Role of neurofilament light polypeptide in head and neck cancer chemoresistance

Baishen Chen, Ju Chen, Michael House, Kevin J. Cullen, Kenneth Nephew, Zhongmin Guo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Resistance to cisplatin-based chemotherapy is responsible for therapeutic failure of many common human cancers including cancer of head and neck (HNC). Mechanisms underlying cisplatin resistance remain unclear. In this study, we identified neurofilament light polypeptide (NEFL) as a novel hypermethylated gene associated with resistance to cisplatin-based chemotherapy in HNC. Analysis of 14 HNC cell lines revealed that downregulation of NEFL expression significantly correlated with increased resistance to cisplatin. Hypermethylation of NEFL promoter CpG islands was observed in cell lines as examined by bisulfite DNA sequencing and methylation-specific PCR (MSP) and tightly correlated with reduced NEFL mRNA and protein expression. Furthermore, in patient samples with HNC (n = 51) analyzed by quantitative MSP, NEFL promoter hypermethylation was associated with resistance to cisplatin-based chemotherapy [relative risk (RR), 3.045; 95% confidence interval (CI), 1.459-6.355; P = 0.007] and predicted diminished overall and disease-free survival for patients treated with cisplatin-based chemotherapy. Knockdown of NEFL by siRNA in the highly cisplatin-sensitive cell line PCI13 increased (P < 0.01) resistance to cisplatin. In cisplatin-resistant O11 and SCC25cp cells, restored expression of NEFL significantly increased sensitivity to the drug. Furthermore, NEFL physically associated with tuberous sclerosis complex 1 (TSC1), a known inhibitor of the mTOR pathway, and NEFL downregulation led to functional activation of mTOR pathway and consequentially conferred cisplatin resistance. This is the first study to show a role for NEFL in HNC chemoresistance. Our findings suggest that NEFL methylation is a novel mechanism for HNC chemoresistance and may represent a candidate biomarker predictive of chemotherapeutic response and survival in patients with HNC.

Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalMolecular Cancer Research
Volume10
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Intermediate Filaments
Head and Neck Neoplasms
Cisplatin
Light
Peptides
Neck
Head
Drug Therapy
Cell Line
Methylation
Down-Regulation
Polymerase Chain Reaction
CpG Islands
Tuberous Sclerosis
DNA Methylation
DNA Sequence Analysis
Small Interfering RNA
Disease-Free Survival
Biomarkers
Confidence Intervals

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Role of neurofilament light polypeptide in head and neck cancer chemoresistance. / Chen, Baishen; Chen, Ju; House, Michael; Cullen, Kevin J.; Nephew, Kenneth; Guo, Zhongmin.

In: Molecular Cancer Research, Vol. 10, No. 3, 03.2012, p. 305-315.

Research output: Contribution to journalArticle

Chen, Baishen ; Chen, Ju ; House, Michael ; Cullen, Kevin J. ; Nephew, Kenneth ; Guo, Zhongmin. / Role of neurofilament light polypeptide in head and neck cancer chemoresistance. In: Molecular Cancer Research. 2012 ; Vol. 10, No. 3. pp. 305-315.
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