Interplays between genetic and environmental mechanisms trigger tumorigenic VEGF signalling in human HCC cell lines: pilot study.
The 'angiogenic switch' concept has been used to discover various pro- and anti-angiogenic molecules as pharmacotherapeutic strategies for cancers and other ischemic and inflammatory diseases; however, surprisingly little is known about the 'tumor angiogenic switch' in response to complex interplay between environmental and genetic mechanisms that are most importantly, hypothesis-driven, largely unsolved at the postgenomic level. The present study's aim is to identify those interplays between the expressing green fluorescence protein (EGFP) transcript and redox-driven vascular endothelial growth factor (VEGF) upstream mechanisms that influence tumorigenic VEGF signalling, by using multifactorial orthogonal statistical analyses, the non-transfected and transfected human hepatocellular carcinoma (HCC) cell lines, and quantitative 'sandwich' Elisa immunoassays. The unique results indicate valuable findings on the postgenomic level as follows. Fusion of the EGFP significantly triggers tumorigenic VEGF signalling in three E3-, F11- and A(3-1)-transfected human HCC cell lines, compared with the parental EGFP-free malignant hepatocellular carcinoma (MHCC)1 cell line; Redox-regulated VEGF upstream mechanism interplays dramatically mediate dual responses, either down- or upregulating tumorigenic VEGF signalling, which depends on individual post-transcriptional regulation or upstream modification of the VEGF promoter in the three MHCC1, SMCC7721 and doxorubicin-resistance 7402/D+ non-transfected human HCC cell lines; and mechanism-based strategies for stimulating beta-adrenergic and P2-purinergic signal transduction and counteracting O2 and Ca2+-inflow significantly trigger tumorigenic VEGF signalling in ATRA/ATRP-driven networks, compared with controls of the non-transfected cell types examined. The contrast data offer first pilot paradigms of searching for hypothesis-driven multifactorial interplays on tumorigenic VEGF signalling, which are valuable for further deciphering postgenome-wide VEGF upstream regulatory networks of switching on the tumor angiogenesis, and developing mechanism-based novel pharmacotherapeutic strategies.
Fang
Y
Y
Department of Anesthesiology and Experimental Research Center, Zhong Shan Hospital, Fudan University, Shanghai, China. yanfang@server.shcnc.ac.cn
Hu
M
M
Liu
K
K
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002681:China; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics* / Q000502:physiology; D010865:Pilot Projects; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013223:Statistics as Topic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051552:beta-Adrenergic Receptor Kinases
D016228:Endothelial Growth Factors; D008164:Luminescent Proteins; D008222:Lymphokines; D018048:Receptors, Purinergic P2; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D049452:Green Fluorescent Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases