A FAM83A Positive Feed-back Loop Drives Survival and Tumorigenicity of Pancreatic Ductal Adenocarcinomas
| Autor: | Wilnelly Hernandez-Sanchez, Mark W. Jackson, Courtney A. Bartel, Neetha Parameswaran, Jacob M. Smigiel, Ahmad M. Khalil, Kristy Miskimen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Carcinogenesis JUNB medicine.medical_treatment Mice Nude lcsh:Medicine Apoptosis medicine.disease_cause Article Targeted therapy Mice 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans lcsh:Science PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology Feedback Physiological 0303 health sciences Multidisciplinary Oncogene business.industry lcsh:R Growth factor signalling Oncogenes Prognosis medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins 3. Good health Gene Expression Regulation Neoplastic Pancreatic Neoplasms Mechanisms of disease 030220 oncology & carcinogenesis Cancer research Female lcsh:Q KRAS business Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Pancreatic ductal adenocarcinomas (PDAC) are deadly on account of the delay in diagnosis and dearth of effective treatment options for advanced disease. The insurmountable hurdle of targeting oncogene KRAS, the most prevalent genetic mutation in PDAC, has delayed the availability of targeted therapy for PDAC patients. An alternate approach is to target other tumour-exclusive effector proteins important in RAS signalling. The Family with Sequence Similarity 83 (FAM83) proteins are oncogenic, tumour-exclusive and function similarly to RAS, by driving the activation of PI3K and MAPK signalling. In this study we show that FAM83A expression is significantly elevated in human and murine pancreatic cancers and is essential for the growth and tumorigenesis of pancreatic cancer cells. Elevated FAM83A expression maintains essential MEK/ERK survival signalling, preventing cell death in pancreatic cancer cells. Moreover, we identified a positive feed-forward loop mediated by the MEK/ERK-activated AP-1 transcription factors, JUNB and FOSB, which is responsible for the elevated expression of oncogenic FAM83A. Our data indicates that targeting the MEK/ERK-FAM83A feed-forward loop opens up additional avenues for clinical therapy that bypass targeting of oncogenic KRAS in aggressive pancreatic cancers. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|