Prognostic impact of miR-34b/c DNA methylation, gene expression, and promoter polymorphism in HPV-negative oral squamous cell carcinomas

Abstract

Micro RNAs (miRNAs) have a key role in gene expression regulation in cancer. The aim of the current study is to evaluate the prognostic value of miR-34b/c promoter hypermethylation, gene expression, and polymorphism in HPV-negative oral squamous cell carcinomas (OSCC). MiR-34b/c promoter hypermethylation and pre-miR-34b/c polymorphism rs4938723 were evaluated in tumor tissues of 148 patients, and miR-34b expression in 123 HPV-negative OSCC. For risk assessment, the control group was comprised of 175 healthy individuals. MiR-34b/c promoter hypermethylation was determined by methylation-specific PCR. Gene expression, genotyping and HPV screening was assessed by Q-PCR. The data from our hospital cohort indicated that miR-34b/c DNA methylation was associated with nodal status (p = 0.048), and predicted the shorter overall survival of HPV-negative OSCC patients (p = 0.008). Down-regulated miR-34b/c expression was associated with smoking (p = 0.047), alcohol use (p = 0.009), stage (p = 0.025), recurrences (p = 0.000), and a poor survival (p = 0.00029). Median values of miR-34b expression were significantly lower in advanced stages III/IV as opposed to stage I/II, p = 0.006, and in nodal positive vs negative patients (p = 0.045). TCGA data also indicated that tumors with stage I–III expressed significantly higher levels of miR-34b, compared to tumors with stage IV (p = 0.035), Low miR-34b/c expression was associated with poor survival in smokers (p = 0.001) and patients with tongue carcinomas (p = 0.00003), and TCGA analysis confirmed these findings although miR-34b expression and miR-34b/c methylation were not associated with survival outcome in the whole TCGA cohort. A significant negative miR-34b/c expression–methylation correlation was observed in our hospital cohort (p = 0.017) and in TCGA cohort. Pre-miR-34b/c polymorphism was not associated with oral cancer risk. Our findings indicate that miR-34b/c hypermethylation and low miR-34b expression could promote the progression and predict the poor prognosis for HPV-negative OSCC, which suggests miR-34b/c as a promising biomarker and therapeutic target for OSCC in the future.

The Potential microRNA Prognostic Signature in HNSCCs: A Systematic Review

“…In the context of HNSCCs, taking, for instance, HPV positivity as a variable, the role of papillomavirus as a risk factor in a subset of head and neck cancers [109], mainly oropharyngeal and laryngeal cancers, has been established, with different epidemiological, clinical, and molecular characteristics compared with HNSCCs, starting with HPV positivity, which was associated with distinctly different and more favorable prognostic survival values [110].…”

Aberrant promoter hypermethylation of miR-335 and miR-145 is involved in breast cancer PD-L1 overexpression

“…Breast pre-invasive lesions have CpG island methylation alterations 22 . Furthermore, increasing evidence shows that some tumor-suppressive miRs are also epigenetically silenced by promoter DNA methylation in cancers 23 – 25 , suggesting these miRs' diagnostic and therapeutic potential and showing that abnormal miR expressions contribute to human cancers 26 .…”

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

“…Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck malignancies as well as the most prevalent oral cancer worldwide ( 1 ), with an estimated 377,713 new cases and 177,757 deaths in 2020 ( 2 ). Despite recent breakthroughs in diagnosis and therapy, the prognosis of OSCC is still poor, with a 5-year survival rate of approximately 50% ( 3 ). As a complex disease, the progression of OSCC may be driven by a complex association pattern between genetic and environmental factors, i.e., gene–environment interaction ( 4 ).…”