RABL6A Promotes Pancreatic Neuroendocrine Tumor Angiogenesis and Progression In Vivo.
Chandra K MaharjanShaikamjad UmesalmaCourtney A KaemmerViviane P MunizCasey BauchleSarah L MottK D ZambaPatrick J BrehenyMariah R LeidingerBenjamin W DarbroSamuel B StephensDavid K MeyerholzDawn E QuellePublished in: Biomedicines (2021)
Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survival in vitro. Here, we investigated the role of RABL6A in pNET progression in vivo using a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenic c-Myc in RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and development in vivo.
Keyphrases
- cell proliferation
- endothelial cells
- poor prognosis
- neuroendocrine tumors
- vascular endothelial growth factor
- induced apoptosis
- high fat diet induced
- signaling pathway
- transcription factor
- stem cells
- risk factors
- cell cycle arrest
- case report
- wound healing
- type diabetes
- wild type
- pi k akt
- free survival
- bone marrow
- mass spectrometry
- cell therapy
- skeletal muscle
- long non coding rna
- high resolution
- replacement therapy