Involvement of c-Met/Hepatocyte Growth Factor Pathway in Cholangiocarcinoma Cell Invasion and Its Therapeutic Inhibition With Small Interfering RNA Specific for c-Met

Leelawat, Kawin; Leelawat, Surang; Tepaksorn, Panada; Rattanasinganchan, Panthip; Leungchaweng, Anicha; Tohtong, Rutaiwan; Sobhon, Prasert

doi:10.1016/j.jss.2006.05.031

Cited by 43 publications

(37 citation statements)

References 16 publications

(17 reference statements)

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“…To the best of our knowledge, this is the first study to demonstrate the signal transduction pathways of bFGF/FGFR in cholangiocarcinoma cells. Previous studies also showed that activation of c-met, a hepatocyte growth factor receptor, or CXCR4 was capable of inducing cholangiocarcinoma cell migration via the activation of the MEK1/2 signaling pathway (20,21). Therefore, we suggest that MEK1/2 is the central signaling pathway for the control of cholangiocarcinoma cell migration.…”

Section: Discussionsupporting

confidence: 62%

Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway

Narong

Leelawat

2011

Oncol Lett

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Abstract. The purpose of this study was to investigate the roles played by basic fibroblast growth factor (bFGF) in the induction of cholangiocarcinoma cell progression and to identify the signal transduction molecules that are activated by bFGF in cholangiocarcinoma cells. FGF receptor-2 (FGFR2) was shown to be expressed in two cholangiocarcinoma cell lines (RMCCA1 and KKU-100). Samples from RMCCA1 and KKU-100 were assayed for the mRNA. Phosphorylation levels were determined by Western blotting. Treatment of the cholangiocarcinoma cells with bFGF enhanced signaling via the phosphorylation of MEK1/2, induced cholangiocarcinoma cell migration and resulted in high levels of actin polymerization. Moreover, treatment with a MEK1/2 inhibitor (U0126) attenuated the effect of bFGF-induced cholangiocarcinoma cell migration. Taken together, these observations indicate that bFGF enhances the migration of cholangiocarcinoma cells and that this enhancement is regulated by the phosphorylation of MEK1/2.

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Section: Discussionsupporting

confidence: 62%

Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway

Narong

Leelawat

2011

Oncol Lett

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“…Although the data is not conclusive, several researchers have suggested that c-Met behaves differently in intrahepatic and extrahepatic cholangiocarcinoma [25,26] . Leelawat et al [27] demonstrated that stimulated overexpression of the c-Met gene in cholangiocarcinoma cells resulted in increased cell migration and invasion. Conversely, inhibition of c-Met expression decreased cellular phosphorylation and ultimately reduced cellular invasiveness.…”

Section: Cholangiocarcinomamentioning

confidence: 99%

“…To date, only one study has reported c-Met targeted therapy in an animal model of cholangiocarcinoma [27] . This study showed that inhibition in c-Met expression or its downstream target MEK1/2 through specific targeted therapy is effective in halting disease progression in vivo.…”

Section: Cholangiocarcinomamentioning

confidence: 99%

c-Met targeted therapy of cholangiocarcinoma

Socoteanu¹,

Mott²,

Alpini³

et al. 2008

WJG

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Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

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“…Two human cholangiocarcinoma cell lines; KKU100 derived from Hilar-cholangiocarcinoma patient [17] (kindly provided by Dr. Banchob Sripa, Department of Pathology, Faculty of Medicine, Khon K aen University) and RMCCA1 derived from Peripheral-cholangiocarcinoma patient [18] were grown in HAM's F12 medium supplemented with 100 mL/1L fetal bovine serum at 37℃ in a 50 mL/L CO2 humidified atmosphere. For signal transduction experiments with CXCL12, cells were starved overnight in serum-free medium.…”

Section: Cell Culturesmentioning

confidence: 99%

Roles of the MEK1/2 and AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell invasion

Leelawat

Leelawat²,

Narong³

et al. 2007

WJG

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AIM:To evaluate the expression of C-X-C motif chemokine receptor 4 (CXCR4) and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS:The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines (RMCCA1 and KKU100) by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 (CXCL12). RESULTS:Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 (ERK1/2) and phosphoinositide 3-kinase (PI3K) and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor (AMD3100) abrogated CXCL12-induced phosphorylation of MEK1/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor (U0126) or PI3K inhibitor (LY294002) also attenuated the effect of CXCL12-induced cholangiocarcinoma cell invasion. CONCLUSION:These results indicated that the a c t i va t i o n o f C XC R 4 a n d i t s s i g n a l i n g p a t hway s (MEK1/2 and Akt) are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.

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Involvement of c-Met/Hepatocyte Growth Factor Pathway in Cholangiocarcinoma Cell Invasion and Its Therapeutic Inhibition With Small Interfering RNA Specific for c-Met

Cited by 43 publications

References 16 publications

Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway

Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway

c-Met targeted therapy of cholangiocarcinoma

Roles of the MEK1/2 and AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell invasion

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