BACKGROUND: Recent evidence suggests an involvement of the tyrosine kinase signaling pathway in the development of ATP-binding cassette (ABC) protein-mediated multidrug resistance in cancer. The aim of our study was to determine the relevance of kinase and multidrug-resistance protein expression in human hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Paired tissue samples of HCC and corresponding peri-neoplastic tissue from 15 patients undergoing surgical resection were analyzed. The gene expression of ABC proteins and mitogen-activated protein kinase (MAPK) signaling cascade kinases was evaluated by real-time PCR and correlated with a series of clinicopathological parameters. In vitro effects of MAPK Kinase (MEK) inhibition were evaluated in HepG2 cells. RESULTS: Overexpression of ABC proteins, tyrosine kinases, or both was detectable in 40%, 86% and 33% of HCC samples, respectively. ABCC1, -2 and -3-mRNA levels were significantly increased in 13%, 20% and 33% of the HCC samples compared to the corresponding peri-neoplastic tissue (p≤0.05). There was an association of ABCC1 and ABCC2 overexpression in HCC tissue (p≤0.05). EGFR, RAF, MEK, ERK and MAPK mRNA were overexpressed in 33%, 33%, 40%, 50% and 50%, respectively compared to the peri-neoplastic tissue (p≤0.05). The expression of ABCC1, ABCC2 and P-glycoprotein correlated statistically with the MEK gene expression. Patients with tyrosine kinase overexpression had significantly higher angioinvasion (p≤0.05). RAF overexpression correlated statistically with increased tumor size (p=0.052). In vitro, MEK inhibition led to a reduced ABCC1 mRNA and protein expression. CONCLUSION: ABC proteins and tyrosine kinases are significantly overexpressed in HCC tissue. The multidrug-resistance phenotype is associated with the MEK expression in HCC. Inhibition of MEK might be a new therapeutic approach to restore chemosensitivity in patients with highly resistant tumors.
BACKGROUND: Recent evidence suggests an involvement of the tyrosine kinase signaling pathway in the development of ATP-binding cassette (ABC) protein-mediated multidrug resistance in cancer. The aim of our study was to determine the relevance of kinase and multidrug-resistance protein expression in humanhepatocellular carcinoma (HCC). MATERIAL AND METHODS: Paired tissue samples of HCC and corresponding peri-neoplastic tissue from 15 patients undergoing surgical resection were analyzed. The gene expression of ABC proteins and mitogen-activated protein kinase (MAPK) signaling cascade kinases was evaluated by real-time PCR and correlated with a series of clinicopathological parameters. In vitro effects of MAPK Kinase (MEK) inhibition were evaluated in HepG2 cells. RESULTS: Overexpression of ABC proteins, tyrosine kinases, or both was detectable in 40%, 86% and 33% of HCC samples, respectively. ABCC1, -2 and -3-mRNA levels were significantly increased in 13%, 20% and 33% of the HCC samples compared to the corresponding peri-neoplastic tissue (p≤0.05). There was an association of ABCC1 and ABCC2 overexpression in HCC tissue (p≤0.05). EGFR, RAF, MEK, ERK and MAPK mRNA were overexpressed in 33%, 33%, 40%, 50% and 50%, respectively compared to the peri-neoplastic tissue (p≤0.05). The expression of ABCC1, ABCC2 and P-glycoprotein correlated statistically with the MEK gene expression. Patients with tyrosine kinase overexpression had significantly higher angioinvasion (p≤0.05). RAF overexpression correlated statistically with increased tumor size (p=0.052). In vitro, MEK inhibition led to a reduced ABCC1 mRNA and protein expression. CONCLUSION:ABC proteins and tyrosine kinases are significantly overexpressed in HCC tissue. The multidrug-resistance phenotype is associated with the MEK expression in HCC. Inhibition of MEK might be a new therapeutic approach to restore chemosensitivity in patients with highly resistant tumors.
Authors: Sebastian Buschauer; Andreas Koch; Philipp Wiggermann; Martina Müller; Claus Hellerbrand Journal: Oncol Lett Date: 2018-01-26 Impact factor: 2.967
Authors: Katrin Hoffmann; Tom Ganten; Daniel Gotthardtp; Boris Radeleff; Utz Settmacher; Otto Kollmar; Silvio Nadalin; Irini Karapanagiotou-Schenkel; Christof von Kalle; Dirk Jäger; Markus W Büchler; Peter Schemmer Journal: BMC Cancer Date: 2015-05-11 Impact factor: 4.430
Authors: Shibo Lin; Katrin Hoffmann; Zhi Xiao; Nan Jin; Uwe Galli; Elvira Mohr; Markus W Büchler; Peter Schemmer Journal: Cancer Cell Int Date: 2013-01-15 Impact factor: 5.722
Authors: N Domanitskaya; J Wangari-Talbot; J Jacobs; E Peiffer; Y Mahdaviyeh; C Paulose; E Malofeeva; K Foster; K Q Cai; Y Zhou; B Egleston; E Hopper-Borge Journal: Br J Cancer Date: 2014-06-17 Impact factor: 7.640