Abstract
Aim:
The purpose of this study was to reveal the effects of hepatocyte growth factor (HGF) variants on human breast cancer cells and the differential signaling pathways of the variants in controlling cell proliferation and invasion.
Methods:
Four HGF variants (NK1, NK2, NK3, and NK4) were created by gene engineering, and the variant DNA fragments were cloned into pGEM-T for DNA sequencing and then transferred to a pTrcHis-A plasmid for expression. Recombinant proteins were purified from Escherichia coli, and a series of assays, including cell proliferation and invasion were carried out. Phosphorylated components in the HGF-c-Met and STAT (signal transducers and activators of transcription) pathways were detected by immunoprecipitation-Western blots.
Results:
All the HGF variants inhibited the vigorous growth of the cancer cells differently and dose-dependently, but the effect of NK3 or NK4 was 7.5-fold higher than NK1 or NK2. In addition, the assays for the phosphorylation of the components in the HGF-c-Met pathway showed that NK3 and NK4 inhibited invasion via the STAT pathway, whereas NK1 and NK2 were via the HGF-c-Met pathway.
Conclusion:
The engineered HGF variants inhibited the proliferation of human breast cancer cells via different signaling pathways, NK1 and NK2 via the HGF-c-Met pathways, and NK3 and NK4 via the STAT pathway, the latter being a possible key route for the inhibition of cell invasion. All of the HGF variants have the potential to become pharmaceutical drugs in the treatment of human cancer.
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This work was supported by grants from the National Science Council of Taiwan (No NSC93-2815-C-110-031-B) and China Medical University (No CMC91-M-34 and CMU95-321).
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Lin, Yl., Chen, Hl., Kuo, Hm. et al. NK3 and NK4 of HGF enhance filamin production via STAT pathway, but not NK1 and NK2 in human breast cancer cells. Acta Pharmacol Sin 29, 728–735 (2008). https://doi.org/10.1111/j.1745-7254.2008.00799.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00799.x
