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Leptin-Notch signaling axis is involved in pancreatic cancer progression.

ABSTRACT: Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.

SUBMITTER: Harbuzariu A

PROVIDER: S-EPMC5352357 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Leptin-Notch signaling axis is involved in pancreatic cancer progression.

Harbuzariu Adriana A Rampoldi Antonio A Daley-Brown Danielle S DS Candelaria Pierre P Harmon Tia L TL Lipsey Crystal C CC Beech Derrick J DJ Quarshie Alexander A Ilies Gabriela Oprea GO Gonzalez-Perez Ruben R RR

Oncotarget 20170101 5

Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells ...[more]

PMID: 27999190

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Project description:Purpose:Aberrant expression of microRNAs contributes to the progression of pancreatic cancer by targeting downstream genes. A novel regulatory axis, miR-1224-5p/ELF3, was identified by bioinformatic analysis and experimental verification. Studies of the underlying molecular mechanisms behind this axis lead to a better understanding of the development of pancreatic cancer. Materials and Methods:The differential expression of miR-1224-5p and ELF3 was verified based on Gene Expression Omnibus (GEO) datasets and clinical samples. The relationship between miR-1224-5p and ELF3 was demonstrated by luciferase assay and Western blot. The related signaling pathways of the miR-1224-5p/ELF3 axis in pancreatic cancer were investigated by gene set enrichment analysis (GSEA) and verified by Western blot. An analysis between ELF3 expression and immune infiltration was performed. Cellular and animal experiments were utilized to explore the effects of miR-1224-5p and ELF3 in pancreatic cancer. Results:Suppressed expression of miR-1224-5p in pancreatic tumor tissues and cancer cells was identified first. Furthermore, miR-1224-5p is correlated with clinicopathological features, and decreased expression of miR-1224-5p indicates poor prognosis. miR-1224-5p serves as a tumor suppressor and inhibits malignant behaviors of pancreatic cancer based on in vivo and in vitro assays. The putative target gene ELF3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Overexpression of ELF3 can improve the malignant behaviors of pancreatic cancer and demonstrates poor prognosis and advanced clinical stage. The inhibitory role of miR-1224-5p in pancreatic cancer is manifested by its direct targeting of ELF3. A negative correlation between ELF3 expression and immune cell infiltration was identified, suggesting an immunosuppressive state resulting from ELF3 overexpression. The PI3K/AKT/Notch signaling pathways and epithelial-to-mesenchymal transition (EMT) are important underlying mechanisms. Conclusion:The miR-1224-5p/ELF3 axis may serve as a new diagnostic, therapeutic, and prognostic biomarker in pancreatic cancer. The related PI3K/AKT/Notch/EMT signaling pathways greatly promote the elucidation of the progression of pancreatic cancer.

Dataset Information

Leptin-Notch signaling axis is involved in pancreatic cancer progression.

Publications

Leptin-Notch signaling axis is involved in pancreatic cancer progression.

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