Hyaluronan activated-metabolism phenotype (HAMP) in pancreatic ductal adenocarcinoma

Abstract

Background: The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is enhanced by its interactions with stromal extracellular matrix, notably with hyaluronan (HA). Our previous studies have demonstrated increased expression of genes involved in HA synthesis and degradation in PDAC, suggesting the presence of an autocrine mechanism which accelerates the production of low-molecular-weight HA. Results: A subset of PDAC (20% of cell lines and 25% of tissues) showed overexpression of multiple genes encoding both HA-synthesizing and HA-degrading enzymes, displaying a phenotype defined as an HA activated-metabolism phenotype (HAMP). Interestingly, HAMP+ cells were more susceptible to the treatment with an HA synthesis inhibitor and HA degradation inhibitor than HAMP- cells. Patients with HAMP+ tumors were significantly associated with shorter survival than those with HAMP- tumors (P = 0.049). Methods: We investigated transcriptional profiling of genes involved in HA synthesis (including HAS2 and HAS3) and degradation (including HYAL1 and KIAA1199) in a panel of PDAC cell lines and primary tissues. Response of PDAC cells to treatment with an HA synthesis inhibitor (4-methylumbelliferone) or HA degradation inhibitor (dextran sulfate) was examined by cell migration assay. Survival was determined by Kaplan–Meier curve and compared by log-rank test. Conclusions: The present study identified a novel phenotype, HAMP, characterized by activation of HA metabolism pathways, in PDAC. HAMP should be further investigated as a prognostic marker as well as a target for personalized medicine.

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

“…Our previous studies identified a novel phenotype, HAMP (hyaluronan-activated metabolism phenotype), characterized by activation of multiple HA metabolism cascades, in PDAC 34 . HAMP was defined as the increased expression of multiple HA metabolism genes, including KIAA1199.…”

HIF1α/CCL7/KIAA1199 axis mediates hypoxia-induced gastric cancer aggravation and glycolysis alteration

“…(31) For example, an enhanced expression of KIAA1199 in the nucleus, as well as cytoplasm, was discovered in colon cancer cells and also the plasma of cancer patients, and had significant correlation with patients' clinical characteristics. (32,33) Kudo et al (34) also found the upregulation of KIAA1199 in pancreatic cancer tissues which was associated with patients' survival outcome. It suggested that KIAA1199 could be regarded as a biomarker for cancer prognosis.…”

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

“…51 This was reinforced by a recent study showing significantly higher HA levels in primary PDACs compared with sites of metastases 59 ; among various metastatic sites, HA was expressed most abundantly in liver metastases. The higher levels of HA in primary tumors in comparison with metastatic sites, in conjunction with the association of high CEMIP protein and poor survival of stage I/II PDAC patients, 27 as well as similar HA abundance in PDAC patients with stage II (95% HA-positive, n = 47) and stage III (86% HA-positive, 15,18,22,25 Not upregulated Kohi et al 25 found high quantity of HYAL1 (measured by ELISA) was significantly associated with more advanced stage. Cheng et al 20 found low expression of HYAL1 (IHC) to be significantly associated with poor survival.…”