Kohi Shiro, Sato Norihiro, Cheng Xiao-Bo, Koga Atsuhiro, Hirata Keiji
From the Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Japan.
Pancreas. 2016 Nov;45(10):1467-1473. doi: 10.1097/MPA.0000000000000670.
Increased production and processing (degradation) of hyaluronan (HA) is critical for cancer invasion and metastasis. Although HA is known to be overexpressed in pancreatic ductal adenocarcinoma (PDAC), little is known about the expression and biological significance of HA-degrading enzymes, hyaluronidases (HYALs), in PDAC.
Expression of HYALs mRNA was examined in PDAC cells by quantitative real-time RT-PCR. HYAL1 protein expression was examined in primary PDAC tumors by enzyme-linked immuno-sorbent assay. The migratory ability of PDAC cells was determined by a transwell cell migration assay.
Screening of mRNA expression of three major HYAL genes (HYAL1, 2, and 3) identified HYAL1 as a gene overexpressed in PDAC cells. Treatment of PDAC cells with 5-aza-2'-deoxycytidine and/or trichostatin A further increased the HYAL1 expression, suggesting a possible involvement of epigenetic mechanisms in the transcriptional regulation of this gene. HYAL1 protein concentrations were significantly higher in primary PDAC tissues as compared with nontumor pancreatic tissues (P = 0.049). Importantly, inhibition of HYAL activity by dextran sulfate significantly inhibited the migration of PDAC cells showing strong HYAL1 expression (P = 0.002).
These findings suggest that overexpression of HYAL1 is a common mechanism that may contribute to the aggressive phenotype of PDAC.
透明质酸（HA）产量增加及加工（降解）对于癌症侵袭和转移至关重要。尽管已知HA在胰腺导管腺癌（PDAC）中过表达，但关于HA降解酶即透明质酸酶（HYALs）在PDAC中的表达及生物学意义却知之甚少。
通过定量实时逆转录聚合酶链反应检测PDAC细胞中HYALs mRNA的表达。通过酶联免疫吸附测定法检测原发性PDAC肿瘤中HYAL1蛋白的表达。采用Transwell细胞迁移试验测定PDAC细胞的迁移能力。
对三种主要HYAL基因（HYAL1、2和3）的mRNA表达进行筛选，发现HYAL1是在PDAC细胞中过表达的基因。用5-氮杂-2'-脱氧胞苷和/或曲古抑菌素A处理PDAC细胞可进一步增加HYAL1的表达，提示表观遗传机制可能参与该基因的转录调控。与非肿瘤胰腺组织相比，原发性PDAC组织中HYAL1蛋白浓度显著更高（P = 0.049）。重要的是，硫酸葡聚糖抑制HYAL活性可显著抑制显示强HYAL1表达的PDAC细胞的迁移（P = 0.002）。
这些发现表明HYAL1过表达是一种可能导致PDAC侵袭性表型的常见机制。
