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1.
Cancer Med ; 9(3): 1131-1140, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31823521

RESUMO

Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and correlates with poor prognosis. EGFR has been demonstrated to be associated with cancer stem cell traits in HNSCC. However, the underlying molecular mechanism is far from elucidated. Here, SOX2, one of the most important stem cell markers, was identified as a binding partner and substrate of EGFR. EGFR signaling inhibition decreases SOX2 expression by promoting its autophagic degradation. Mechanistically, EGFR activation induces SOX2 phosphorylation at the Y277 site and reduces its ubiquitination, which inhibits its association with p62 and subsequent autophagic degradation. Gefitinib, an EGFR tyrosine kinase inhibitor, shows in vitro and in vivo protective effects against oral cancer cells that can be reversed through autophagy inhibition. Our study suggests that EGFR plays an important role in the development of cancer stem cells by stabilizing SOX2. Targeting EGFR in combination with conventional chemotherapy might be a promising strategy for the treatment of HNSCC through elimination of cancer stem cells.


Assuntos
Autofagia/fisiologia , Gefitinibe/farmacologia , Neoplasias Bucais/patologia , Fatores de Transcrição SOXB1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe/uso terapêutico , Humanos , Leupeptinas/farmacologia , Macrolídeos/farmacologia , Masculino , Camundongos , Neoplasias Bucais/tratamento farmacológico , Mutagênese , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Fatores de Transcrição SOXB1/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Clin Exp Med ; 8(7): 10459-70, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26379836

RESUMO

Mesenchymal stem cells (MSCs) are a reliable cell source for tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear; thus, their use is limited. Here, we investigate HOXB7 function in the osteogenic differentiation potentials of MSCs using stem cells from apical papilla (SCAPs) and bone marrow stem cells (BMSCs). The HOXB7 gene is highly expressed in BMSCs compared with dental tissue-derived MSCs. We found that, in vitro, over-expression of HOXB7 in SCAPs enhanced alkaline phosphatase (ALP) activity and mineralization. HOXB7 over-expression affected the mRNA expression of osteonectin (ON), collagen alpha-2(I) chain (COL1A2), bone sialoprotein (BSP), and osteocalcin (OCN), led to the expression of the key transcription factor, runt-related transcription factor 2 (RUNX2), and promoted SCAP osteogenic differentiation in vitro. The knock-down of HOXB7 inhibited ALP activity, mineralization, and the expression of ON, BSP, COL1A2, OCN, and RUNX2 in BMSCs in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis was triggered when HOXB7 was activated. Furthermore, Over-expression of HOXB7 significantly increased the levels of HOXB7 associated with the BSP promoter by ChIP assays. Taken together, these results indicate that HOXB7 enhances SCAP osteogenic differentiation by up-regulating RUNX2 and directly activating transcript of BSP. Thus, the activation of HOXB7 signaling might improve tissue regeneration mediated by MSCs. These results provide insight into the mechanism underlying the directed differentiation of MSCs.

3.
Chin J Dent Res ; 14(1): 7-13, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21734941

RESUMO

Radiation therapy for malignant tumours in the head and neck region are inevitably associated with significant long-term injury to the salivary glands, often resulting in salivary gland hypofunction. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective method to eliminating this problem caused by radiation treatments. Although many studies have been done in animal models, the mechanism of this injury in humans is still unclear. In this review, an animal model (miniature pigs) used in irradiated research is mainly discussed. This review also presents the progress made to date on the gene transfer-mediated functional restoration of irradiated salivary glands and the possibilities provided by future interventions to prevent radiation damage to salivary glands.


Assuntos
Aquaporina 1/genética , Técnicas de Transferência de Genes , Lesões Experimentais por Radiação/terapia , Glândulas Salivares/efeitos da radiação , Xerostomia/terapia , Animais , Irradiação Craniana/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Proteínas Serina-Treonina Quinases/genética , Lesões Experimentais por Radiação/complicações , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Glândulas Salivares/lesões , Suínos , Porco Miniatura , Xerostomia/etiologia
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