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Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

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Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
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Division of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan
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Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Department of Surgery, Mackay Memorial Hospital, Taipei 10449, Taiwan
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Liver Medical Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
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Nursing and Management, Mackay Junior College of Medicine, New Taipei City 25245, Taiwan
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Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
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Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
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Author to whom correspondence should be addressed.
Genes 2019, 10(10), 766; https://doi.org/10.3390/genes10100766
Received: 3 September 2019 / Revised: 16 September 2019 / Accepted: 27 September 2019 / Published: 28 September 2019
(This article belongs to the Special Issue Genetic Markers in Pancreatic Cancer)
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment. View Full-Text
Keywords: bioinformatics; cell cycle; in silico; pancreatic ductal adenocarcinoma; SMAD4 bioinformatics; cell cycle; in silico; pancreatic ductal adenocarcinoma; SMAD4
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MDPI and ACS Style

Hsieh, Y.-Y.; Liu, T.-P.; Chou, C.-J.; Chen, H.-Y.; Lee, K.-H.; Yang, P.-M. Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma. Genes 2019, 10, 766.

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