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Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/β-Catenin Signaling

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Abstract

Purpose

Fatty acid-binding protein 7 (FABP7) involved in intracellular lipid dynamics, is highly expressed in melanomas and associated with decreased patient survival. Several studies put FABP7 at the center of melanoma cell proliferation. However, the underlying mechanisms are not well deciphered. This study examines the effects of FABP7 on Wnt/β-catenin signaling that enhances proliferation in melanoma cells.

Methods

Skmel23 cells with FABP7 silencing and Mel2 cells overexpressed with wild-type FABP7 (FABP7wt) and mutated FABP7 (FABP7mut) were used. Cell proliferation and migration were analyzed by proliferation and wound-healing assay, respectively. Transcriptional activation of the Wnt/β-catenin signaling was measured by luciferase reporter assay. The effects of a specific FABP7 inhibitor, MF6, on proliferation, migration, and modulation of the Wnt/β-catenin signaling were examined.

Results

FABP7 siRNA knockdown in Skmel23 decreased proliferation and migration, cyclin D1 expression, as well as Wnt/β-catenin activity. Similarly, FABP7wt overexpression in Mel2 cells increased these effects, but FABP7mut abrogated these effects. Pharmacological inhibition of FABP7 function with MF6 suppressed FABP7-regulated proliferation of melanoma cells.

Conclusion

These results suggest the importance of the interaction between FABP7 and its ligands in melanoma proliferation modulation, and the beneficial implications of therapeutic targeting of FABP7 for melanoma treatment.

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Abbreviations

CCND1:

Cyclin D1

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

FABP7:

Fatty acid binding protein 7

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSK3β:

Glycogen synthase kinase-3β

LCFAs:

Long chain fatty acids

MF6:

4-(2-(5-(2-chlorophenyl)-1-(4-isopropylphenyl)-1H-pyrazol-3-yl)-4-fluorophenoxy) butanoic acid

MUFAs:

Monounsaturated fatty acids

PUFAs:

Polyunsaturated fatty acids

TCF/LEF:

T cell factor/lymphoid-enhancing factor

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ACKNOWLEDGEMENT AND DISCLOSURES

We thank the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core (Tohoku University Graduate School of Medicine) for their support. The authors declare no competing interests.

Funding

This work was supported in part by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (No. 17 K15539 and 20 K11527 to Y.K., No. 19H04026 to Y. O.), in part by AMED under Grant Number JP17dm0107071 (to K.F. and Y.O.).

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Authors and Affiliations

  1. Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Banlanjo Abdulaziz Umaru, Yoshiteru Kagawa, Subrata Kumar Shil, Naoki Arakawa, Yijun Pan, Hirofumi Miyazaki, Shuhei Kobayashi, Shuhan Yang & Yuji Owada

  2. Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan

    An Cheng, Yifei Wang, Yasuharu Shinoda & Kohji Fukunaga

  3. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan

    Yukiko Kiniwa & Ryuhei Okuyama

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  1. Banlanjo Abdulaziz Umaru
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  2. Yoshiteru Kagawa
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  15. Yuji Owada
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Contributions

Banlanjo Abdulaziz Umaru, Yoshiteru Kagawa. and Yuji Owada conceived and designed the study and wrote the manuscript with comments from all authors. Banlanjo Abdulaziz Umaru, Yoshiteru Kagawa, Subrata Kumar Shil, Naoki Arakawa, Hirofumi Miyazaki, Shuhei Kobayashi, Shuhan Yang, An Cheng, Yifei Wang, and Yasuharu Shinoda performed experiments. Yukiko Kiniwa, Ryuhei Okuyama, and Kohji Fukunaga provided reagents and technical assistance.

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Correspondence to Yoshiteru Kagawa.

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Umaru, B.A., Kagawa, Y., Shil, S.K. et al. Ligand Bound Fatty Acid Binding Protein 7 (FABP7) Drives Melanoma Cell Proliferation Via Modulation of Wnt/β-Catenin Signaling. Pharm Res 38, 479–490 (2021). https://doi.org/10.1007/s11095-021-03009-9

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