RESUMEN
Matrix metalloproteinase-12 (MMP12), or macrophage metalloelastase, plays important roles in extracellular matrix (ECM) component degradation. Recent reports show MMP12 has been implicated in the pathogenesis of periodontal diseases. To date, this review represents the latest comprehensive overview of MMP12 in various oral diseases, such as periodontitis, temporomandibular joint dysfunction (TMD), orthodontic tooth movement (OTM), and oral squamous cell carcinoma (OSCC). Furthermore, the current knowledge regarding the distribution of MMP12 in different tissues is also illustrated in this review. Studies have implicated the association of MMP12 expression with the pathogenesis of several representative oral diseases, including periodontitis, TMD, OSCC, OTM, and bone remodelling. Although there may be a potential role of MMP12 in oral diseases, the exact pathophysiological role of MMP12 remains to be elucidated. Understanding the cellular and molecular biology of MMP12 is essential, as MMP12 could be a potential target for developing therapeutic strategies targeting inflammatory and immunologically related oral diseases.
Asunto(s)
Metaloproteinasa 12 de la Matriz , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/enzimología , Metaloproteinasa 12 de la Matriz/metabolismo , Neoplasias de la Boca/enzimología , Periodontitis/patologíaRESUMEN
The gene encoding aldehyde dehydrogenase 7 family member A1 (ALDH7A1) has been associated with the development and prognosis in multiple cancers; however, the role of ALDH7A1 polymorphisms in oral cancer remains unknown. For this purpose, the influences of ALDH7A1 rs13182402 and rs12659017 on oral cancer development and prognosis were analyzed. Our resulted showed that ALDH7A1 rs13182402 genotype had less pathologic nodal metastasis among betel quid chewer. ALDH7A1 rs13182402 also corresponded to higher expressions in upper aerodigestive mucosa, whole blood, the musculoskeletal system and oral cancer tissues than did the ALDH7A1 wild type. Furthermore, ALDH7A1 overexpression in oral cancer cells increased in vitro migration, whereas its silencing reduced cell migration. Conversely, ALDH7A1 expression in tumor tissues and in patients with advanced disease was lower than that in normal tissues and in patients with early-stage disease. When the patients were classified into ALDH7A1-high and -low-expression groups, the high-ALDH7A1 group had superior outcomes in progression-free survival than the low-ALDH7A1 group (5-year survival of 58.7% vs. 48.0%, P = 0.048) did. In conclusion, patients with high ALDH7A1 expression might, however, have more favorable prognoses than those with low ALDH7A1 expression have.
Asunto(s)
Aldehído Deshidrogenasa , Neoplasias de la Boca , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Humanos , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Polimorfismo Genético , PronósticoRESUMEN
OBJECTIVES: This study aimed to determine expressions of methyltransferase-like 3 (METTL3) and METTL14, two enzymes essential for mRNA methylation at the adenosine (m6 A), in oral squamous cell carcinoma (OSCC) and to investigate in vitro aggressiveness of their aberrant expressions. METHODS: METTL3 and METTL14 expressions in 50 OSCC and 11 normal oral tissues were examined by immunohistochemistry. METTL3 and METTL14 expressions and m6 A amounts were determined in three OSCC cell lines, including HN5, HN6, and HN15. Cell proliferation, migration, and invasion were studied by BrdU, wound healing, and Transwell chamber assays, after silencing of METTL3, METTL14, or both by siRNA transfection. RESULTS: Immunostaining of METTL3 and METTL14 was localized in cancer cell nuclei. The mean percentages of METTL3- and METTL14-positive cells were significantly increased in OSCC tissues (p < 0.001). The percentages of METTL3- and METTL14-positive cells were correlated with the advanced pTNM stages (p < 0.05) and with the degrees of histopathological differentiation in OSCC (r = 0.564 and r = 0.316, respectively; p < 0.001). By the COX multivariate analysis, both overexpressed METTL3 and METTL14 were significantly associated with short overall survival (p < 0.05). Both METTL3 and METTL14 expressions and the m6 A amounts were significantly increased in HN6 (p < 0.05). Silencing of METTL3 and METTL14 in HN6 significantly inhibited cell proliferation (p < 0.01), but it failed to mitigate cell migration or invasion. CONCLUSIONS: METTL3 and METTL14 are overexpressed in OSCC tissues and in the HN6 OSCC cell line that promotes cell proliferation. Overexpressed METTL3 or METTL14 is found to be an independent prognostic factor for short overall survival in patients with OSCC.
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Metiltransferasas/metabolismo , Neoplasias de la Boca/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Línea Celular Tumoral , Proliferación Celular , Humanos , Metiltransferasas/genética , ARN MensajeroRESUMEN
Studies suggested that long noncoding HAR1A RNA may be a tumor suppressor, but its association with oral cancer remains unclear. Here, we show the functional role and mechanisms of HAR1A in oral cancer progression. Microarray analysis was performed to screen the related candidates of long noncoding RNA (lncRNA) in human monocytes. Following lncRNA HAR1A, the regulation of HAR1A, ALPK1, myosin IIA, and BRD7 was tested using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in oral cancer cells. The inflammatory and epithelial-to-mesenchymal transition marker expressions were analyzed using enzyme-linked immunosorbent assay and western blot. Phenotypic experiments were verified by colony formation assay, transwell migration assay, and Annexin V-apoptotic assay. In the nuclei of cancer cells, HAR1A functions upstream of signaling pathways and knockdown of HAR1A promoted ALPK1 expression and downregulated BRD7 resulting in inflammation and oral cancer progression. In monocytes, the expressions of TNF-α and CCL2 were increased following HAR1A knockdown and reduced following ALPK1 knockdown. HAR1A knockdown upregulated the expression of ALPK1, slug, vimentin, fibronectin, and N-cadherin but reduced the expression of E-cadherin in oral cancer cells. Myosin IIA was primarily located in the cytoplasm and that its decrease in the nuclei of oral cancer cells was likely to demonstrate suppressive ability in late-stage cancer. Our findings suggest that the HAR1A, BRD7, and myosin IIA are tumor suppressors while ALPK1 has oncogene-like property in the nucleus and is involved in inflammation and oral cancer progression. More research for HAR1A activators or ALPK1 inhibitors is required to develop potential therapeutic agents for advanced oral cancer. KEY MESSAGES: lncRNA HAR1A, BRD7, and myosin IIA are tumor suppressors whereas ALPK1 has an oncogenic-like property in the nucleus. lncRNA HAR1A/ALPK1/BRD7/myosin IIA axis plays a critical role in the progression of oral cancer. lncRNA HAR1A localizes upstream of signaling pathways to inhibit ALPK1 expression and then upregulated BRD7. lncRNA HAR1A and ALPK1 are involved in cancer progression via epithelial-to-mesenchymal transition regulations. ALPK1 inhibitors are potential kinase-targeted therapeutic agents for patients with advanced oral cancer.
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Proteínas Cromosómicas no Histona/metabolismo , Neoplasias de la Boca/enzimología , Miosina Tipo IIA no Muscular/metabolismo , Proteínas Quinasas/metabolismo , ARN Largo no Codificante/metabolismo , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Proteínas Cromosómicas no Histona/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Invasividad Neoplásica , Miosina Tipo IIA no Muscular/genética , Proteínas Quinasas/genética , ARN Largo no Codificante/genética , Transducción de SeñalRESUMEN
BACKGROUND/AIM: Phosphodiesterase 5 (PDE5) holds clinical relevance in several pathological states, including lung, breast, and prostate cancer. In this study, we examined PDE5 expression in oral squamous cell carcinoma (OSCC)-derived cell lines and tissues, and the anti-tumour effect of PDE5 inhibitor, sildenafil citrate (SC). MATERIALS AND METHODS: Cell proliferation, cell invasion, and gap closure assays were performed in six OSCC-derived cell lines upon treatment with varying concentrations of SC. PDE5 expression was determined in primary OSCC tissues by western blotting and immunohistochemistry. RESULTS: Elevated PDE5 expression was observed in all cell lines. A concentration-dependent decrease in cell viability, invasion rate, and migration was observed after SC treatment. A significant correlation (p=0.05) was observed between elevated PDE5 expression and lymphatic infiltration in OSCC tissues. CONCLUSION: PDE5 plays an important role in carcinogenesis of OSCC, and the specific inhibition of PDE5 may be an effective chemotherapeutic strategy.
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Carcinoma de Células Escamosas/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Neoplasias de la Boca/enzimología , Citrato de Sildenafil/farmacología , Western Blotting , Carcinoma de Células Escamosas/patología , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Inmunohistoquímica , Neoplasias de la Boca/patología , Inhibidores de Fosfodiesterasa 5/farmacologíaRESUMEN
OBJECTIVE: To explore the role of RN181 in the pathogenesis of oral squamous cell carcinoma (OSCC) cells via mediating ERK/MAPK signaling. METHODS: The expression of RN181 was detected in OSCC tissues and cells. CAL27 and SCC-15 cells were divided into Control, Empty, RN181, si-RN181, U0126 (an inhibitor of ERK/MAPK pathway) and si-RN181 + U0126 groups. MTT was used to determine cell proliferation, flow cytometry to determine cell cycle and apoptosis, Transwell assay and wound healing test to determine cell invasion and migration, respectively. Western blotting was used to measure the protein expression. Furthermore, a xenograft tumor model was established to observe the effect of RN181 on the in vivo growth of OSCC cells. RESULTS: RN181 was down-regulated in OSCC tissues and cells. As compared to the Control group, CAL27 and SCC-15 cells in the RN181 group and U0126 group presented with decreases in the proliferation, invasion and migration, but increases in the cell ratio at the G0/G1 phase and apoptosis, while the p-ERK 1/2/ERK 1/2 was down-regulated. Cells in the si-RN181 group manifested the opposite changes. U0126 could reverse the positive effect of si-RN181 on the growth of OSCC cells. In vivo experiment demonstrated that the tumor growth and weight were reduced in the RN181 group, with decreased Ki67 positive expression and elevated TUNEL positive cells. CONCLUSION: RN181 was down-regulated in OSCC, and it could inhibit the proliferation, invasion and migration, cause the G0/G1 arrest, while promote the apoptosis of OSCC cells via inhibiting ERK/MAPK pathway.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas , Neoplasias de la Boca/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Ubiquitina-Proteína Ligasas/fisiología , Adulto , Anciano , Animales , Apoptosis , Butadienos/farmacología , Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Antígeno Ki-67/biosíntesis , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Nitrilos/farmacología , Transducción de Señal , Cicatrización de HeridasRESUMEN
BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most relevant malignant neoplasm among all head and neck tumours due to its high prevalence and unfavourable prognosis. Tumour invasion and metastasis that affect prognosis are result of a set of complex events that cells with invasive potential use to spread to other regions. These cells use several mechanisms to invade tissues, including a type of finger-like membrane protrusion called invadopodia. This study aims to investigate the immunoexpression of invaopodia related-proteins TKs5, cortactin, TKs4 and MT1-MMP in OSCC and correlate it to clinicopathological data. METHODS: An immunohistochemical evaluation of fifty cases of OSCCs and 20 cases of oral mucosa (OM) were assessed. The expression of invadopodia proteins were analysed in comparison to normal tissue (OM) and correlated to different clinical-stage and histological grade of OSCC. RESULTS: TKs5, cortactin, TKs4 and MT1-MMP were significantly overexpressed in OSCC when compared to OM (p < 0.0001). Among tumour stages, TKs5 showed a statistical difference in immunolabelling between stage I and III (p = 0.026). Cortactin immunolabelling was statistically higher in grade I than in grade II and III. No differences were seen on TKs4 expression based on tumour staging or grading. MT1-MMP was higher expressed and showed statistical difference between stages I and III and grades I compared to II and III. CONCLUSIONS: The invadopodia related-proteins were found to be overexpressed in OSCC when compared to OM, suggesting invadopodia formation and activity. Besides overexpressed in OSCC, cortactin, TKs4 and TKs5 showed no or ambiguous differences in protein expression when compared among clinical-stages or histological grades groups. Conversely, the expression of MT1-MMP increased in advanced stages and less differentiated tumours, suggesting MT1-MMP expression as a promising prognostic marker in OSCC.
Asunto(s)
Biomarcadores de Tumor/análisis , Metaloproteinasa 14 de la Matriz/análisis , Neoplasias de la Boca/enzimología , Podosomas/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras del Transporte Vesicular/análisis , Cortactina/análisis , Estudios Transversales , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Clasificación del Tumor , Estadificación de Neoplasias , Podosomas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND/AIM: This study aimed to elucidate the role of glutathione peroxidase 4 (GPX4) on the sterol regulatory element binding proteins (SREBPs)-proliferation pathway in oral cancer cells, and determine its protein expression in oral cancer tissues. MATERIALS AND METHODS: Quantitative RT-PCR and immunoblot analysis were carried out. Cell viability assay, apoptosis detection assay, immunohistochemistry and GPX4 knockdown were performed. RESULTS: The levels of both GPX4 mRNA and protein were highest in SAS cells. GPX4 knockdown in SAS cells, a human oral squamous cell carcinoma cell line, using GPX4 siRNA resulted in a reduction in cell number, which appeared to be due to non-apoptotic cell death such as ferroptosis. Furthermore, SREBP was clearly down-regulated by GPX4 knockdown in SAS cells. Immunopositivity for GPX4 was revealed on the membrane of human oral squamous cell carcinoma cells, and this was correlated with p53 immunoreactivity. CONCLUSION: GPX4 appears to play an important role in oral cancer proliferation.
Asunto(s)
Proliferación Celular , Neoplasias de la Boca/enzimología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
There is increasing evidence that the core clock gene Period 1 (PER1) plays important roles in the formation of various tumors. However, the biological functions and mechanism of PER1 in promoting tumor progression remain largely unknown. Here, we discovered that PER1 was markedly downregulated in oral squamous cell carcinoma (OSCC). Then, OSCC cell lines with stable overexpression, knockdown, and mutation of PER1 were established. We found that PER1 overexpression significantly inhibited glycolysis, glucose uptake, proliferation, and the PI3K/AKT pathway in OSCC cells. The opposite effects were observed in PER1-knockdown OSCC cells. After treatment of PER1-overexpressing OSCC cells with an AKT activator or treatment of PER1-knockdown OSCC cells with an AKT inhibitor, glycolysis, glucose uptake, and proliferation were markedly rescued. In addition, after treatment of PER1-knockdown OSCC cells with a glycolysis inhibitor, the increase in cell proliferation was significantly reversed. Further, coimmunoprecipitation (Co-IP) and cycloheximide (CHX) chase experiment demonstrated that PER1 can bind with RACK1 and PI3K to form the PER1/RACK1/PI3K complex in OSCC cells. In PER1-overexpressing OSCC cells, the abundance of the PER1/RACK1/PI3K complex was significantly increased, the half-life of PI3K was markedly decreased, and glycolysis, proliferation, and the PI3K/AKT pathway were significantly inhibited. However, these effects were markedly reversed in PER1-mutant OSCC cells. In vivo tumorigenicity assays confirmed that PER1 overexpression inhibited tumor growth while suppressing glycolysis, proliferation, and the PI3K/AKT pathway. Collectively, this study generated the novel findings that PER1 suppresses OSCC progression by inhibiting glycolysis-mediated cell proliferation via the formation of the PER1/RACK1/PI3K complex to regulate the stability of PI3K and the PI3K/AKT pathway-dependent manner and that PER1 could potentially be a valuable therapeutic target in OSCC.
Asunto(s)
Proliferación Celular , Glucólisis , Neoplasias de la Boca/enzimología , Proteínas de Neoplasias/metabolismo , Proteínas Circadianas Period/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Receptores de Cinasa C Activada/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Proteínas Circadianas Period/genética , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carga TumoralRESUMEN
Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-ß (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells.
Asunto(s)
Aneuploidia , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , ADN Polimerasa beta/metabolismo , Neoplasias de la Boca/mortalidad , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Proliferación Celular , ADN Polimerasa beta/antagonistas & inhibidores , ADN Polimerasa beta/genética , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mitosis , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.
Asunto(s)
Abietanos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Neoplasias de la Boca/radioterapia , Inhibidores de Proteínas Quinasas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Abietanos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de la radiación , Humanos , Ratones Desnudos , Simulación del Acoplamiento Molecular , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Fármacos Sensibilizantes a Radiaciones/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To discover the role of miR-590-5p in oral squamous cell carcinoma (OSCC) progression and the corresponding mechanism via the targeting RECK. METHODS: OSCC (n=85) and normal oral tissues (n=60) were collected to quantify the miR-590-5p expression by using qRT-PCR. Then SCC-15 and OEC-M1 cells were selected and divided into Mock, inhibitor NC, miR-590-5p inhibitor, si-RECK and miR-590-5p inhibitor + si-RECK groups. Dual-luciferase reporter gene assay was used to verify if miR-590-5p could target RECK. The biological behaviors of OSCC cells were evaluated by MTT, Wound-healing, Transwell and Flow cytometry. The expression of miR-590-5p and RECK was measured by qRT-PCR and Western blotting , respectively. RESULTS: Overexpression of miR-590-5p was found in OSCC tissues. The expression of miR-590-5p was significantly associated with the clinical TNM stage, differentiation degree, and lymph node metastasis of OSCC. RECK was identified as a direct target of miR-590-5p. Compared with the Mock group, cells in the miR-590-5p inhibitor group were decreased in terms of proliferation, invasion, and migration, and increased in cell apoptosis, accompanied by down-regulated miR-590-5p, Bcl-2/Bax and MMP-9, and up-regulated RECK. By contrast, si-RECK group presented completely opposite changes, and si-RECK reversed the inhibitory effect of miR-590-5p inhibitor on the OSCC cell growth. CONCLUSION: MiR-590-5p expression was obviously increased in OSCC, and inhibiting miR-590-5p enhanced the expression of its target gene RECK, thereby suppressing proliferation, migration and invasion of OSCC cells and promoting apoptosis of OSCC cells.
Asunto(s)
Apoptosis , Movimiento Celular , Proliferación Celular , Proteínas Ligadas a GPI/metabolismo , MicroARNs/metabolismo , Neoplasias de la Boca/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Adulto , Anciano , Estudios de Casos y Controles , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , MicroARNs/genética , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Invasividad Neoplásica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Oral squamous cell carcinoma (OSCC) is the major cause of morbidity and mortality in head and neck cancer patients worldwide. This malignant disease is challenging to treat because of the lack of effective curative strategies and the high incidence of recurrence. This study aimed to investigate the efficacy of a single and dual approach targeting ribosome biogenesis and protein translation to treat OSCC associated with the copy number variation (CNV) of ribosomal DNA (rDNA). Here, we found that primary OSCC tumors frequently exhibited a partial loss of 45S rDNA copy number and demonstrated a high susceptibility to CX5461 (a selective inhibitor of RNA polymerase I) and the coadministration of CX5461 and INK128 (a potent inhibitor of mTORC1/2). Combined treatment displayed the promising synergistic effects that induced cell apoptosis and reactive oxygen species (ROS) generation, and inhibited cell growth and proliferation. Moreover, INK128 compromised NHEJ-DNA repair pathway to reinforce the antitumor activity of CX5461. In vivo, the cotreatment synergistically suppressed tumor growth, triggered apoptosis and strikingly extended the survival time of tumor-bearing mice. Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzotiazoles/farmacología , Benzoxazoles/farmacología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Neoplasias de la Boca/tratamiento farmacológico , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , ARN Polimerasa I/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , ADN Ribosómico/genética , ADN Ribosómico/metabolismo , Sinergismo Farmacológico , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , ARN Polimerasa I/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Peroxiredoxin 2 (PRDX2) is upregulated in various cancers including oral squamous cell carcinoma (OSCC). It is a known tumor promoter in some cancers, but its role in OSCC is unclear. This study aimed to investigate the effect of arecoline, an alkaloid of the betel nut, and human papillomavirus type 16 (HPV16) E6/E7 oncoproteins on induction of PRDX2 expression, and also the effects of PRDX2 overexpression in oral cell lines. Levels of PRDX2 protein were determined using western blot analysis of samples of exfoliated normal oral cells (n = 75) and oral lesion cells from OSCC cases (n = 75). Some OSCC cases were positive for HPV infection and some patients had a history of betel quid chewing. To explore the level of PRDX2 by western blot, the proteins were extracted from oral cell lines that were treated with arecoline or retroviruses containing HPV16 E6 gene and HPV16 E6/E7 expressing vector. For analysis of PRDX2 functions, cell proliferation, cell-cycle progression, apoptosis and migration was compared between oral cells overexpressing PRDX2 and cells with PRDX2-knockdown. PRDX2 expression levels tended to be higher in OSCC samples that were positive for HPV infection and had history of betel quid chewing. Arecoline treatment in vitro at low concentrations and overexpression of HPV16 E6 or E6/E7 in oral cells induced PRDX2 overexpression. Interestingly, in oral cells, PRDX2 promoted cell proliferation, cell-cycle progression (G2/M phase), cell migration and inhibited apoptosis. Upregulation of PRDX2 in oral cells was induced by arecoline and HPV16 oncoproteins and promoted growth of OSCC cells.
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Arecolina/farmacología , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Boca/genética , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Peroxirredoxinas/genética , Proteínas Represoras/genética , Anciano , Apoptosis/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Papillomavirus Humano 16/química , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Peroxirredoxinas/antagonistas & inhibidores , Peroxirredoxinas/metabolismo , Plásmidos/química , Plásmidos/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , TransfecciónRESUMEN
Background: Oral squamous cell carcinoma (OSCC) that comprises about 90% of all oral cancer cases is associated with poor prognosis due to its highly metastatic nature. The majority of OSCC treatment options are related detrimental side-effects. Hypothesis/Purpose: The present study aimed at deciphering the effects of a bioactive phytochemical, sodium danshensu, on human oral cancer cell metastasis. Methods and Results: The treatment of FaDu and Ca9-22 cells with different doses of sodium danshensu (25, 50, and 100 µM) caused a significant reduction in cellular motility, migration, and invasion, as compared to the untreated cells. This effect was associated with a reduced expression of MMP-2, vimentin and N-cadherin, together with an enhanced expression of E-cadherin and ZO-1. Further investigation on the molecular mechanism revealed that treatment with sodium danshensu caused significant reduction in p38 phosphorylation; however, phosphorylation of ERK1/2 significantly decreased only in FaDu cells, whereas p-JNK1/2 did not show any alteration. A combination of p38 and JNK1/2 inhibitors with sodium danshensu also reduced the migration in the FaDu and Ca9-22 cell lines. Conclusion: Collectively, the present study findings reveal that sodium danshensu execute anti-metastatic effect by suppressing p38 phosphorylation in human oral cancer. The study identifies sodium danshensu as a potential natural anticancer agent that can be used therapeutically to manage highly metastatic OSCC.
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Carcinoma de Células Escamosas/enzimología , Movimiento Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Lactatos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias de la Boca/enzimología , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Neoplasias de la Boca/patología , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & controlRESUMEN
BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. Therefore, novel therapeutic options are needed to improve prognosis of OSCC. Recently, microRNAs (miRs) have received increasing attention as a potential therapeutic tool for carcinomas. However, no definitive miR-based drugs for patients with OSCC have been reported to date. The aim of this study was to identify new miRs potentially involved in cellular processes associated with OSCC malignancy, which could lead to novel therapeutic strategies. MATERIALS AND METHODS: We identified miRs that are modulated in OSCC and possibly regulate OSCC malignancy, using miR microarray on OSCC cell lines. RESULTS: miR-935 and miR-509-3p were down-regulated in OSCC cell lines and patient tissues. When miR-935 was overexpressed in HSC-3-M3 cells, proliferation, migration, and invasion of the cell line was suppressed, whereas apoptosis was increased. Moreover, we showed that the gene inositol polyphosphate-4-phosphatase type I A (INPP4A) is a potential target whose expression is positively regulated by miR-935. CONCLUSION: miR-935 may function as a tumor suppressor by inhibiting OSCC malignancy via INPP4A induction. Therefore, miR-935 can be a new therapeutic candidate for OSCC treatment.
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Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , MicroARNs/metabolismo , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Apoptosis/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Neoplasias de la Boca/patología , Invasividad Neoplásica , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Histone deacetylases (HDACs) are considered as an essential regulator of cellular proliferation, differentiation, and apoptosis. The HDAC2 enzyme of Class I HDACs plays an important role in tumor progression of human malignancies. OBJECTIVE: The aim of the present study was to analyze the HDAC2 gene expression in pre-oral cancer and oral squamous cell carcinoma (OSCC), and its association with clinico-pathological features. METHODS: The HDAC2 protein expression was analyzed through the immunohistochemistry and western blot techniques in 82 oral pre-malignant, 90 OSCC, and 16 normal control tissues. qRT-PCR was used to quantify the mRNA fold change in all groups. RESULTS: The HDAC2 protein and mRNA levels were significantly higher in OSCC and pre-oral cancer groups compared to the controls. Immunostaining of HDAC2 protein was enhanced in 84.4% of OSCC and 67.1% of pre-cancerous tissue sections (p< 0.01). The mean protein level was analyzed as 1.96 ± 0.44 in oral carcinoma, 1.61 ± 0.39 in pre-cancer and 0.96 ± 0.10 in control tissues. In addition, HDAC2 mean protein level was associated with histological differentiation (OR = 25, p< 0.05) and tumor-node-metastasis (TNM) stages (OR = 6.2, p< 0.05) of OSCC patients. CONCLUSIONS: The upregulated HDAC2 gene in pre-cancer and OSCC tissues indicates its crucial role in the transformation of pre-malignant to malignant carcinoma. It could be a potential cancer biomarker of prognosis and targeted therapy in OSCC.
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Histona Desacetilasa 2/metabolismo , Neoplasias de la Boca/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Progresión de la Enfermedad , Femenino , Histona Desacetilasa 2/genética , Humanos , Masculino , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Regulación hacia ArribaRESUMEN
OBJECTIVES: To evaluate the anti-inflammatory and antiproliferative effect of syringic acid (SRA) on oral squamous cell carcinoma (OSCC) SCC131 cells via suppression of NF-κB-induced PI3K/Akt signalling pathway. METHODS: The present study assesses the anticancer effects of SRA alongside human oral cancer (HOC) SCC131 cells through the fabrication of reactive oxygen species (ROS) and activated apoptosis. DAPI and Rh-123 staining were used to assess the apoptotic nuclear characteristic, mitochondrial membrane potential, cell adhesion and migration by fluorescence microscope with SRA treatment. KEY FINDINGS: Syringic acid inhibits cell viability (IC50 values of 25 µm), adhesion, migration and induced apoptosis. MTT assay demonstrated SRA-induced apoptotic events, inhibition of invasion and angiogenic signalling in SCC131 cell line. Furthermore, SRA treated with SCC131 cells suppresses the protein expression of inflammatory, angiogenesis and PI3K/Akt signalling pathways. It is suggested that SRA prevents the translocation of NF-κB and PI3K/Akt activated products to the nucleus, thereby suppressing angiogenesis via downregulation of vascular endothelial growth factor. CONCLUSIONS: Therefore, addition of SRA to SCC131 cells may provide a promising natural therapeutic strategy against squamous cell carcinomas with potential application in clinical analysis.
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Antineoplásicos/farmacología , Ácido Gálico/análogos & derivados , Neoplasias de la Boca/tratamiento farmacológico , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ácido Gálico/farmacología , Humanos , Mediadores de Inflamación/metabolismo , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , Invasividad Neoplásica , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.
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Antineoplásicos/farmacología , Diterpenos/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Proteína Sequestosoma-1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Desnudos , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Especies Reactivas de Oxígeno/metabolismo , Proteína Sequestosoma-1/genética , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oral cancer-a type of head and neck cancer-is estimated to be the fifth most common cancer in Taiwan. However, efficacious therapies for oral cancer are still lacking due to drug resistance and recurrence. Consequently, the identification of new anticancer agents for clinical treatment is needed. Juniperus indica Bertol is a plant of the Juniperus genus often used as a treatment in traditional medicine due to its anti-inflammatory, antibacterial and diuretic functions. The biofunctions of Juniperus indica Bertol including its anticancer potential, have not been fully explored. As a result, the aim of this research was to investigate the anticancer activity of Juniperus indica Bertol extract (JIB extract) and determine whether JIB extract has synergistic effects with cisplatin in oral cancer. These results are the first to demonstrate that JIB extract exhibits anticancer capacity and synergizes with cisplatin to treat oral cancer. Our findings indicate that JIB extract has a potential to develop anticancer agent and chemo therapeutic adjuvant for oral cancer.