Smoking-induced control of miR-133a-3p alters the expression of EGFR and HuR in HPV-infected oropharyngeal cancer

Abstract

PurposeHuman papillomavirus (HPV) infected oropharyngeal squamous cell carcinoma (OPSCC) patients have a better prognosis compared to HPV(-) counterparts. However, a subset of HPV(+) patients with a smoking history fail to respond to the standard of care treatments such as radiation and chemotherapy. To understand the underlying mechanism driving HPV(+) OPSCC patient resistance to treatment and recurrence, we sought to identify and characterize the differentially expressed miRNAs and their target genes in HPV(+) smokers and non-smokers.Experimental designMicroRNA expression analysis was performed using Nanostring in tumor tissues isolated from a prospective cohort of HPV(+) smoking (n = 9) and HPV(+) (n = 13) non-smoking OPSCC patients. Identified miRNAs of interest were further validated using qRT-PCR in cigarette smoke extract (CSE) treated HPV(+) and E6/E7 overexpressing HPV(-) cells.ResultsIn comparison to OPSCC HPV(+) non-smokers, 38 miRNAs were significantly altered in the HPV(+) smoker patients cohort and out of that 9 were downregulated. Altered miRNA expression was also detected in the serum and metastatic lymph nodes of HPV(+) smokers versus non-smokers. Expression of miR-133a-3p was significantly downregulated in OPSCC smokers, HPV(+) cells and E6/E7 overexpressing HPV(-) cells treated with CSE. Reduction of miR-133a-3p induced the upregulation of miR-133a-3p target mRNAs EGFR and HuR.ConclusionsOur results indicate that miR-133a-3p is a target of smoking-induced changes in HPV(+) patients and alters the expression of EGFR and HuR which may promote HPV associated oropharyngeal cancer. Therefore, future treatment strategies for HPV(+) OPSCC smokers should focus on EGFR inhibition and the development of selective therapies to target HuR.

A Current Update on Human Papillomavirus-Associated Head and Neck Cancers

“…Cigarette smoke has been suggested to contribute to HPV + HNC progression by altering the expression pattern of miRNA in epithelial cells especially miRNA-133a-3p [49,50]; miRNA-133a-3p inhibits proliferation/invasion of HNC [51] and acts as a tumor suppressor miRNA [52]. A recent study demonstrated that smoking or cigarette smoke extract, down-regulates the expression levels of miRNA-133a-3p [50]; down-regulation of miRNA-133a-3p is associated with an increase in the expression levels of epithelial growth factor receptor (EGFR) and Hu-antigen R (involved in post-transcriptional regulation), which contribute to tumor growth [50,53]. Thus, smoking contributes to the progression of HPV + HNC by upregulating the expression of EGFR and HuR.…”

Emerging roles of MiR-133a in human cancers

“…Among the dysregulated hypoxiaassociated microRNAs, miR-133a-3 was considered to be a novel prognosis biomarker for hypoxic tumors with elevated risk for distant metastasis [100]. MiR-133a-3p dysregulation was also found in smoking-induced HPV (+) oropharyngeal cancer patients [101]. Taken together, the dysregulation of miR-133a occurs at the early stage of tumorigensis, and low expression of miR-133a frequently indicates poor prognosis, which is consistent with its tumorsuppressive role in cancer development and progression.…”

Risk of HPV-related extra-cervical cancers in women treated for cervical intraepithelial neoplasia

“…There is recent hypothesis about the role of HPV in these cancers [32]. The most plausible cause of correlation between cervical and lung or bladder cancers is the common risk factor of smoking [32][33][34].…”