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Updated: Jan 4, 2026
Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
Published on: November 5, 2014
SMAD4 Y353C promotes the progression of PDAC
Zusen Wang1, Yongxing Li2, Shixiong Zhan1
1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China.
Background:
SMAD4 is frequently inactivated and associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Abnormal SMAD4 expression also plays an important role in the malignant progression of PDAC.
Methods:
We investigated SMAD4 status in PDAC by immunohistochemical methods to explore the relationships between SMAD4 expression and clinicopathological features and then detected SMAD4 mutations by Sanger sequencing in 95 patients with PDAC to identify new mutation sites in PDAC. We further evaluated the effects of a missense mutation, Y353C, in the SMAD4 MH2 domain, on cell proliferation and migration in vitro.
Results:
Immunohistochemistry showed that the expression of SMAD4 in PDAC carcinoma tissue was significantly lower than that in normal pancreatic tissue, and negative SMAD4 expression was closely related to tumour diameter, staging, lymph node metastasis and differentiation. Sanger sequencing analysis showed that the rate of SMAD4 mutation was 11.8% in 85 PDAC cases, and the novel SMAD4 Y353C missense mutation identified in this study promoted cell migration and invasion without affecting cell proliferation in vitro. Furthermore, SMAD4 Y353C resulted in reduced expression of E-cadherin and increased expression of Vimentin compared with wild-type SMAD4 overexpression.
Conclusion:
This study supports the key role of SMAD4 as a tumour suppressor gene in PDAC and shows that SMAD4 Y353C is associated with poor progression of PDAC.
Insights
SMAD4 inactivation is linked to poor pancreatic ductal adenocarcinoma (PDAC) prognosis. A novel SMAD4 Y353C mutation promotes PDAC cell invasion, highlighting SMAD4
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SMAD4 inactivation is common in pancreatic ductal adenocarcinoma (PDAC) and linked to poor prognosis.
- Altered SMAD4 expression significantly influences PDAC's malignant progression.
Purpose of the Study:
- To investigate SMAD4 expression and its correlation with clinicopathological features in PDAC.
- To identify novel SMAD4 mutation sites in PDAC and evaluate the functional impact of the Y353C missense mutation.
Main Methods:
- Immunohistochemistry was used to assess SMAD4 expression in PDAC tissues.
- Sanger sequencing was employed to detect SMAD4 mutations in 95 PDAC patients.
- In vitro assays evaluated the effects of the SMAD4 Y353C mutation on cell proliferation and migration.
Main Results:
- Reduced SMAD4 expression in PDAC tissues correlated with larger tumor size, advanced stage, lymph node metastasis, and poor differentiation.
- SMAD4 mutations occurred in 11.8% of PDAC cases, with a novel Y353C missense mutation identified.
- The SMAD4 Y353C mutation enhanced cell migration and invasion without affecting proliferation, reducing E-cadherin and increasing Vimentin expression.
Conclusions:
- SMAD4 functions as a tumor suppressor gene in PDAC.
- The identified SMAD4 Y353C mutation is associated with aggressive PDAC progression and metastasis.
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