Yonsei Med J.  2019 Oct;60(10):898-904. 10.3349/ymj.2019.60.10.898.

Sonic Hedgehog Pathway as the Prognostic Marker in Patients with Extensive Stage Small Cell Lung Cancer

• Lim S
• Lim SM
• Kim MJ
• Park SY
• Kim JH

• KMID: 2459142
• DOI: http://doi.org/10.3349/ymj.2019.60.10.898

Abstract

PURPOSE
Sonic hedgehog (Shh) signaling pathway is known to play a crucial role in carcinogenesis in various malignancies, including lung cancer regarding tumorigenesis, angiogenesis, and cellular differentiation. The aim of this study was to investigate the value of components of Shh pathway as a prognostic marker in extensive stage small cell lung cancer (ES-SCLC) patients.
MATERIALS AND METHODS
We retrospectively analyzed data of 36 patients who were diagnosed with ES-SCLC between 2008 and 2012 at a single center. We performed immuo-histochemistry for glioma-associated oncogene homolog zinc finger protein 1 (Gli1), patched, Shh, and Ptch-mediated repression of smoothened (Smo) proteins using formalin-fixed, paraffin-embedded tissue derived from primary tumors. We then conducted survival analysis to evaluate the prognostic impact of these markers.
RESULTS
All 36 patients received platinum-based doublet chemotherapy. The median progression free survival and median overall survival were 6.9 months [95% confidence interval (CI), 6.5-7.3] and 11.7 months (95% CI, 9.1-14.3), respectively. The overall response rate was 84%. Of the 36 tissue specimens examined, over-expression of Gli1, Patched, Shh, and Smo was found in 12 (33.3%), five (13.9%), five (13.9%), and six (16.7%) cases, respectively. We found that high expression of Shh was associated with worse progression free survival (6.3 vs. 7.6 months, p=0.005) and overall survival (9.2 vs. 12.0 months, p=0.039) by both univariate and multivariate analyses, whereas other markers were not related to patient prognosis.
CONCLUSION
A high proportion of small cell lung cancer tumors express proteins related to Shh pathway, and over-expression of Shh is correlated with poor prognosis.

Keyword

Small cell lung cancer; prognostic factors; hedgehog proteins; drug therapy

MeSH Terms

Carcinogenesis
Disease-Free Survival
Drug Therapy
Hedgehog Proteins
Hedgehogs*
Humans
Lung Neoplasms
Multivariate Analysis
Oncogenes
Prognosis
Repression, Psychology
Retrospective Studies
Small Cell Lung Carcinoma*
Zinc Fingers
Hedgehog Proteins

Figure

• 

  Fig. 1 Representative immune-histochemical staining intensity for Gli1, patched, sonic hedgehog (Shh), and Ptch-mediated repression of smoothened (Smo) in patients with extensive stage small cell lung cancer. 0, no staining; 1+, mild; 2+, moderate; 3+, strong staining (×400).

• 

  Fig. 2 Frequency of overexpression for each protein. Gli1, glioma-associated oncogene homolog zinc finger protein 1; Shh, sonic hedgehog; Smo, Ptch-mediated repression of smoothened.

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  Fig. 3 Kaplan-Meier analysis of progression free survival (PFS) (A) and overall survival (OS) (B) according to sonic hedgehog (Shh) expression.

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