Sung-Hwa Sohn,1,* Bohyun Kim,1,* Hee Jung Sul,1 Bo Youn Choi,1 Hyeong Su Kim,2 Dae Young Zang1,2

1Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang 14066, Republic of Korea; 2Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea

*These authors contributed equally to this work

Correspondence: Dae Young ZangDivision of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do 14068, Republic of KoreaTel +82-31-380-4167Fax +82-31-386-1528Email fhdzang@gmail.com

Purpose: CD44 isoforms are highly expressed in cancer stem cells, initiating tumor growth and sustaining tumor self-renewal. Among these isoforms, CD44 variant 9 (CD44v9) is overexpressed in chronic inflammation-induced cancer. CD44 and the mesenchymal-to-epithelial transition (MET) receptor tyrosine kinase are coactivated in some gastric cancers (GCs). In this study, we characterized MET and CD44 expression and signaling in human GC cell lines and analyzed differences in the susceptibility of these lines to foretinib.Patients and Methods: We analyzed cell viability and the rate of apoptotic cells using MTS assays and flow cytometry, respectively. Gene and protein expression were assessed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting, respectively.Results: Foretinib treatment resulted in dose-dependent inhibition of growth in c-MET-amplified MKN45 and SNU620 cells with concomitant induction of apoptosis, but not in c-MET-reduced MKN28 and AGS cells. Foretinib treatment also significantly reduced phosphor-c-MET, phosphor-AKT, beta-catenin, and COX-2 protein expression in MKN45 and SNU620 cells. Interestingly, foretinib significantly reduced CD44, CD44v9, COX-2, OCT3/4, CCND1, c-MYC, VEGFA, and HIF-1a gene expression in CD44 and MET coactivated MKN45 cells and increased CD44s gene expression; in contrast, these drugs were only slightly active against SNU620 cells.Conclusion: The results of this study indicate that foretinib could be a therapeutic agent for the prevention or treatment of GCs positive for CD44v9 and c-MET.

Keywords: c-MET, CD44v9, foretinib, gastric cancer, OCT3/4

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