High expression of Sonic hedgehog signaling proteins is related to the favorable outcome, EGFR mutation, and lepidic predominant subtype in primary lung adenocarcinoma

Ann Surg Oncol. 2013 Dec:20 Suppl 3:S570-6. doi: 10.1245/s10434-013-3022-6. Epub 2013 May 26.


Background: Dysregulation of the Sonic hedgehog (SHH) signaling pathway has been identified in many human malignancies. However, it remains unclear whether this pathway is activated in human lung adenocarcinoma.

Methods: We investigated the expression of the SHH ligand and its downstream molecules, such as glioma-associated oncogene homologue (GLI)-1, GLI-2, GLI-3, and ATP-binding cassette G2 (ABCG2), in 166 cases of surgically resected lung adenocarcinoma by immunohistochemistry. Correlations between the expression of SHH-related proteins and clinicopathologic parameters, histologic subtypes, and prognostic significance were statistically analyzed.

Results: SHH was highly expressed in the 36.1 % (60/166), GLI-1, GLI-2, and ABCG2 were found in 90/164 (54.9 %), 26/166 (15.7 %), and 139/165 (84.2 %), respectively, and GLI-3 was positive in all cases. SHH was more frequently highly expressed in nonsmokers, patients with no recurrences, lepidic predominant subtype, and with EGFR mutation (p < 0.05, respectively). The high expression of SHH and GLI-1 was related to better overall survival and progression-free survival (p < 0.05).

Conclusions: The SHH signaling pathway is frequently up-regulated in a subset of lung adenocarcinoma and is significantly associated with EGFR mutation and lepidic subtype. Although SHH signaling protein expression is not an independent prognostic marker, the expression of these proteins can predict a better prognostic outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / secondary
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • ErbB Receptors / genetics*
  • Female
  • Follow-Up Studies
  • Hedgehog Proteins / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Prognosis
  • Survival Rate
  • Tissue Array Analysis
  • Transcription Factors / metabolism
  • Young Adult
  • Zinc Finger Protein GLI1


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Biomarkers, Tumor
  • GLI1 protein, human
  • Hedgehog Proteins
  • Neoplasm Proteins
  • SHH protein, human
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • EGFR protein, human
  • ErbB Receptors