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Article

Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma

1
Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia 40296-710, Brazil
2
Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Bahia 41253-190, Brazil
3
D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
4
Department of Oral Diagnosis, School of Dentistry, Campinas State University (UNICAMP), Piracicaba, São Paulo 13414-903, Brazil
5
Department of Pathology, School of Medicine and School of Dentistry, Federal University of Bahia (UFBA), Salvador, Bahia 40110-909, Brazil
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(18), 6487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186487
Received: 19 June 2020 / Revised: 29 July 2020 / Accepted: 30 July 2020 / Published: 5 September 2020
(This article belongs to the Special Issue Hedgehog Signaling 2.0)
(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways. View Full-Text
Keywords: IGF-1; hedgehog; PI3K-AKT IGF-1; hedgehog; PI3K-AKT
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MDPI and ACS Style

Ferreira Mendes, J.M.; de Faro Valverde, L.; Torres Andion Vidal, M.; Paredes, B.D.; Coelho, P.; Allahdadi, K.J.; Coletta, R.D.; Souza, B.S.d.F.; Rocha, C.A.G. Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma. Int. J. Mol. Sci. 2020, 21, 6487. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186487

AMA Style

Ferreira Mendes JM, de Faro Valverde L, Torres Andion Vidal M, Paredes BD, Coelho P, Allahdadi KJ, Coletta RD, Souza BSdF, Rocha CAG. Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma. International Journal of Molecular Sciences. 2020; 21(18):6487. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186487

Chicago/Turabian Style

Ferreira Mendes, Jéssica M., Ludmila de Faro Valverde, Manuela Torres Andion Vidal, Bruno D. Paredes, Paulo Coelho, Kyan J. Allahdadi, Ricardo D. Coletta, Bruno S.d.F. Souza, and Clarissa A.G. Rocha 2020. "Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma" International Journal of Molecular Sciences 21, no. 18: 6487. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186487

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