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Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization
Lidong Wang1, David G Heidt, Cheong J Lee
1Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Abstract:
Pancreatic cancer is a deadly disease characterized by late diagnosis and resistance to therapy. Much progress has been made in defining gene defects in pancreatic cancer, but a full accounting of its molecular pathogenesis remains to be provided. Here, we show that expression of the ataxia-telangiectasia group D complementing gene (ATDC), also called TRIM29, is elevated in most invasive pancreatic cancers and pancreatic cancer precursor lesions. ATDC promoted cancer cell proliferation in vitro and enhanced tumor growth and metastasis in vivo. ATDC expression correlated with elevated beta-catenin levels in pancreatic cancer, and beta-catenin function was required for ATDC's oncogenic effects. ATDC was found to stabilize beta-catenin via ATDC-induced effects on the Disheveled-2 protein, a negative regulator of glycogen synthase kinase 3beta in the Wnt/beta-catenin signaling pathway.
Insights
Elevated expression of ataxia-telangiectasia group D complementing gene (ATDC) drives pancreatic cancer growth and metastasis. ATDC stabilizes beta-catenin, a key protein in the Wnt/beta-catenin signaling pathway, promoting oncogenic effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Pancreatic cancer is a lethal malignancy with late diagnosis and therapeutic resistance.
- Understanding the molecular drivers of pancreatic cancer pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of ataxia-telangiectasia group D complementing gene (ATDC), also known as TRIM29, in pancreatic cancer.
- To elucidate the molecular mechanisms by which ATDC contributes to pancreatic cancer progression.
Main Methods:
- Quantitative analysis of ATDC expression in pancreatic tumors and precursor lesions.
- In vitro studies assessing the impact of ATDC on cancer cell proliferation.
- In vivo experiments evaluating ATDC's effects on tumor growth and metastasis.
- Analysis of the Wnt/beta-catenin signaling pathway components, including beta-catenin and Disheveled-2.
Main Results:
- ATDC expression is significantly elevated in most invasive pancreatic cancers and precursor lesions.
- Overexpression of ATDC promotes pancreatic cancer cell proliferation in vitro and enhances tumor growth and metastasis in vivo.
- ATDC expression correlates with increased beta-catenin levels, and beta-catenin signaling is essential for ATDC's oncogenic functions.
- ATDC stabilizes beta-catenin by influencing Disheveled-2, a key regulator in the Wnt/beta-catenin pathway.
Conclusions:
- ATDC is a novel oncogene in pancreatic cancer, promoting tumor progression and metastasis.
- The Wnt/beta-catenin signaling pathway, regulated by ATDC through Disheveled-2, is a critical mediator of ATDC's oncogenic activity.
- Targeting ATDC or the Wnt/beta-catenin pathway may offer therapeutic strategies for pancreatic cancer.
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