Oncotarget

Research Papers:

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

Yuzan Kudo, Shiro Kohi, Keiji Hirata, Michael Goggins and Norihiro Sato _

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Oncotarget. 2019; 10:5592-5604. https://doi.org/10.18632/oncotarget.27172

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Abstract

Yuzan Kudo1, Shiro Kohi1,2, Keiji Hirata1, Michael Goggins2 and Norihiro Sato1

1 Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

2 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Correspondence to:

Norihiro Sato,email: norisato@med.uoeh-u.ac.jp

Keywords: hyaluronan; synthesis; degradation; pancreatic cancer; prognosis

Abbreviations: PDAC: pancreatic ductal adenocarcinoma; HA: hyaluronan; HAMP: hyaluronan activated-metabolism phenotype

Received: July 04, 2019     Accepted: August 12, 2019     Published: September 24, 2019

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.


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