Hypoxia promotes metastasis in human gastric cancer by up-regulating the 67-kDa laminin receptor
Hypoxia promotes metastasis in human gastric cancer by up-regulating the 67-kDa laminin receptor
复制标题
缺氧通过上调 67-kDa 层粘连蛋白受体促进人胃癌转移。
DOI：
10.1111/j.1349-7006.2010.01592.x
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发表时间：
2010-07-01
期刊：
影响因子：
5.7
通讯作者：
Zhang, Helong
中科院分区：
文献类型：
--
作者：
Liu, Lili;Sun, Li;Zhang, Helong
已有研究表明67 kDa的层粘连蛋白受体(67LR)与肿瘤转移密切相关。我们最近发现，67LR前体37LRP是低氧暴露于胃癌中的低氧诱导因子-1(HIF-1)靶基因。在此，我们研究了67LR在胃癌低氧转移和侵袭中的作用。免疫组织化学分析、Western blotting和RT-PCR检测表明，67LR在体内转移性胃癌中高表达。通过RNA干扰抑制67LR蛋白显著降低了胃癌细胞系SGC7901和MKN-45的粘附性、侵袭性和体内转移能力。免疫印迹分析显示，67LR可上调尿激酶型纤溶酶原激活物(UPA)和基质金属蛋白酶(MMP)-9的表达，降低基质金属蛋白酶组织抑制物(TIMP)-1的蛋白表达。我们进一步表明，低氧诱导67LR的表达具有时间依赖性，这种诱导可被HIF-1小干扰(Si)RNA抑制。ERK和JNK抑制剂均显著抑制缺氧诱导的67LR的表达以及随后的uPA和MMP9的表达。抗67LR的siRNA或抗MMP9和uPA的抗体显著抑制缺氧诱导的体外侵袭能力。综上所述，这些结果表明67LR通过增加uPA和MMP9的表达来促进胃癌细胞的侵袭和转移能力，ERK和JNK信号通路参与了缺氧诱导的67LR的表达以及随后uPA和MMP9的表达。(癌症科学2010)。
It has been reported that the 67-kDa laminin receptor (67LR) is implicated in cancer metastasis. We recently showed that 37LRP, the 67LR precursor, is a hypoxia-inducible factor 1 (HIF-1) target gene exposed to hypoxia in gastric cancer. Here, we investigated the role of 67LR in hypoxic metastasis and invasion in gastric cancer. Immunohistochemical analysis, western blotting, and RT-PCR assays revealed that 67LR was highly expressed in metastatic gastric cancers in vivo. Knockdown of the 67LR protein by RNA interference significantly decreased the adhesive, invasive, and in vivo metastatic abilities of the gastric cancer cell lines SGC7901 and MKN-45. Western blot analysis showed that 67LR increased the expression of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9, and decreased tissue inhibitor of matrix metalloproteinase (TIMP)-1 protein. We further showed that hypoxia induced 67LR expression in a time-dependent manner and this induction was inhibited by HIF-1 small-interfering (si) RNA. Both ERK and JNK inhibitors significantly inhibited hypoxia-induced expression of 67LR and the subsequent expression of uPA and MMP 9. SiRNA against 67LR or antibody against MMP9 and uPA significantly inhibited hypoxia-induced in vitro invasive ability. Taken together, these results reveal that 67LR promotes the invasive and metastatic ability of the gastric cancer cells through increasing uPA and MMP 9 expression, with involvement of the ERK and JNK signal pathway in hypoxia-induced 67 LR expressions and subsequent uPA and MMP9 expression. (Cancer Sci 2010).