Elevated expression of BIRC6 protein in non-small-cell lung cancers is associated with cancer recurrence and chemoresistance

J Thorac Oncol. 2013 Feb;8(2):161-70. doi: 10.1097/JTO.0b013e31827d5237.

Abstract

Introduction: Non-small-cell lung cancer (NSCLC) is an aggressive, highly chemoresistant disease. Reliable prognostic assays and more effective treatments are critically required. BIRC6 (baculoviral inhibitors of apoptosis proteins repeat-containing 6) protein is a member of the inhibitors of apoptosis protein family thought to play an important role in the progression or chemoresistance of many cancers. In this study, we investigated whether BIRC6 expression can be used as a prognostic marker or potential therapeutic target for NSCLC.

Methods: In a retrospective analysis, BIRC6 protein expression was determined for 78 resected primary NSCLCs and nine benign lung tissues. Twenty-nine chemoresistant or chemosensitive subrenal capsule NSCLC tissue xenografts were assessed for BIRC6 expression, using immunohistochemistry, and 13 of them for BIRC6 gene copy number, using array comparative genomic hybridization analysis. The effect of small interfering RNA-induced BIRC6 knockdown on the growth of human NSCLC cell cultures and apoptosis (in combination with cisplatin) was investigated.

Results: Elevated BIRC6 protein expression in NSCLC tissues was associated with poor 3-year relapse-free patient survival, lymph node involvement, and advanced pathological tumor, node, metastasis stage. In patient-derived lung squamous cell carcinoma xenografts, chemoresistance was associated with elevated BIRC6 expression and increased gene copy number. Small interfering RNA-induced BIRC6 down-regulation inhibited growth of the NSCLC cells and sensitized the cells to cisplatin.

Conclusions: BIRC6 may play an important role in the malignant progression and chemoresistance of NSCLC. Elevated BIRC6 protein expression may serve as a predictive marker for chemoresistance of NSCLCs and a poor prognostic factor for NSCLC patients. Down-regulation of the BIRC6 gene as a therapeutic approach may be effective, especially in combination with conventional chemotherapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / metabolism
  • Carcinoma, Large Cell / mortality
  • Carcinoma, Large Cell / pathology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Cell Proliferation / drug effects
  • Cisplatin / administration & dosage
  • Comparative Genomic Hybridization
  • Drug Resistance, Neoplasm*
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology*
  • Neoplasm Staging
  • Prognosis
  • RNA, Small Interfering / genetics
  • Retrospective Studies
  • Survival Rate
  • Vinblastine / administration & dosage
  • Vinblastine / analogs & derivatives
  • Vinorelbine
  • Xenograft Model Antitumor Assays

Substances

  • BIRC6 protein, human
  • Biomarkers, Tumor
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Vinblastine
  • Cisplatin
  • Vinorelbine