Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer

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.

KIAA1199 Correlates With Tumor Microenvironment and Immune Infiltration in Lung Adenocarcinoma as a Potential Prognostic Biomarker

“…For example, EGFR activating mutations as in frame deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21 are related with the therapeutic effect of first generation quinazoline reversible EGFR tyrosine kinase inhibitors (TKIs) in NSCLC patients. KIAA1199 mutation in the GG domain was reported to cause hearing loss due to the folding change of protein structure [ 13 ], meanwhile its carcinogenic effect was thought to be related to the overexpression of KIAA1199 [ 17 , 20 ], suggesting that KIAA1199 gene copy number amplification is responsible for the malignant progression of LUAD. However, whether other gene alteration types, such as missense mutations, are involved in the malignant progression of LUAD is still unknown and needs to be further investigated.…”

“…KIAA1199, also known as cell migration inducing protein (CEMIP) or hyaluronan binding protein (HYBID), was reported to cause non-syndromic hearing loss and depolymerize hyaluronic acid (HA) [12,13]. In recent years, welldocumented studies have demonstrated that KIAA1199 plays a role in promoting malignant progression and predicts poor prognosis of cancer patients, including gastric cancer [14][15][16], pancreatic cancer [17], colorectal cancer [18,19], prostate cancer [20,21] and so on. Studies have shown that KIAA1199 can promote sorafenib tolerance and the metastasis of hepatocellular carcinoma [22], facilitate extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis [23] and accelerate metastasis in other tumors [18][19][20].…”

CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer

“…The CEMIP locus is further surrounded by four T-cell factor 4 (TCF4)–binding sites, reflecting the fact that CEMIP is a target of the Wnt signaling pathway [ 6 , 47 , 48 ]. It also contains a hypoxia response element, consistent with the increased CEMIP expression observed under low-oxygen conditions through the stabilization of hypoxia-inducible-factor-2α (HIF-2α) [ 17 , 49 ]. The basic promoter activity of CEMIP is also regulated by DNA methylation and in human breast cancer hypomethylation correlates with high CEMIP expression [ 10 , 44 ].…”

“…CEMIP-enhanced cell migration requires endoplasmic reticulum (ER) localization, where it forms a stable complex with the chaperone binding immunoglobulin protein BiP [ 29 ]. Hypoxia stimulates CEMIP-dependent motility in colorectal and PDAC cancer cells [ 17 , 49 ]. Furthermore, CEMIP induces invasion in NSCLC and ovarian cancer cells in a manner that is associated with the increased expression of PI3K and AKT [ 19 , 74 ].…”

Immunometabolism in the tumor microenvironment and its related research progress

“…In addition to activating HIF-1α signal, hypoxia also has other different effects. For example, hypoxia induces the expression of hyaluronic acid synthase and reduces the synthesis of hyaluronic acid degrading enzymes, resulting in high hyaluronic acid concentrations in hypoxia environments ( 38 ). Based on this phenomenon, a recent study used nanosystems to remotely enhance hyaluronidase activity, promote hyaluronic acid degradation, and reduce HIF-1α expression, alleviating the immunosuppressive tumor microenvironment ( 39 ).…”