Kudo Yuzan, Kohi Shiro, Hirata Keiji, Goggins Michael, Sato Norihiro
Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Oncotarget. 2019 Sep 24;10(54):5592-5604. doi: 10.18632/oncotarget.27172.
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. 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). We investigated transcriptional profiling of genes involved in HA synthesis (including and ) and degradation (including and ) 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. 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.
胰腺导管腺癌（PDAC）与基质细胞外基质（尤其是与透明质酸（HA））的相互作用增强了其侵袭性。我们之前的研究表明，参与HA合成和降解的基因在PDAC中的表达增加，这表明存在一种自分泌机制，可加速低分子量HA的产生。一部分PDAC（20%的细胞系和25%的组织）显示出多种编码HA合成酶和HA降解酶的基因过表达，呈现出一种被定义为HA激活代谢表型（HAMP）的表型。有趣的是，与HAMP-细胞相比，HAMP+细胞对HA合成抑制剂和HA降解抑制剂的治疗更敏感。HAMP+肿瘤患者的生存期明显短于HAMP-肿瘤患者（P = 0.049）。我们研究了一组PDAC细胞系和原发性组织中参与HA合成（包括 和 ）和降解（包括 和 ）的基因的转录谱。通过细胞迁移试验检测PDAC细胞对HA合成抑制剂（4-甲基伞形酮）或HA降解抑制剂（硫酸葡聚糖）治疗的反应。通过Kaplan-Meier曲线确定生存期，并通过对数秩检验进行比较。本研究在PDAC中鉴定出一种以HA代谢途径激活为特征的新表型HAMP。HAMP应作为一种预后标志物以及个性化医学的靶点进行进一步研究。
