Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.
Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways.
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DOI：
10.1007/s10585-011-9404-x
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发表时间：
2011-12
影响因子：
4
通讯作者：
Liu, Chen
中科院分区：
文献类型：
--
作者：
Ogunwobi, Olorunseun O.;Liu, Chen
关键词：
晚期肝细胞癌（HCC）是癌症死亡的重要原因。上皮-间充质转化（EMT）已被证明是癌症进展和转移的重要生物学过程。我们使用BNL CL. 2（BNL）和BNL 1 ME A着重阐明诱导EMT促进HCC癌变和随后转移的因素。7R.1（1 MEA）细胞系。BNL细胞是正常肝细胞，而1 MEA细胞是由BNL细胞的化学转化衍生的HCC细胞。对其形态特征进行了研究。测定肝细胞生长因子（HGF）、EMT标志物和HGF信号传导介质的表达水平，并比较功能特征。用HGF处理BNL细胞，并分析对EMT标志物和HGF信号传导介质的影响。BNL细胞显示特征性上皮形态，而1 MEA细胞显示间充质特征。1 MEA细胞比BNL细胞表达和分泌更多的HGF。1 MEA细胞中E-cadherin、Alb、AAT的表达明显减少，FN、Collagen-1、Vimentin、Snail和Slug的表达明显增加。1 MEA细胞中环氧化酶2（考克斯2）、Akt和磷酸化Akt（pAkt）表达增加。此外，1 MEA细胞具有增加的迁移能力，抑制考克斯-2和Akt而不是细胞外信号调节激酶（ERK）。抑制考克斯-2、Akt和ERK可逆转1 MEA细胞的分子间充质特征。HGF处理BNL细胞后，E-cadherin表达下降，FN、vimentin、snail、slug、考克斯-2、Akt、pAkt表达增加，细胞迁移、侵袭和克隆形成能力增强。我们的结论是，HCC的发展与HGF的上调有关，HGF通过上调考克斯-2和Akt促进EMT和癌变。因此，HGF信号传导可能是晚期和转移性HCC治疗的靶点。
Advanced hepatocellular carcinoma (HCC) is an important cause of cancer mortality. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process in cancer progression and metastasis. We have focused on elucidating factors that induce EMT to promote carcinogenesis and subsequent metastasis in HCC using the BNL CL.2 (BNL) and BNL 1ME A. 7R.1 (1MEA) cell lines. BNL cells are normal hepatocytes whereas the 1MEA cells are HCC cells derived from chemical transformation of the BNL cells. Their morphological characteristics were examined. Expression levels of hepatocyte growth factor (HGF), markers of EMT and mediators of HGF signaling were determined and functional characteristics were compared. BNL cells were treated with HGF and effects on EMT-marker and mediators of HGF signaling were analyzed. BNL cells display characteristic epithelial morphology whereas 1MEA cells display mesenchymal characteristics. 1MEA cells express and secrete more HGF than BNL cells. There was significantly decreased expression of E-cadherin, albumin, AAT and increased expression of fibronectin, collagen-1, vimentin, snail and slug in 1MEA cells. There was also increased expression of cyclooxygenase-2 (COX-2), Akt and phosphorylated Akt (pAkt) in 1MEA cells. Moreover, 1MEA cells had increased migratory capacity inhibited by inhibition of COX-2 and Akt but not extracellular signal regulated kinase (ERK). Molecular mesenchymal characteristics of 1MEA cells were reversed by inhibition of COX-2, Akt and ERK. Treatment of BNL cells with HGF led to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, snail, slug, COX-2, Akt, pAkt and increased migration, invasiveness and clonogenicity. We conclude that development of HCC is associated with upregulation of HGF which promotes EMT and carcinogenesis via upregulation of COX-2 and Akt. Consequently, HGF signaling may be targeted for therapy in advanced and metastatic HCC.
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影响因子：
8
作者：
Khoury, H;Dankort, DL;Park, M
通讯作者：
Park, M
影响因子：
30.8
作者：
KAARTINEN, V;VONCKEN, JW;GROFFEN, J
通讯作者：
GROFFEN, J
影响因子：
13.5
作者：
Ding, Wei;You, Hanning;Dang, Hien;LeBlanc, Francis;Galicia, Vivian;Lu, Shelly C.;Stiles, Bangyan;Rountree, C. Bart
通讯作者：
Rountree, C. Bart
影响因子：
29.4
作者：
Dooley, Steven;Hamzavi, Jafar;Mertens, Peter R.
通讯作者：
Mertens, Peter R.
影响因子：
4.8
作者：
Kaimori, Aki;Potter, James;Koteish, Ayman
通讯作者：
Koteish, Ayman