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

PLoS One. 2018 Oct 5;13(10):e0205077. doi: 10.1371/journal.pone.0205077. eCollection 2018.


Purpose: Human 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 design: MicroRNA 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.

Results: In 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.

Conclusions: Our 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Line, Tumor
  • Cohort Studies
  • ELAV-Like Protein 1 / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Oropharyngeal Neoplasms / complications
  • Oropharyngeal Neoplasms / metabolism*
  • Oropharyngeal Neoplasms / pathology
  • Papillomaviridae
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Prospective Studies
  • RNA, Messenger / metabolism
  • Smoking / adverse effects*
  • Smoking / metabolism*
  • Smoking / pathology
  • Tobacco Smoke Pollution / adverse effects


  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • MIRN133 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Tobacco Smoke Pollution
  • EGFR protein, human
  • ErbB Receptors