Oncotarget

Research Papers:

A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth

Jihyun Park _, Sun Young Kim, Ha-Jung Kim, Kyoung-Mee Kim, Eun Young Choi and Myung-Soo Kang

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Oncotarget. 2016; 7:28670-28683. https://doi.org/10.18632/oncotarget.8764

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Abstract

Jihyun Park1,*, Sun Young Kim2,*, Ha-Jung Kim1, Kyoung-Mee Kim1,3,4, Eun Young Choi5, Myung-Soo Kang1,4,5

1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University and Samsung Medical Center, Seoul 06351, Korea

2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul 06351, Korea

3Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul 06351, Korea

4Samsung Biomedical Research Institute (SBRI), Seoul 06351, Korea

5BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Seoul 03080, Korea

*These authors have contributed equally to this work

Correspondence to:

Eun Young Choi, email: [email protected]

Myung-Soo Kang, email: [email protected]

Keywords: CD44, FGFR2, c-Myc, regulation, cancer

Received: December 09, 2015     Accepted: March 28, 2016     Published: April 16, 2016

ABSTRACT

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.


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