Stress induced phosphoprotein 1 overexpression controls proliferation, migration and invasion and is associated with poor survival in oral squamous cell carcinoma

Mauricio Rocha Dourado; Amr Elseragy; Bruno Cesar da Costa; Fábio Haach Téo; Gustavo Narvaes Guimarães; Renato Assis Machado; Maija Risteli; Wafa Wahbi; Clarissa Araujo Gurgel Rocha; Lívia Máris Ribeiro Paranaíba; Wilfredo Alejandro González-Arriagada; Sabrina Daniela da Silva; Ana Lucia Carrinho Ayroza Rangel; Marcelo Rocha Marques; Carlos Rossa Junior; Tuula Salo; Ricardo D Coletta

doi:10.3389/fonc.2022.1085917

Stress induced phosphoprotein 1 overexpression controls proliferation, migration and invasion and is associated with poor survival in oral squamous cell carcinoma

Front Oncol. 2023 Jan 11:12:1085917. doi: 10.3389/fonc.2022.1085917. eCollection 2022.

Authors

Mauricio Rocha Dourado¹, Amr Elseragy², Bruno Cesar da Costa¹, Fábio Haach Téo¹, Gustavo Narvaes Guimarães³, Renato Assis Machado^{1

4}, Maija Risteli², Wafa Wahbi⁵, Clarissa Araujo Gurgel Rocha^{6

7

8}, Lívia Máris Ribeiro Paranaíba⁹, Wilfredo Alejandro González-Arriagada¹⁰, Sabrina Daniela da Silva¹¹, Ana Lucia Carrinho Ayroza Rangel¹², Marcelo Rocha Marques³, Carlos Rossa Junior¹³, Tuula Salo^{2

5

14}, Ricardo D Coletta¹

Affiliations

¹ Department of Oral Diagnosis, and Graduate Program in Oral Biology, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil.
² Cancer and Translational Medicine Research Unit, Faculty of Medicine, and Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
³ Department of Biosciences and Graduate Program in Oral Biology, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil.
⁴ Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC/USP), Bauru, São Paulo, Brazil.
⁵ Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, and Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland.
⁶ Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil.
⁷ Federal University of Bahia, Salvador, Bahia, Brazil.
⁸ Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), Salvador, Brazil.
⁹ Department of Pathology and Parasitology, Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
¹⁰ Facultad de Odontología, and Centro de Investigación e Innovación Biomédica (CIIB), Universidad de los Andes, Santiago, Chile.
¹¹ Lady Davis Institute for Medical Research and Segal Cancer Center, Jewish General Hospital, and Department of Otolaryngology-Head and Neck Surgery, McGill University, Montreal, QC, Canada.
¹² Department of Oral Pathology and Oral Medicine, Dental School, Western Paranaí State University, Cascavel, Paraná, Brazil.
¹³ Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil.
¹⁴ HUSLAB, Department of Pathology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Abstract

Objective: Although there have been remarkable achievements in the molecular landscape of oral squamous cell carcinoma (OSCC) in recent years, bringing advances in the understanding of its pathogenesis, development and progression, little has been applied in the prognosis and choosing the optimal treatment. In this study, we explored the influence of the stress induced phosphoprotein 1 (STIP1), which is frequently reported to be highly expressed in many cancers, in OSCCs.

Methods: STIP1 expression was assessed in the TCGA database and in two independent cohorts by immunohistochemistry. Knockdown strategy was applied in OSCC cell lines to determine the impact of STIP1 on viability, proliferation, migration and invasion. The zebrafish model was applied for studying tumor formation and metastasis in vivo. The association of STIP1 and miR-218-5p was explored by bioinformatics and mimics transfection.

Results: STIP1 was highly expressed in OSCCs and significantly associated with shortened survival and higher risk of recurrence. STIP1 down-regulation decreased proliferation, migration and invasion of tumor cells, and reduced the number of metastases in the Zebrafish model. STIP1 and miR-218-5p were inversely expressed, and the transfection of miR-218-5p mimics into OSCC cells decreased STIP1 levels as well as proliferation, migration and invasion.

Conclusion: Our findings show that STIP1 overexpression, which is inversely associated with miR-218-5p levels, contributes to OSCC aggressiveness by controlling proliferation, migration and invasion and is a determinant of poor prognosis.

Keywords: MIR-218-5p; STIP1; invasion; oral cancer; prognosis; proliferation.

Grants and funding

This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2018/16077-6 to RC), and from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 407814/2018-3 and 407814/2018-3 to RC). MD (2021/13595-9) and BC (2021/08943-8) were research fellows supported by FAPESP. AE, MR, WW and TS were funded by Universities of Oulu and Helsinki, the Sigrid Juselius Foundation, and Oulu and Helsinki University Hospital special state support for research.