Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterised by dense desmoplasia and hypoxic microenvironment. Our previous reports demonstrated that hyaluronan (HA), especially low-molecular-weight HA, provides a favourable microenvironment for PDAC progression. However, the effect of hypoxia on HA metabolism remains unknown. Using quantitative real-time RT-PCR and western blot analysis, we analysed the changes in the expression of HA-synthesizing enzymes (HAS2 and HAS3) and HA-degrading enzymes (HYAL1, KIAA1199/CEMIP) in PDAC cell lines under hypoxic conditions. Hypoxia increased the mRNA and protein expression of KIAA1199, whereas it decreased HYAL1 expression. The expression of HAS3 was increased and HAS2 remained unchanged in response to hypoxia. The effect of KIAA1199 on hypoxia-induced cell migration was determined using a transwell migration assay and small-interfering RNA (siRNA). Hypoxia enhanced the migratory ability of PDAC cells, which was inhibited by KIAA1199 knockdown. We also used immunohistochemistry to analyse the protein expression of hypoxia inducible factor (HIF) 1α and KIAA1199 in PDAC tissues. There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases worldwide, with the lowest survival rate among all cancer types[1]
We investigated the relationship between hypoxia and HA metabolism in PDAC cells
(2) Hypoxia enhanced the migration of PDAC cells, whereas knockdown of KIAA1199 inhibited the migration enhanced by hypoxia
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases worldwide, with the lowest survival rate among all cancer types[1]. HA plays a critical role in a variety of malignant behaviours including cell proliferation, migration, invasion, metastasis, angiogenesis, and resistance to drug d elivery[7,8,9,10,11,12]. Previous studies have shown that KIAA1199 is overexpressed in various cancers, and is associated with an aggressive p henotype[15,16,17,18,19]. KIAA1199 enhances the motility of colon cancer cells and is called the cell migration-inducing protein (CEMIP). Many signalling pathways including mitogen-activated protein kinase (MAPK) signalling[25], are known to be altered by hypoxic conditions in PDAC cells[25], the effect of hypoxia on HA metabolism is unknown. We investigated the relationship between hypoxia and HA metabolism in PDAC cells
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