"]

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.

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