Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance

Clin Cancer Res. 2011 Jun 15;17(12):4155-66. doi: 10.1158/1078-0432.CCR-10-3381. Epub 2011 May 3.

Abstract

Purpose: High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out.

Experimental design: A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity.

Results: Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log-rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies.

Conclusions: In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnosis*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / physiopathology*
  • Adenocarcinoma / therapy
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / diagnosis*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / physiopathology*
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism*
  • Neoplasm Staging
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Radiation Tolerance* / genetics
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Inhibitor of Differentiation Protein 1
  • RNA, Messenger
  • RNA, Small Interfering