Ma Xiu Mei, Shen Zhi Hua, Liu Zhi Yao, Wang Fang, Hai Ling, Gao Lin Tao, Wang Hai Sheng
Department of Pathology, The Affiliated Hospital of Inner Mongolia Medical University Hohhot 010059, Inner Mongolia Autonomous Region, China ; Department of Pathology, School of Basic Medical Sciences of Inner Mongolia Medical University Hohhot 010059, Inner Mongolia Autonomous Region, China.
The Graduate Faculty of Inner Mongolia Medical University Hohhot 010059, Inner Mongolia Autonomous Region, China.
Int J Clin Exp Pathol. 2014 Aug 15;7(9):5609-21. eCollection 2014.
Gastric cancer is one of the most common cancers and it remains difficult to cure, primarily because most cancer stem like cells possess higher capability of invasion and metastasis. Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins and activating signaling molecules. There were less associated with heparanase of molecular biology mechanism in human gastric cancer. We first evaluated the endogenous expression of heparanase in human gastric cancer cell lines and found Heparanase expression higher in SGC-7901 than MGC-803. Using the technology of RNAi in SGC-7901 cells down regulated heparanase gene, and reduced SGC-7901 cells migration and invasion. On the other hand, recombinant heparanase protein added in MGC-803 cells enhanced MGC-803 cell migration and invasion. The elevated cell migration and invasion were impaired by treatment of Src inhibitor pp2 or p38 inhibitor SB 203580. We further found that Stable knockdown of heparanase in SGC-7901 cells decreased phosphorylation of Src and p38. The phosphorylation of p38 was inhibited in response to pp2 treatment while the addition of SB 203580 to SGC-7901 cells did not change phosphorylation of Src. These data suggest that heparanase facilitates invasion and migration of human gastric cancer cells probably through elevating phosphorylation of Src and p38.
胃癌是最常见的癌症之一，且仍然难以治愈，主要原因是大多数癌症干细胞样细胞具有更高的侵袭和转移能力。乙酰肝素酶部分地通过增强蛋白质表达和激活信号分子，充当侵袭性肿瘤表型的主要调节因子。在人类胃癌中，与乙酰肝素酶相关的分子生物学机制较少。我们首先评估了乙酰肝素酶在人胃癌细胞系中的内源性表达，发现SGC-7901中乙酰肝素酶的表达高于MGC-803。在SGC-7901细胞中使用RNAi技术下调乙酰肝素酶基因，并减少SGC-7901细胞的迁移和侵袭。另一方面，向MGC-803细胞中添加重组乙酰肝素酶蛋白可增强MGC-803细胞的迁移和侵袭。Src抑制剂pp2或p38抑制剂SB 203580的处理削弱了细胞迁移和侵袭的增强。我们进一步发现，SGC-7901细胞中乙酰肝素酶的稳定敲低降低了Src和p38的磷酸化。pp2处理可抑制p38的磷酸化，而向SGC-7901细胞中添加SB 203580不会改变Src的磷酸化。这些数据表明，乙酰肝素酶可能通过提高Src和p38的磷酸化促进人胃癌细胞的侵袭和迁移。
