Exosomal zinc transporter ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer

Abstract

Pancreatic cancer is one of the deadliest cancers with rapid disease progression. Further elucidation of its underlying molecular mechanisms and novel biomarkers for early detection is necessary. Exosomes are small extracellular vesicles that are released by multiple cell types acting as message carriers during intercellular communication and are promising biomarker candidates. However, the role of pancreatic cancer cell‐derived exosomes in cancer progression and the application of these vesicles as novel diagnostic biomarkers have not been fully studied. In this study, we found that PC‐1.0 (a highly malignant pancreatic cell line) cell‐derived exosomes could be taken up by and enhance PC‐1 (a moderately malignant pancreatic cell line) cell proliferation, migration and invasion abilities. We identified ZIP4 as the most upregulated exosomal protein in PC‐1.0 cells from our proteomic analysis. In vitro and in vivo (a subcutaneous BALB/c nude mouse model) studies showed that exosomal ZIP4 can significantly promote pancreatic cancer growth. Using clinical blood samples, we compared the diagnostic values of serum exosomal ZIP4 levels between malignant pancreatic cancer patients (n = 24) and benign pancreatic disease patients (n = 32, AUC = .89), and between biliary disease patients (n = 32, AUC = .8112) and healthy controls (n = 46, AUC = .8931). In conclusion, exosomal ZIP4 promotes cancer growth and is a novel diagnostic biomarker for pancreatic cancer.

Integrated whole genome microarray analysis and immunohistochemical assay identifies COL11A1, GJB2 and CTRL as predictive biomarkers for pancreatic cancer

“…IHC analysis of the patients’ pancreatic cancer tissue sections and its paired para-cancerous tissue sections was performed as previously described [ 24 ]. Antibody against COL11A1, GJB2 and CTRL was used at the dilution range of 1:300 (Abcam, Cambridge, UK).…”

Zinc dysregulation in cancers and its potential as a therapeutic target

“…The underlying mechanisms for ZIP4 involvement in the proliferation and metastasis of pancreatic cancer can be multifaceted. These mechanisms include the activation of the zinc finger transcription factor CREB-mediated IL-6/STAT3/cyclin D1 pathway, the overexpression of neuropilin-1 (NRP-1), vascular endothelial growth factor (VEGF), and matrix metalloproteases (MMP-2 and MMP-9), repression of zona occludens-1 (ZO-1) and claudin-1 by zinc finger E-box binding homeobox 1 (ZEB1), and RAB27B-mediated release of extracellular vesicles from cancer cells 81 – 83 ( Figure 3C ).…”

<p>The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways</p>

“…A subcutaneous tumor model was utilized to assess the function of ELF3 and miR-1224-5p in pancreatic cancer progression in vivo according to previously described methods. 28 BALB/c nude mice (28 days old, female) were provided by Huafukang Biotechnology (Beijing, China). An SPF animal laboratory was used to house the nude mice.…”