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H-Ras通过激活ERK1/2和NF-κB选择性地上调MMP-9和COX-2:对大鼠肝上皮细胞侵袭表型的影响

H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells.

作者信息

Lee Ki Won, Kim Mi-Sung, Kang Nam Joo, Kim Do-Hee, Surh Young-Joon, Lee Hyong Joo, Moon Aree

机构信息

Department of Food Biotechnology, School of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.

出版信息

Int J Cancer. 2006 Oct 15;119(8):1767-75. doi: 10.1002/ijc.22056.

Abstract

One of the most frequent events in carcinogenesis is uncontrolled activation of Ras signaling pathway. A previous study demonstrated that the introduction of H-Ras into the normal WB-F344 rat liver epithelial (WB) cell line and adult male F344 rats resulted in tumorigenicity. The present study investigated whether H-Ras induced the invasive and migrative phenotypes in WB cells, and subsequently aimed at characterizing the underlying mechanisms. H-Ras induced the invasive and migrative phenotypes of WB cells with a selective up-regulation of matrix metalloproteinase (MMP)-9, but not MMP-2. Cyclooxygenase (COX)-2 and the subsequent production of prostaglandin E2 (PGE2) were also induced by H-Ras. Treatment of H-Ras WB cells with GM6001 and NS398, the inhibitors of MMPs and COX-2, respectively, significantly inhibited the H-Ras-induced invasive and migrative phenotypes. DNA binding activity of nuclear factor (NF)-kappaB, but not that of activator protein (AP)-1, was increased by H-Ras. Caffeic acid phenethyl ester and Bay 11-7082, specific inhibitors of NF-kappaB and IKK, respectively, significantly inhibited the expression of MMP-9 and COX-2, invasion and migration of H-Ras WB cells, revealing NF-kappaB as a transcriptional factor responsible for H-Ras-induced malignant phenotypic conversion of WB cells. Activation of ERKs pathway was critical for H-Ras-induced invasive and migrative phenotypes, up-regulation of MMP-9 and COX-2 as well as enhanced DNA binding activity of NF-kappaB in WB cells. Taken together, these results demonstrate that H-Ras up-regulates MMP-9 and COX-2 through activation of ERKs and IKK-IkappaBalpha-NF-kappaB signal pathway which may contribute to the malignant progression of WB rat liver epithelial cells.

摘要

致癌过程中最常见的事件之一是Ras信号通路的失控激活。先前的一项研究表明,将H-Ras导入正常的WB-F344大鼠肝上皮(WB)细胞系和成年雄性F344大鼠中会导致致瘤性。本研究调查了H-Ras是否诱导WB细胞出现侵袭和迁移表型,随后旨在阐明其潜在机制。H-Ras诱导WB细胞出现侵袭和迁移表型,并选择性地上调基质金属蛋白酶(MMP)-9,而不是MMP-2。环氧合酶(COX)-2以及随后前列腺素E2(PGE2)的产生也由H-Ras诱导。分别用MMPs抑制剂GM6001和COX-2抑制剂NS398处理H-Ras WB细胞,可显著抑制H-Ras诱导的侵袭和迁移表型。H-Ras增加了核因子(NF)-κB的DNA结合活性,但不增加激活蛋白(AP)-1的DNA结合活性。分别为NF-κB和IKK的特异性抑制剂的咖啡酸苯乙酯和Bay 11-7082,显著抑制MMP-9和COX-2的表达、H-Ras WB细胞的侵袭和迁移,揭示NF-κB是负责H-Ras诱导的WB细胞恶性表型转化的转录因子。ERK通路的激活对于H-Ras诱导的WB细胞侵袭和迁移表型、MMP-9和COX-2的上调以及NF-κB的DNA结合活性增强至关重要。综上所述,这些结果表明,H-Ras通过激活ERK和IKK-IκBα-NF-κB信号通路来上调MMP-9和COX-2,这可能有助于WB大鼠肝上皮细胞的恶性进展。

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