RESUMEN
As the second most prevalent malignant tumor of head and neck, laryngeal squamous cell carcinoma (LSCC) imposes a substantial health burden on patients worldwide. Within recent years, resistance to oxidative stress and N6-methyladenosine (m6A) of RNA have been proved to be significantly involved in tumorigenesis. In current study, we investigated the oncogenic role of m6A modified long non coding RNAs (lncRNAs), specifically HOXA10-AS, and its downstream signaling pathway in the regulation of oxidative resistance in LSCC. Bioinformatics analysis revealed that heightened expression of HOXA10-AS was associated with the poor prognosis in LSCC patients, and N (6)-Methyladenosine (m6A) methyltransferase-like 3 (METTL3) was identified as a factor in promoting m6A modification of HOXA10-AS and further intensify its RNA stability. Mechanistically, HOXA10-AS was found to play as a competitive endogenous RNA (ceRNA) by sequestering miR-29 b-3p and preventing its downregulation of Integrin subunit alpha 6 (ITGA6), ultimately enhancing the oxidative resistance of tumor cells and promoting the malignant progression of LSCC. Furthermore, our research elucidated the mechanism by which ITGA6 accelerates Keap1 proteasomal degradation via enhancing TRIM25 expression, leading to increased Nrf2 stability and exacerbating its aberrant activation. Additionally, we demonstrated that ITGA6 enhances γ-secretase-mediated Notch signaling activation, ultimately promoting RBPJ-induced TRIM25 transcription. The current study provides the evidence supporting the effect of m6A modified HOXA10-AS and its downstream miR-29 b-3p/ITGA6 axis on regulating oxidative resistance and malignant progression in LSCC through the Notch and Keap1/Nrf2 pathways, and proposed that targeting this axis holds promise as a potential therapeutic approach for treating LSCC.
Asunto(s)
Adenina/análogos & derivados , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Proteínas Homeobox A10 , Integrina alfa6 , Neoplasias Laríngeas , MicroARNs , ARN Largo no Codificante , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , MicroARNs/genética , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patología , Carcinoma de Células Escamosas/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias de Cabeza y Cuello/genética , Estrés Oxidativo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , ARN Largo no Codificante/genética , Metiltransferasas/metabolismoRESUMEN
Myosin superfamily, a large and diverse family of molecular motors important for cell motility and migration, has been illustrated to play contradictory roles during the development of several kinds of tumors. However, the function and prognostic values of MYOs in head and neck squamous cell carcinoma (HNSCC) still remain largely unknown. In the current manuscript, the expression levels and clinical data of MYOs in HNSCC were investigated by online databases, including Oncomine, GEPIA, GEO, TCGA, HPA, UALCAN, Kaplan-Meier plotter, and CancerSEA; we found that the expression levels of MYO1B, MYO5A, and MYO10 were significantly elevated in HNSCC tissues, which were also correlated with the unfavorable overall survival (OS) of the patients. Furthermore, MYO1B/MYO5A/MYO10 interacting genes were identified, and the protein-protein interaction (PPI) networks were constructed by STRING and GeneMANIA. The enrichment analysis revealed that MYO1B/MYO5A/MYO10 associated genes mainly participated in cell metastasis and EMT processes, which were also confirmed by cell functional experiments. At last, the ssGSEA method was conducted to investigate the extent of immune cell infiltration, and we found that both the expression of MYO1B/MYO5A/MYO10 were closely correlated with the infiltration of immune cells in HNSCC. These findings implied that MYO1B, MYO5A, and MYO10 as novel prognostic factors for HNSCC and provided new strategy for HNSCC treatment.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/genética , Humanos , Miosinas , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
Hypopharyngeal squamous cell carcinoma (HSCC) is highly malignant and extremely aggressive, making it one of the worst prognoses among all kinds of head and neck squamous cell carcinoma (HNSCC); therefore, gaining insight into molecular mechanisms of HSCC is of profound significance. In the current manuscript, we revealed the elevated expression of long noncoding RNA (lncRNA) LEF1-AS1 in HNSCC which was associated with the poor prognosis by bioinformatic analysis. Moreover, we noticed that LEF1-AS1 dramatically accelerated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in HSCC cell line FaDu. Most importantly, we illustrated that LEF1-AS1 played as a competitive endogenous RNA (ceRNA) via sponging miR-221-5p and thereby positively regulated gap junction protein alpha 1 (GJA1) expression, thus aggravated tumor progression and EMT. In conclusion, for the first time, we demonstrated lncRNA LEF1-AS1 as a novel biomarker for HNSCC and suggested LEF1-AS1/miR-221-5p/GJA1 axis as promising diagnostic and therapeutic target for HSCC treatment.
Asunto(s)
Conexina 43 , Neoplasias de Cabeza y Cuello , Factor de Unión 1 al Potenciador Linfoide , MicroARNs , ARN Largo no Codificante , Carcinoma de Células Escamosas de Cabeza y Cuello , Biomarcadores , Proliferación Celular/genética , Conexina 43/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Humanos , Factor de Unión 1 al Potenciador Linfoide/genética , MicroARNs/genética , Invasividad Neoplásica/genética , ARN Largo no Codificante/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
Laryngeal squamous cell carcinoma (LSCC) is the most common malignant tumor, which occurs in the head and neck. Current treatments for LSCC are all largely weakened by increasing drug resistance. Our study aimed to investigate the effects of long noncoding RNA (lncRNA) H19 on drug resistance in LSCC. In our study, we found that the level of H19 was sharply upregulated in LSCC tissues and drug-resistant cells compared with the control. Besides, the expression of high-mobility group B1 (HMGB1) was elevated, and microRNA107 (miR-107) was suppressed in drug-resistant cells compared with the control. Further study revealed that the interference of H19 by short hairpin RNA (shRNA) effectively suppressed high autophagy level and obvious drug resistance in drug-resistant cells. Besides that, miR-107 was predicted as a target of H19 and inhibiting effects of H19 shRNA on autophagy and drug resistance were both reversed by miR-107 inhibitor. Moreover, HMGB1 was predicted as a target of miR-107 in LSCC cells and knockdown of HMGB1 was able to suppress autophagy and drug resistance in LSCC cells. In addition, our investigation demonstrated that H19 shRNA exerted an inhibiting effect on autophagy and drug resistance by downregulating HMGB1 by targeting miR-107. Finally, the in vivo experiment revealed that LV-H19 shRNA strongly suppressed drug resistance compared with the usage of cisplatin individually. Taken together, our research indicated an H19-miR-107-HMGB1 axis in regulating the autophagy-induced drug resistance in LSCC in vitro and in vivo, providing novel targets for molecular-targeted therapy and broadening the research for LSCC.
Asunto(s)
Autofagia , Cisplatino/farmacología , Proteína HMGB1/metabolismo , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patología , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Anciano , Animales , Autofagia/genética , Secuencia de Bases , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: Until now, little is known about the role of miRNAs in the invasion and metastasis of Laryngeal squamous cell carcinoma (LSCC). OBJECTIVES: This study aimed to explore the relationship between microRNA and the invasion and metastasis of LSCC. MATERIAL AND METHODS: The highly metastatic laryngocarcinoma cells were obtained from the established animal model with spontaneous lymph node metastasis of LSCC in our previous study. MicroRNA expression profiling and bioinformatic analysis were performed to analyze the microRNA expression changes in the highly metastatic laryngocarcinoma cells and the parental tumor cells (HEP-2). RT-PCR was performed for further validation of the result of microarray. RESULTS: A total of 40 microRNAs were found to be significantly altered in the highly metastatic laryngocarcinoma cells compared to controls. Bioinformatic analysis identified that 19 key microRNAs might involve in LSCC development. Moreover, RT-PCR confirmed that miR-25, miR-100, miR-125b-5p and let-7g were differentially expressed in different laryngocarcinoma cells and human tumor specimens. CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that microRNA play an important role in the invasion and metastasis of LSCC, and provide the clues for studying the function of microRNA as well as opportunities to analyze the complex molecular abnormalities driving LSCC progression.
