Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways
Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC data...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223003001 |
| _version_ | 1797857682672058368 |
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| author | Rocío Granda-Díaz Lorea Manterola Francisco Hermida-Prado René Rodríguez Laura Santos Vanessa García-de-la-Fuente María Teresa Fernández M. Daniela Corte-Torres Juan P. Rodrigo Saúl Álvarez-Teijeiro Charles H. Lawrie Juana M. Garcia-Pedrero |
| author_facet | Rocío Granda-Díaz Lorea Manterola Francisco Hermida-Prado René Rodríguez Laura Santos Vanessa García-de-la-Fuente María Teresa Fernández M. Daniela Corte-Torres Juan P. Rodrigo Saúl Álvarez-Teijeiro Charles H. Lawrie Juana M. Garcia-Pedrero |
| author_sort | Rocío Granda-Díaz |
| collection | DOAJ |
| description | Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions. |
| first_indexed | 2024-04-09T21:00:45Z |
| format | Article |
| id | doaj.art-5a46cdfd2e04469382727fa6d5ac3cf3 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-09T21:00:45Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-5a46cdfd2e04469382727fa6d5ac3cf32023-03-29T09:23:29ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-05-01161114512Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathwaysRocío Granda-Díaz0Lorea Manterola1Francisco Hermida-Prado2René Rodríguez3Laura Santos4Vanessa García-de-la-Fuente5María Teresa Fernández6M. Daniela Corte-Torres7Juan P. Rodrigo8Saúl Álvarez-Teijeiro9Charles H. Lawrie10Juana M. Garcia-Pedrero11Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, SpainMolecular Oncology group, Biodonostia Research Institute, San Sebastián, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, SpainCIBERONC, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Sarcomas and Experimental Therapies, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, SpainHistopathology Unit, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, SpainBiobank of Principado de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain; Correspondence to: Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.Molecular Oncology group, Biodonostia Research Institute, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Sino-Swiss Institute of Advanced Technology (SSIAT), Shanghai University, Shanghai, China; Correspondence to: Biodonostia Research Institute, San Sebastián, Spain.Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain; Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), University of Oviedo, Oviedo, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain; Correspondence to: Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions.http://www.sciencedirect.com/science/article/pii/S0753332223003001Head and neck squamous cell carcinomamiR-301aTherapeutic targetSignalingPI3KERK |
| spellingShingle | Rocío Granda-Díaz Lorea Manterola Francisco Hermida-Prado René Rodríguez Laura Santos Vanessa García-de-la-Fuente María Teresa Fernández M. Daniela Corte-Torres Juan P. Rodrigo Saúl Álvarez-Teijeiro Charles H. Lawrie Juana M. Garcia-Pedrero Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways Biomedicine & Pharmacotherapy Head and neck squamous cell carcinoma miR-301a Therapeutic target Signaling PI3K ERK |
| title | Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways |
| title_full | Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways |
| title_fullStr | Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways |
| title_full_unstemmed | Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways |
| title_short | Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways |
| title_sort | targeting oncogenic functions of mir 301a in head and neck squamous cell carcinoma by pi3k pten and mek erk pathways |
| topic | Head and neck squamous cell carcinoma miR-301a Therapeutic target Signaling PI3K ERK |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223003001 |
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