CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation
Autor: | Gregory B. Vanden Heuvel, Sebastian Mühl, Patrick Michl, Irene Esposito, Jan Riedel, Katharina Theuerkorn, Bence Sipos, Heidi Griesmann |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research EGFR pancreatic cancer transgenic mice medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Genetic model medicine Transcription factor RC254-282 ADAM17 Kinase Chemistry CUX1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer KRAS mutation medicine.disease 030104 developmental biology cell proliferation Oncology 030220 oncology & carcinogenesis Cancer research KRAS Signal transduction MEK-ERK |
Zdroj: | Cancers Volume 13 Issue 10 Cancers, Vol 13, Iss 2462, p 2462 (2021) |
ISSN: | 2072-6694 |
DOI: | 10.3390/cancers13102462 |
Popis: | The transcription factor CUX1 has been implicated in either tumor suppression or progression, depending on the cancer entity and the prevalent CUX1 isoform. Previously, we could show that CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis in pancreatic cancer cell lines. However, in vivo evidence for its impact on pancreatic carcinogenesis, isoform-specific effects and downstream signaling cascades are missing. We crossbred two different CUX1 isoform mouse models (p200 CUX1 and p110 CUX1) with KC (KrasLSL-G12D/+ Ptf1aCre/+) mice, a genetic model for pancreatic precursor lesions (PanIN). In the context of oncogenic KRASs, both mice KCCux1p200 and KCCux1p110 led to increased PanIN formation and development of invasive pancreatic ductal adenocarcinomata (PDAC). In KCCux1p110 mice, tumor development was dramatically more accelerated, leading to formation of invasive PDAC within 4 weeks. In vitro and in vivo, we could show that CUX1 enhanced proliferation by activating MEK-ERK signaling via an upstream increase of ADAM17 protein, which in turn led to an activation of EGFR. Additionally, CUX1 further enhanced MEK-ERK activation through upregulation of the serine/threonine kinase MOS, phosphorylating MEK in a KRAS-independent manner. We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets. |
Databáze: | OpenAIRE |
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