Hypomethylation and downregulation of miR-23b-3p are associated with upregulated PLAU: a diagnostic and prognostic biomarker in head and neck squamous cell carcinoma

Zirong Huo; Xiaoguang Li; Jieyu Zhou; Yuqin Fan; Zhentao Wang; Zhihua Zhang

doi:10.1186/s12935-021-02251-w

Hypomethylation and downregulation of miR-23b-3p are associated with upregulated PLAU: a diagnostic and prognostic biomarker in head and neck squamous cell carcinoma

Cancer Cell Int. 2021 Oct 26;21(1):564. doi: 10.1186/s12935-021-02251-w.

Authors

Zirong Huo^#^{1

2

3}, Xiaoguang Li^#^{1

2

3}, Jieyu Zhou^{1

2

3}, Yuqin Fan^{1

2

3}, Zhentao Wang^{4

5

6}, Zhihua Zhang^{7

8

9}

Affiliations

¹ Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Ear Institute Shanghai Jiaotong University, Shanghai, China.
³ Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China.
⁴ Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
⁵ Ear Institute Shanghai Jiaotong University, Shanghai, China. [email protected].
⁶ Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. [email protected].
⁷ Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
⁸ Ear Institute Shanghai Jiaotong University, Shanghai, China. [email protected].
⁹ Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. [email protected].

^# Contributed equally.

Abstract

Background: DNA methylation and miRNA-target genes play an important part in the early development of various tumors and have been studied as tumor biomarkers. Although previous studies have reported a cluster of molecular events (such as aberrant alterations of genomics and epigenetics), little is known of the potential biomarkers for early diagnosis and prognostic evaluation in head and neck squamous cell carcinoma (HNSCC).

Methods: Multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database and clinical samples were applied to evaluate the beneficial biomarkers in HNSCC. We focused on the role of plasminogen activator urokinase (PLAU), including diagnostic and prognostic significance, gene expression analysis, aberrant DNA methylation characteristics, interaction of miRNAs and associated signaling pathways.

Results: We found that PLAU was aberrantly upregulated in HNSCC, regardless of the mRNA or protein level. The results of receiver operating characteristic (ROC) curve and Cox regression analysis revealed that PLAU was a diagnostic and independent prognostic factor for patients with HNSCC. Hypomethylation of PLAU was closely related to poor survival in HNSCC. Additionally, miR-23b-3p was predicted to target PLAU and was significantly downregulated in HNSCC tissues. Therefore, our findings suggested that PLAU functioned as a promoter in the pathological process of HNSCC. DNA hypomethylation and downregulation of miR-23b-3p were associated with PLAU overexpression. Finally, our findings provided evidence of a significant interaction between PLAU-target and miRNAs-target pathways, indicating that miR-23b-3p suppresses malignant properties of HNSCC by targeting PLAU via Ras/MAPK and Akt/mTOR signaling pathways.

Conclusions: PLAU is overexpressed and may serve as an independent diagnostic and prognostic biomarker in HNSCC. Hypomethylation and downregulation of miR-23b-3p might account for the oncogenic role of PLAU in HNSCC.

Keywords: Bioinformatics; HNSCC; Methylation; PLAU; Prognosis; miRNA.

Grants and funding

81900928/National Natural Science Foundation of China