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Cited by 19Pancreatic and Hepatic Oncology ResearchHedgehog Signaling Pathway StudiesCholangiocarcinoma and Gallbladder Cancer Studies

The Loss of SMAD4/DPC4 Expression Associated with a Strongly Activated Hedgehog Signaling Pathway Predicts Poor Prognosis in Resected Pancreatic Cancer

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Xu, Jin-Zhi, Wang, Wen-Quan, Zhang, Wu-Hu, Xu, Hua-Xiang, Gao, He-Li, Zhang, Shi-Rong, Wu, Chun-Tao, Li, Shuo +4 more·2019·Journal of Cancer
DOI 10.7150/jca.30883PMC PMC6692626
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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway.However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear.Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance.Results: SMAD4 lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC.The mutational status of p16 had no effect on patient survival.High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses.Pearson's χ 2 test showed a medium correlation between the SMAD4 lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001).Patients with the SMAD4 lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study.Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.

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  • Patients with SMAD4 loss, high Gli1 and SMO expressions had significantly worse overall and recurrence-free survival.

    “Patients with SMAD4 loss, high Gli1 and SMO expressions had significantly worse overall and recurrence-free survival.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [80]

  • Another study involving 237 patients identified SMAD4 loss and an activated Hedgehog (Shh) signaling pathway as predictors of poor prognosis.

    “Another study involving 237 patients identified SMAD4 loss and an activated Hedgehog (Shh) signaling pathway as predictors of poor prognosis.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [80]

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Authors
Xu, J.-Z., Wang, W.-Q., Zhang, W.-H., Xu, H.-X., Gao, H.-L., Zhang, S.-R., Wu, C.-T., Li, S., Li, H., Xu, J., Yu, X.-J., & Liu, L.
Affiliations
Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Wang, Wen-Quan
  • Liu, Liang
ORCID
Venue
Journal of Cancer
Publisher
Ivyspring International Publisher
Published
2019
Volume
10
Issue
17
Pages
4123-4131
ISSN
1837-9664 (ISSN-L)
DOI
10.7150/jca.30883
PMC
PMC6692626
OpenAlex
W2964289988
Cited by
19
References
1
Citations by year
2025: 2 · 2024: 3 · 2022: 5 · 2021: 6 · 2020: 3
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Cancer (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (81625016)
  • National Natural Science Foundation of China (81802675, 81872366, 81802380, 81472670, 81625016, 81871941)
  • Science and Technology Commission of Shanghai Municipality (18XD1401200)
  • National Science Fund for Distinguished Young Scholars (81625016)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
Keywords
pancreatic ductal adenocarcinoma, SMAD4, Sonic hedgehog signaling, Gli1, GLI2, Smoothened, KRAS, TP53, CDKN2A/p16, prognostic factors, resectable pancreatic cancer, overall survival, recurrence-free survival, tumor stroma

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