A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth.
Despite their suggested importance, the mechanistic roles of FGFR2 and gastric cancer stem cell (GCSC) marker CD44 remain unclear. We investigated cross talk between CD44 and FGFR2. FGFR2 and CD44 positively regulate each other's expression. While FGFR2 suppresses c-Myc transcription, CD44 activates it. c-Myc in turn augments FGFR2 transcription. CD44 knockdown (KD) depleted FGFR2 and other GCSC markers, decreased c-Myc and Sox2 expression, and suppressed tumor growth, whereas CD44 activation led to FGFR2 induction. FGFR2 KD decreased most GCSC marker expression, including CD44, but increased c-Myc and Sox2 expression and attenuated tumor growth. FGFR2 kinase inhibitor and FGFR2 neutralizing antibody decreased the CD44+/hi GCSC fraction. Conversely, FGFR2 overexpression increased CD44 and accelerated tumor growth in mice. FGFR2 was co-expressed and colocalized diffusively with CD44, EpCAM, and LGR5. In contrast, phospho-FGFR2 colocalized densely with CD44, forming an aggregated signaling complex that was prevented by FGFR2 inhibition. The c-Myc KD depleted FGFR2 but not CD44. Similarly to CD44+/hi phenotypes, sorted FGFR+/hi cells had larger volumes, formed more tumor spheres, grew faster in vivo with bigger tumor mass, and expressed more CD44, EpCAM, and HER2. These findings suggest that FGFR2+/hi cells have stemness properties. Moreover, in situ FGFR2 expression in patient-derived gastric cancer tissue correlated with tumorigenic potential in a xenograft model. In conclusion, CD44 and FGFR2 maintain stemness in gastric cancer by differentially regulating c-Myc transcription.
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul 06351, Korea.
Jihyun
J
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul 06351, Korea.
Sun Young
SY
Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul 06351, Korea.
Ha-Jung
HJ
Kim
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul 06351, Korea.|Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul 06351, Korea.|Samsung Biomedical Research Institute (SBRI), Seoul 06351, Korea.
Kyoung-Mee
KM
Kim
BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Seoul 03080, Korea.
Eun Young
EY
Choi
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul 06351, Korea.|Samsung Biomedical Research Institute (SBRI), Seoul 06351, Korea.|BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Seoul 03080, Korea.
Myung-Soo
MS
Kang
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051497:Receptor, Fibroblast Growth Factor, Type 2
CD44; FGFR2; c-Myc; cancer; regulation