Paiva Premila, Van Damme Marie-Paule, Tellbach Marianne, Jones Rebecca L, Jobling Tom, Salamonsen Lois A
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Gynecol Oncol. 2005 Aug;98(2):193-202. doi: 10.1016/j.ygyno.2005.02.031.
The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, while its cleaved fragments stimulate angiogenesis. The aims of this study were to assess the levels of HA and how it might be regulated in endometrial cancer.
Endometrial carcinomas were grouped according to histologic grade (Grade 1-3). HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24). Real-time RT-PCR was used to determine the mRNA expression of Hyal 1, Hyal 2 (n = 13) and Hyal 3 (n = 11) in endometrial carcinomas.
HA, its synthases and degradative enzymes were identified in endometrial carcinomas of all histologic grades. HA was predominantly localized to tumor-associated stroma. Semiquantitative analysis revealed increased HA levels with tumor grade, however, this increase only attained significance in Grade 2 carcinomas (P < 0.05). HA staining intensity scores were significantly associated with the presence of myometrial invasion (P < 0.05). Alternatively, HAS was predominantly localized in tumor epithelial cells, and its levels did not vary with tumor grade. Expression of Hyal 3 and Hyal 2 mRNA were >1000-fold and >30-fold greater respectively than that of Hyal 1 mRNA, the major Hyal expressed in other cancers. No Hyal type varied with tumor grade.
This is the first study to demonstrate the cellular localization of HA and its synthases and that Hyal 3 mRNA is predominant in endometrial cancer. The results suggest a role for elevated HA in endometrial cancer progression.
细胞外糖胺聚糖透明质酸（HA）及其降解酶透明质酸酶（Hyal）在肿瘤转移和血管生成中发挥重要作用。HA促进肿瘤细胞黏附和迁移，而其裂解片段刺激血管生成。本研究旨在评估子宫内膜癌中HA的水平及其调控方式。
子宫内膜癌根据组织学分级（1-3级）分组。HA组织化学采用生物素化HA结合肽（n = 15），而HA合酶（HAS）免疫组织化学采用识别HAS1、HAS2、HAS3的抗体（n = 24）。实时逆转录聚合酶链反应用于测定子宫内膜癌中Hyal 1、Hyal 2（n = 13）和Hyal 3（n = 11）的mRNA表达。
在所有组织学分级的子宫内膜癌中均鉴定出HA及其合酶和降解酶。HA主要定位于肿瘤相关间质。半定量分析显示，HA水平随肿瘤分级增加，然而，这种增加仅在2级癌中具有统计学意义（P < 0.05）。HA染色强度评分与肌层浸润的存在显著相关（P < 0.05）。另外，HAS主要定位于肿瘤上皮细胞，其水平不随肿瘤分级变化。Hyal 3和Hyal 2 mRNA的表达分别比其他癌症中主要表达的Hyal 1 mRNA高>1000倍和>30倍。没有任何一种Hyal类型随肿瘤分级变化。
这是首次证明HA及其合酶细胞定位以及Hyal 3 mRNA在子宫内膜癌中占主导地位的研究。结果提示HA升高在子宫内膜癌进展中起作用。
