Hyaluronan stimulates pancreatic cancer cell motility

// Xiao-Bo Cheng 1, 2 , Shiro Kohi 1 , Atsuhiro Koga 1 , Keiji Hirata 1 , Norihiro Sato 1 1 Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan 2 Department of Breast Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, China Correspondence to: Xiao-Bo Cheng, e-mail: c13840564883@163.com & chengxiaobo@med.uoeh-u.ac.jp Norihiro Sato, e-mail: norisato@med.uoeh-u.ac.jp Keywords: hyaluronan, pancreatic cancer, migration, hyaluronan synthase genes, hyaluronidase genes Received: September 01, 2015      Accepted: November 28, 2015      Published: December 14, 2015 ABSTRACT Hyaluronan (HA) accumulates in pancreatic ductal adenocarcinoma (PDAC), but functional significance of HA in the aggressive phenotype remains unknown. We used different models to investigate the effect of HA on PDAC cell motility by wound healing and transwell migration assay. Changes in cell motility were examined in 8 PDAC cell lines in response to inhibition of HA production by treatment with 4-methylumbelliferone (4-MU) and to promotion by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or by co-culture with tumor-derived stromal fibroblasts. We also investigated changes in cell motility by adding exogenous HA. Additionally, mRNA expressions of hyaluronan synthases and hyaluronidases were examined using real time RT-PCR. Inhibition of HA by 4-MU significantly decreased the migration, whereas promotion of HA by TPA or co-culture with tumor-derived fibroblasts significantly increased the migration of PDAC cells. The changes in HA production by these treatments tended to be associated with changes in HAS3 mRNA expression. Furthermore, addition of exogenous HA, especially low-molecular-weight HA, significantly increased the migration of PDAC cells. These findings suggest that HA stimulates PDAC cell migration and thus represents an ideal therapeutic target to prevent invasion and metastasis.