Hedgehog signaling pathway molecules and ALDH1A1 expression in early-stage non-small cell lung cancer

Lung Cancer. 2012 May;76(2):191-6. doi: 10.1016/j.lungcan.2011.10.015. Epub 2011 Nov 23.


Introduction: The Hedgehog Signaling Pathway (HHSP) has been implicated in the development of multiple cancers. HHSP activation may primarily be hedgehog ligand-dependent in non-small cell lung cancer (NSCLC); while a subset may be ligand-independent. In this study NSCLC primary tumors were used to identify correlations between multiple biomarkers thought to be involved in the HHSP and the clinical outcomes of patients with NSCLC. Identification of such correlations could be used to aid in NSCLC treatment and predicting patient prognosis.

Methods: A tissue microarray representing 248 clinically annotated stage I-II NSCLC cases was stained using immunohistochemistry (IHC) and scored for HHSP proteins namely, SHH, PTCH1, SMO, GLI1, and GLI2; as well as, ALDH1A1, a putative cancer stem cell marker. Data was analyzed for correlation between IHC staining, EGFR and KRAS mutations, and clinical characteristics including relapse-free survival (RFS) and overall survival (OS).

Results: In adenocarcinoma, there were significant correlations of IHC expression between SHH and downstream HHSP receptor SMO (p=0.017) and transcription factor GLI1 (p=0.001), while SMO correlated with GLI1 (p=0.007). In squamous cell carcinoma, SHH significantly correlated with GLI2 protein expression (p=0.003). After multiple testing correction, there was no significant correlation between any of the six markers and RFS or OS.

Conclusions: Key downstream components of the HHSP show correlation with sonic hedgehog ligand (SHH) expression, suggesting that ligand-dependent signaling is more prevalent in primary NSCLC tumors. Surprisingly, in early-stage NSCLC, there were no significant correlations between HHSP proteins or ALDH1A1 and RFS or OS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase / biosynthesis*
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase 1 Family
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Disease-Free Survival
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Immunohistochemistry / methods
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Ligands
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Retinal Dehydrogenase
  • Signal Transduction
  • Smoothened Receptor
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger Protein Gli2
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Biomarkers, Tumor
  • GLI2 protein, human
  • Hedgehog Proteins
  • KRAS protein, human
  • Kruppel-Like Transcription Factors
  • Ligands
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • SMO protein, human
  • Smoothened Receptor
  • Transcription Factors
  • Zinc Finger Protein Gli2
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins