SMO expression level correlates with overall survival in patients with malignant pleural mesothelioma

Our plain-English summary of SMO expression level correlates with overall survival in patients with malignant pleural mesothelioma, by Y. Zhang, J. He, F. Zhang, et al (Journal of Experimental & Clinical Cancer Research, 2013).

The study

• Authors: Y. Zhang, J. He, F. Zhang, H. Li, D. Yue, C. Wang, D.M. Jablons, B. He, N. Lui
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2013;32(1):7
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is an aggressive, treatment-resistant tumor arising from mesothelium of pleura, peritoneum and pericardium. Despite current combined regimen, its prognosis remains dismal, calling for more effective targeted therapies. We investigated whether aberrant Hh activation may play a role in mesothelioma.

Methods: SMO and SHH expression levels were analyzed in 46 mesothelioma tissue specimens with real-time RT-PCR, and correlation with survival was analyzed with univariate and multivariate Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. We also examined multiple mesothelioma cell lines for SMO expression and the effect of Hh inhibition by a specific SMO antagonist on cell proliferation by MTS assay.

Results: We observed strong correlation between higher SMO and SHH expression levels with poorer overall survival. Remarkably, Hh inhibition by a specific SMO inhibitor significantly suppressed cell proliferation in the mesothelioma cell lines examined.

Conclusion: Our data strongly support that Hh signaling deregulation plays critical roles in proliferation of mesothelioma, and consistently exerts significant impact on prognosis of the disease. Therefore our findings revealed the hitherto unappreciated role of Hh activation in mesothelioma, and pinpointed Hh signaling antagonist as a potential new therapy against this devastating disease.

In plain English

This study examined tumors from 46 patients operated on for malignant pleural mesothelioma at the authors' institution from April 2000 to January 2010. It also tested three mesothelioma cell lines. Asbestos exposure was not studied. The authors measured expression levels of two Hedgehog pathway genes, SMO and SHH, in the tumors and compared them with survival. Forty-five of the 46 patients died during follow-up. Higher SMO levels were associated with worse overall survival. The hazard ratio was 1.05 (95% CI 1.00-1.10, p = 0.05) unadjusted and 1.06 (95% CI 1.00-1.12, p = 0.03) after adjusting for age, sex and tumor type. SHH, measured in only part of the group, was linked to higher risk of death in both the unadjusted and adjusted models (p = 0.04 in each). A comparison of patients above versus below the median SHH level was not statistically significant (p = 0.45). Cyclopamine, a drug that blocks SMO, suppressed growth of the cell lines. The authors concluded that Hedgehog signaling plays a critical role in mesothelioma and that blocking it is a potential new therapy. They noted the small patient numbers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of stored surgical tumor specimens with survival analysis (Cox proportional hazards models, Kaplan-Meier curves, log-rank test), plus laboratory experiments on mesothelioma cell lines
• Who was studied: 46 patients who had surgical resection for malignant pleural mesothelioma at the authors' institution, April 2000 to January 2010 (mean age 67.2; 35 men, 11 women; 39 epithelioid tumors). Also three mesothelioma cell lines: NCI-H28, REN and H290.
• Exposure: No asbestos exposure was measured. The factors studied were SMO and SHH expression levels (mRNA and protein) in tumor tissue and, in the cell lines, treatment with the SMO-blocking drug cyclopamine.
• Main results:
  • Median follow-up was 11.8 months. 45 of the 46 patients died, 31 of them within two years of their operations.
  • Unadjusted model: higher SMO expression was associated with worse overall survival (hazard ratio 1.05, 95% CI 1.00-1.10, p = 0.05).
  • Model adjusted for age, sex and histological type: SMO expression remained associated with worse survival (hazard ratio 1.06, 95% CI 1.00-1.12, p = 0.03).
  • SHH, unadjusted model: higher SHH expression was significantly associated with higher risk of death (95% CI 1-28%, p = 0.04; data not shown). When patients were split at the median SHH level, the log-rank test was not significant (p = 0.45).
  • SHH added to the adjusted model: SHH expression remained significant. Higher SMO (95% CI 8-72%, p = 0.009) and higher SHH (95% CI 1-26%, p = 0.04) were both associated with increased risk of death. These data were not shown.
  • In the three mesothelioma cell lines, cyclopamine suppressed cell proliferation in a dose-dependent manner. No numerical values are given in the text.
• The authors' conclusion: The authors concluded that higher SMO and SHH expression levels were strongly associated with poorer overall survival, and that blocking Hedgehog signaling stopped proliferation in mesothelioma cell lines. They wrote that this strongly supports Hedgehog signaling being essential for mesothelioma tumor growth, and they pointed to Hedgehog signaling antagonists as a potential new therapy.
• Limitations the authors state:
  • The authors stated that their results are limited by the relatively small number of patients, which they attributed to the low incidence of malignant pleural mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Overall Survival, Pleural Mesothelioma, Mesothelioma, Mesothelium, Pleura, Peritoneum, Pericardium, Prognosis.

Related studies

• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)
• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)
• Discussion — (2014)
• High Expression of SMO and GLI1 Genes with Poor Prognosis in Malignant Mesothelioma — G.Y. Ma, S. Shi, et al. (2023)
• Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells — S. Avino, P. De Marco, et al. (2016)
• BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients — M. De Marco, N. Del Papa, et al. (2022)

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