Gene therapy with SOCS1 induces potent preclinical antitumor activities in oral squamous cell carcinoma.
Animals
Apoptosis
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Genetic Therapy
Head and Neck Neoplasms
Humans
Mice
Mouth Neoplasms
/ genetics
STAT3 Transcription Factor
/ genetics
Signal Transduction
Squamous Cell Carcinoma of Head and Neck
/ genetics
Suppressor of Cytokine Signaling 1 Protein
/ genetics
apoptosis
cell cycle
oral squamous cell carcinoma
signal transducer and activator of transcription-3
suppressor of cytokine signaling-1
Journal
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
ISSN: 1600-0714
Titre abrégé: J Oral Pathol Med
Pays: Denmark
ID NLM: 8911934
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
revised:
29
11
2021
received:
08
10
2021
accepted:
02
12
2021
pubmed:
9
12
2021
medline:
19
2
2022
entrez:
8
12
2021
Statut:
ppublish
Résumé
Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC. Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo. JAK inhibitor I inhibited the proliferation of KOSC2 cl3-43 or T3M-1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M-1 clone2 cells, but not KOSC2-cl3-43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3-43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl-1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3-43 or T3M-1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo. SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC.
Sections du résumé
BACKGROUND
BACKGROUND
Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC.
METHODS
METHODS
Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo.
RESULTS
RESULTS
JAK inhibitor I inhibited the proliferation of KOSC2 cl3-43 or T3M-1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M-1 clone2 cells, but not KOSC2-cl3-43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3-43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl-1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3-43 or T3M-1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo.
CONCLUSION
CONCLUSIONS
SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC.
Substances chimiques
SOCS1 protein, human
0
STAT3 Transcription Factor
0
Socs1 protein, mouse
0
Suppressor of Cytokine Signaling 1 Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126-133Subventions
Organisme : AMED
ID : JP20ck0106417
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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