RESUMO
Carcinoma cells possess high proliferative and invasive potentials and exhibit a resilience against stresses, metabolic disorder, and therapeutic efforts. These properties are mainly acquired by genetic alterations including driver gene mutations. However, the detailed molecular mechanisms have not been fully elucidated. Here, we provide a novel mechanism connecting oncogenic signaling and the tumorigenic properties by a transforming growth factor-ß1-stimulated clone 22 (TSC-22) family protein, THG-1 (also called as TSC22D4). THG-1 is localized at the basal layer of normal squamous epithelium and overexpressed in squamous cell carcinomas (SCCs). THG-1 knockdown suppressed SCC cell proliferation, invasiveness, and xenograft tumor formation. In contrast, THG-1 overexpression promoted the EGF-induced proliferation and stratified epithelium formation. Furthermore, THG-1 is phosphorylated by the receptor tyrosine kinase (RTK)-RAS-ERK pathway, which promoted the oncogene-mediated tumorigenesis. Moreover, THG-1 involves in the alternative splicing of CD44 variants, a regulator of invasiveness, stemness, and oxidative stress resistance under the RTK pathway. These findings highlight the pivotal roles of THG-1 as a novel effector of SCC tumorigenesis, and the detection of THG-1 phosphorylation by our established specific antibody could contribute to cancer diagnosis and therapy.
Assuntos
Carcinoma de Células Escamosas , Humanos , Carcinogênese/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/genética , Oncogenes/genética , Fosforilação , Fatores de Transcrição/genética , AnimaisRESUMO
Laryngeal squamous cell carcinoma (LSCC), although one of the most common head and neck cancers, has a static or slightly decreased survival rate because of difficulties in early diagnosis, lack of effective molecular targeting therapy, and severe dysfunction after radical surgical treatments. Therefore, a novel therapeutic target is crucial to increase treatment efficacy and survival rates in these patients. Glycoprotein NMB (GPNMB), whose role in LSCC remains elusive, is a type 1 transmembrane protein involved in malignant progression of various cancers, and its high expression is thought to be a poor prognostic factor. In this study, we showed that GPNMB expression levels in LSCC samples are significantly higher than those in normal tissues, and GPNMB expression is observed mostly in growth-arrested cancer cells. Furthermore, knockdown of GPNMB reduces monolayer cellular proliferation, cellular migration, and tumorigenic growth, while GPNMB protein displays an inverse relationship with Ki-67 levels. Therefore, we conclude that GPNMB may be an attractive target for future LSCC therapy.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , MicroRNAs , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Transcrição/metabolismoRESUMO
Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3-5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 µM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity.
Assuntos
Antineoplásicos , Ototoxicidade , Camundongos , Animais , Cisplatino/toxicidade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ototoxicidade/metabolismo , Estradiol/farmacologia , Estradiol/metabolismo , Apoptose , Camundongos Endogâmicos C57BL , Células Ciliadas Auditivas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Antineoplásicos/toxicidadeRESUMO
OBJECTIVE: To evaluate the gustatory function before and after vestibular schwannoma (VS) surgery. METHODS: In this retrospective study, we evaluated the gustatory function of 12 patients who underwent VS surgery at Tsukuba University Hospital between 2012 and 2018. Gustatory function was examined using electrogustometry before VS surgery and 3 months, 6 months and 1 year after surgery. Electrogustometry was tested at the area mapped to the chorda tympani nerve, glossopharyngeal nerve and greater superficial petrosal nerve (GSPN). Intergroup mean comparisons of the threshold were performed using a one-way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test. RESULTS: The gustatory function mapped to the chorda tympani nerve was significantly disturbed 6 months after the surgery as compared with the preoperative function (p = 0.033) and that the dysfunction recovered at 1 year. However, gustatory function mapped to the glossopharyngeal nerve and greater superficial petrosal nerve (GSPN) was not impaired. CONCLUSION: The gustatory function mapped to the chorda tympani nerve is impaired after surgery for VS. The dysfunction peaked at 6 months after surgery, and recovered within 1 year.