RESUMEN
AIM: To investigate the immunohistochemical (IHC) expression and the diagnostic value of c-MYC, Cyclin D1, and Ki-67∕MIB-1 in follicular adenomas (FAs), follicular carcinomas (FCs), and anaplastic carcinomas (ACs) of the thyroid gland, as well as in their corresponding adjacent, non-neoplastic thyroid tissue (NNTT). MATERIALS AND METHODS: We conducted a retrospective study of patients who were pathologically diagnosed with FA, FC, or AC after total thyroidectomy. Tissue microarrays with cores taken from neoplastic and adjacent NNTT were constructed. Immunohistochemistry for anti-c-MYC, anti-Cyclin D1, and anti-Ki-67∕MIB-1 antibodies was performed, and the positivity was evaluated. RESULTS: Twenty-eight specimens were included. Nuclear c-MYC positivity was observed in 4∕11 FCs, and 3∕4 ACs, whereas cytoplasmic c-MYC positivity was found in 16∕24 NNTTs. Globally, there were statistically significant differences between neoplasms and NNTTs, with higher nuclear c-MYC and Cyclin D1 expression observed in neoplasms (p=0.017 and p=0.001, respectively). In contrast, cytoplasmic positivity was seen solely in NNTTs (p=0.001). Cyclin D1 positivity was noted in 11∕13 FAs, 7∕11 FCs, 2∕4 ATCs, and only in one NNTT. A statistically significant correlation was found between MIB1 and c-MYC nuclear positivity (p=0.040). CONCLUSIONS: Our findings exhibit a clear difference in the IHC expression of c-MYC and Cyclin D1 between different types of thyroid tumors, as well as between the neoplastic and NNTT. Nuclear c-MYC positivity excludes the benign nature of a thyroid lesion, in contrast to cytoplasmic positivity, which demonstrates normal or hyperplastic nature.
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Ciclina D1 , Antígeno Ki-67 , Proteínas Proto-Oncogénicas c-myc , Glándula Tiroides , Neoplasias de la Tiroides , Humanos , Ciclina D1/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Femenino , Masculino , Antígeno Ki-67/metabolismo , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Adulto , Inmunohistoquímica/métodos , AncianoAsunto(s)
Ciclina D1 , Neoplasias Renales , Sarcoma de Células Claras , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patología , Sarcoma de Células Claras/metabolismo , Masculino , Neoplasias Renales/genética , Neoplasias Renales/patología , Femenino , Niño , Preescolar , Lactante , Pronóstico , Tasa de Supervivencia , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Recurrencia Local de Neoplasia , Inmunohistoquímica , Estadificación de Neoplasias , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Fusión Oncogénica/genética , Ciclina BRESUMEN
In search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH3 as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH3 co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSOd6 or its mixture with D2O using 1H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers.
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Antineoplásicos , Ciclina D1 , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Transición Epitelial-Mesenquimal , Factor de Transcripción STAT3 , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Transición Epitelial-Mesenquimal/efectos de los fármacos , Línea Celular Tumoral , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas c-myc/metabolismo , Femenino , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ligandos , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis químicaRESUMEN
Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Sinergismo Farmacológico , Neoplasias Pulmonares , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteínas Proto-Oncogénicas p21(ras) , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Animales , Línea Celular Tumoral , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Transducción de Señal/efectos de los fármacos , Ciclina D1/metabolismo , Ciclina D1/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Femenino , Proteína 11 Similar a Bcl2/metabolismo , Proteína 11 Similar a Bcl2/genéticaRESUMEN
High-grade serous ovarian cancer (HGSC) is an aggressive disease with poor prognosis. The oncoprotein ZNF703 is implicated in driving HGSC pathogenesis, but factors regulating its abundance remain unclear. In this study, we aim to investigate the potential connection between ZNF703 dysregulation and ubiquitin-mediated protein degradation in HGSC. Bioinformatics prediction was performed using BioGRID database. HGSC representative cell lines were utilized for in vitro and in vivo studies. Results showed that ZNF703 protein was stabilized upon proteasome inhibition, suggesting a regulation via ubiquitination. The ubiquitin E3 ligase PARK2 was found to interact with ZNF703 in a dose-dependent manner, promoting its polyubiquitination and subsequent proteasomal degradation. Re-expression of PARK2 in HGSC cells led to reduced ZNF703 levels together with decreased Cyclin D1/E1 abundance and G1 cell cycle arrest. ZNF703 overexpression alone increased S phase cells, Cyclin D1/E1 levels, and xenograft tumor growth, while co-expression with PARK2 mitigated these oncogenic effects. Collectively, our findings identify ZNF703 as a bona fide substrate of PARK2, reveal a tumor suppressive function for PARK2 in attenuating ZNF703-mediated G1/S transition and HGSC growth through instigating its degradation. This study elucidates a pivotal PARK2-ZNF703 axis with therapeutic implications for targeted intervention in HGSC.
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Proliferación Celular , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Complejo de la Endopetidasa Proteasomal , Ubiquitina-Proteína Ligasas , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/genética , Línea Celular Tumoral , Animales , Ratones , Ubiquitinación , Ciclina D1/metabolismo , Ciclina D1/genética , Proteínas Oncogénicas/metabolismo , Proteínas Oncogénicas/genética , Ratones Desnudos , Proteolisis , Ciclina E/metabolismo , Ciclina E/genética , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica , Proteínas PortadorasRESUMEN
Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell-cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death. Together, these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.
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Ácidos y Sales Biliares , Proliferación Celular , Hepatectomía , Hepatocitos , Regeneración Hepática , Ratones Noqueados , Receptores de Calcitriol , Animales , Regeneración Hepática/efectos de los fármacos , Regeneración Hepática/fisiología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Masculino , Ratones , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Ciclina D1/metabolismo , Ciclina D1/genética , Ciclina E/metabolismo , Ciclina E/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Ratones Endogámicos C57BL , Vitamina D/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas OncogénicasRESUMEN
Constituents of cigarette smoke are known to be carcinogens. Additionally, there is mounting evidence that the liver is an organ susceptible to tobacco carcinogenicity. Nicotine, the primary constituent of tobacco, plays a role in cancer progression. In our previous study, it was found that nicotine enhances the proliferation of a human normal fetal hepatic (WRL68) cell due to the activation of p53 mutation at Ser249 (p53-RS)/STAT1/CCND1 signaling pathway. Here, we further elucidated the mechanism of regulating this pathway. Firstly, dose-dependent increase of SETDB1 protein level in WRL68 cells upon exposure to nicotine (1.25, 2.5, and 5⯵M), significantly enhanced cellular proliferation. In addition, the upregulation of SETDB1 protein was necessary for the nuclear translocation of p53-RS to establish a ternary complex with STAT1 and SETDB1, which facilitated p53-RS di-methylation at K370 (p53-RS/K370me2). After that, the activation of CCND1/PI3K/AKT pathway was initiated when STAT1 stability was enhanced by p53-RS/K370me2, ultimately resulting in cell proliferation. Altogether, the study revealed that the increase in SETDB1 expression could potentially have a significant impact on the activation of CCND1/PI3K/AKT pathway through p53-RS/K370me2, leading to the proliferation of WRL68 cells induced by nicotine, which could contribute to hepatocellular carcinoma for smokers. Besides, the results of this study provided a foundation for the development of anticancer therapies for cancers associated with tobacco use.
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Proliferación Celular , Ciclina D1 , N-Metiltransferasa de Histona-Lisina , Nicotina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Nicotina/toxicidad , Ciclina D1/metabolismo , Ciclina D1/genética , N-Metiltransferasa de Histona-Lisina/genética , Proliferación Celular/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Metilación/efectos de los fármacos , Línea Celular , Factor de Transcripción STAT1/metabolismoRESUMEN
Uterine spindle cell lesions share a dilemmatic overlapped features that needed to be addressed by the pathologist to reach a conclusive accurate diagnosis for its prognostic value and different management decisions. Usage of combined IHC panel can be an aiding guiding tool in this context. The aim of this study is to evaluate the diagnostic value of combined BCOR, Cyclin D1, and CD10 IHC panel in differentiating endometrial stromal sarcoma from other uterine spindle cell lesions. This study included 60 cases categorized into endometrial stromal sarcoma group (ESS) (12 cases high-grade endometrial stromal sarcoma [HGESS] and 18 cases low-grade endometrial stromal sarcoma [LGESS]), malignant uterine spindle cell lesions group (5 cases adenosarcoma [AS], 6 cases leiomyosarcoma [LS], 4 cases carcinosarcoma [CS]), and benign uterine lesions group (5 cases endometrial stromal nodule [ESN], 5 cases leiomyoma, and 5 cases adenomyosis). IHC staining procedure and evaluation for BCOR, Cyclin D1, and CD10 was performed on all studied cases. BCOR IHC staining was positive in all HGESS (12/12) of ESS group cases, with diffuse pattern in 75% of cases. BCOR-diffuse staining pattern was not recorded in any of LGESS (0/18), malignant mesenchymal lesions group (0/15), and also benign lesions group (0/15). Cyclin D1 positivity was observed only in HGESS cases, in parallel with positive-BCOR expression. On the contrary, CD10 was negatively expressed in all HGESS and positive in all LGESS, ESN, and adenomyosis cases. A specificity of 100% and sensitivity of 75% were recorded in differentiating HGESS from malignant mesenchymal lesions (including LMS, AS, and CS) and also HGESS from LGESS when using the combined panel BCOR +ve D /Cyclin D1 +ve / CD10 -ve , considering only the BCOR-diffuse staining pattern. In conclusion, BCOR +ve D /Cyclin D1 +ve /CD10 -ve as a combined panel is 100% specific and with lesser sensitivity in diagnosing HGESS as well as differentiating it from LGESS and other malignant uterine spindle cell lesions.
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Ciclina D1 , Neprilisina , Proteínas Proto-Oncogénicas , Proteínas Represoras , Sarcoma Estromático Endometrial , Humanos , Femenino , Neprilisina/metabolismo , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/metabolismo , Sarcoma Estromático Endometrial/patología , Proteínas Represoras/metabolismo , Ciclina D1/metabolismo , Diagnóstico Diferencial , Persona de Mediana Edad , Adulto , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Inmunohistoquímica , Biomarcadores de Tumor/metabolismo , Anciano , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologíaRESUMEN
OBJECTIVE: One of the biggest therapy challenges for nasopharyngeal cancer (NPC) is still radioresistance. The radioresistance in NPC is thought to be caused by cyclin D1 overexpression. The purpose of this study was to determine how cyclin D1 contributes to radiation resistance in NPC. METHODS: Adhering to the PRISMA guidelines, we systematically reviewed studies on cyclin D1-associated radioresistance in NPC from 2012 until 2023. From our search, 15 studies were included. RESULTS: Cyclin D1's role in radiotherapy resistance is elucidated through several mechanisms, notably SHP-1 and B-catenin. Overexpression of SHP-1 led to an increase in cyclin D1, a higher proportion of cells in the S-phase, and radioresistance. Conversely, inhibiting ß-catenin and cyclin D1 expression enhances radiation sensitivity. CONCLUSION: In conclusion, Cyclin D1 has a strong correlation with radiation resistance; downregulation of the protein increases radiosensitivity, while overexpression of the protein promotes radioresistance.
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Ciclina D1 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Tolerancia a Radiación , Humanos , Ciclina D1/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , beta Catenina/metabolismo , Pronóstico , Estadificación de NeoplasiasRESUMEN
The aging process is linked to numerous cellular changes, among which are modifications in the functionality of dermal fibroblasts. These fibroblasts play a crucial role in sustaining the healing of skin wounds. Reduced cell proliferation is a hallmark feature of aged dermal fibroblasts. Long intergenic non-coding RNA (lincRNAs), such as LincRNA-EPS (Erythroid ProSurvival), has been implicated in various cellular processes. However, its role in aged dermal fibroblasts and its impact on the cell cycle and its regulator, Cyclin D1 (CCND1), remains unclear. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of LincRNA-EPS was achieved through plasmid transfection. Cell proliferation was detected using the MTT assay. Real-time PCR was used to quantify relative gene expressions. Our findings indicate a noteworthy decline in the expression of LincRNA-EPS in aged dermal fibroblasts, accompanied by reduced levels of CCND1 and diminished cell proliferation in these aging cells. Significantly, the overexpression of LincRNA-EPS in aged dermal fibroblasts resulted in an upregulation of CCND1 expression and a substantial increase in cell proliferation. Mechanistically, LincRNA-EPS induces CCND1 expression by sequestering miR-34a, which was dysregulated in aged dermal fibroblasts, and directly targeting CCND1. These outcomes underscore the crucial role of LincRNA-EPS in regulating CCND1 and promoting cell proliferation in aged dermal fibroblasts. Our study provides novel insights into the molecular mechanisms underlying age-related changes in dermal fibroblasts and their implications for skin wound healing. The significant reduction in LincRNA-EPS expression in aged dermal fibroblasts and its ability to induce CCND1 expression and enhance cell proliferation highlight its potential as a therapeutic target for addressing age-related skin wound healing.
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Proliferación Celular , Ciclina D1 , Fibroblastos , ARN Largo no Codificante , Ciclina D1/metabolismo , Ciclina D1/genética , Fibroblastos/metabolismo , Fibroblastos/citología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Ratones , Piel/metabolismo , Piel/citología , MicroARNs/genética , MicroARNs/metabolismo , Células Cultivadas , Envejecimiento de la Piel/genética , Dermis/citología , Dermis/metabolismo , Senescencia Celular/genética , Regulación de la Expresión Génica , Cicatrización de Heridas/genética , Envejecimiento/genéticaRESUMEN
The aim of this study was to investigate the effects of polyphyllin â ¦ (PP â ¦) on proliferation, apoptosis, and cell cycle of diffuse large B-cell lymphoma (PLBCL) cell lines U2932 and SUDHL-4. The DLBCL cell lines were divided into a control group and a PPâ ¦ group, and experiments were conducted using MTT assay, flow cytometry, and Western blotting.Results showed that compared with the control group, PPâ ¦ significantly inhibited the proliferation of U2932 and SUDHL-4 cells (P<0.05). Apoptosis assays demonstrated that treatment with 0.50 and 1.00 µmol/L PP â ¦ significantly increased the apoptosis rates of both cell lines (P<0.05), upregulated apoptosis-related proteins, and downregulated Bcl-2 protein level (P<0.05). Cell cycle analysis revealed that PPâ ¦ treatment led to an increase in G0/G1-phase cells (P<0.05) and a decrease in G2/M-phase cells (P<0.05), significantly downregulated cyclin D1, CDK4, CDK6, and survivin protein expression (P<0.05). In conclusion, PPâ ¦ exerted anti-lymphoma effects by inhibiting proliferation, promoting apoptosis, and inducing G0/G1 phase arrest in DLBCL cells.
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Apoptosis , Ciclo Celular , Proliferación Celular , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclo Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Diosgenina/farmacología , Diosgenina/análogos & derivados , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismoRESUMEN
Cleft palate is the most common facial birth defect worldwide. It is caused by environmental factors or genetic mutations. Environmental factors such as pharmaceutical exposure in women are known to induce cleft palate. The aim of the present study was to investigate the protective effect of Sasa veitchii extract against medicine-induced inhibition of proliferation of human embryonic palatal mesenchymal cells. We demonstrated that all-trans-retinoic acid inhibited human embryonic palatal mesenchymal cell proliferation in a dose-dependent manner, whereas dexamethasone treatment had no effect on cell proliferation. Cotreatment with Sasa veitchii extract repressed all-trans-retinoic acid-induced toxicity in human embryonic palatal mesenchymal cells. We found that cotreatment with Sasa veitchii extract protected all-trans-retinoic acid-induced cyclin D1 downregulation in human embryonic palatal mesenchymal cells. Furthermore, Sasa veitchii extract suppressed all-trans-retinoic acid-induced miR-4680-3p expression. Additionally, the expression levels of the genes that function downstream of the target genes ( ERBB2 and JADE1 ) of miR-4680-3p in signaling pathways were enhanced by cotreatment with Sasa veitchii extract and all-trans-retinoic acid compared to all-trans-retinoic acid treatment. These results suggest that Sasa veitchii extract suppresses all-trans-retinoic acid-induced inhibition of cell proliferation via modulation of miR-4680-3p expression.
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Proliferación Celular , Fisura del Paladar , Hueso Paladar , Extractos Vegetales , Tretinoina , Humanos , Tretinoina/farmacología , Proliferación Celular/efectos de los fármacos , Hueso Paladar/efectos de los fármacos , Hueso Paladar/embriología , Hueso Paladar/citología , Extractos Vegetales/farmacología , MicroARNs/metabolismo , MicroARNs/genética , MicroARNs/efectos de los fármacos , Ciclina D1/metabolismo , Ciclina D1/genética , Células Cultivadas , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Objective: To explore the effects of hinokiol on the cell cyle and apoptosis of CNE1 nasopharyngeal carcinoma cells and the relevant molecular mechanism. Methods: The CNE1 cells were cultured in vitro and incubated with different concentrations of honokiol, and the cells were divided into blank control group, 10 µmol/L, 20 µmol/L and 40 µmol/L hinokiol treatment groups, and 10 µg/ml cisplatin group. Cell viability was determined by methylthiazolyldiphenyl- tetrazolium bromide (MTT) method, the cell cycle distribution was detected by flow cytometry, mitochondrial membrane potential was detected by mitochondrial membrane potential test kit, apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method, and the proteins expression of proliferating cell nuclear antigen (PCNA) and G1/S specific cyclin D1 (cyclin D1) were detected by immunoblotting. RNA-Seq was conducted in the hinokiol-treated cells. The mRNA expression of yes-associated protein delta (YAP) was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The proteins expression of phosphor-YAP (p-YAP) and nuclear YAP were detected by immunoblotting, the nuclear distribution of YAP protein was detected by immunofluorescence in the cells with or without treated with the mammalian STE20-like kinase 1/2 (MST1/2) inhibitor (XMU-MP-1), hinokiol, and XMU-MP-1+hinokiol. Statistical analysis of the data was conducted using GraphPad Prism 8.0 software. Resluts Compared with the control group, the cell viablity of CNE1 cells, the levels of mitochondrial membrane potential, the proteins expression of PCNA and cyclin D1 in hinokiol treatment groups were markedly decreased (all P values<0.05), while the proportion of G0/G1 phase cells and the ratio of TUNEL-positive cells were significantly increased (both P values<0.05). Transcriptome analysis showed that differential genes were mainly enriched in Wnt signaling pathway, tumor necrosis factor pathway, and Hippo signaling pathway. The mRNA level of YAP and the protein expression of YAP in the nucleus were decreased and the level of p-YAP protein was increased in cells treated with hinokiol, which were significantly different from control group (all P values<0.05). Compared with the hinokiol group, XMU-MP-1+hinokiol groups showed the decrease of p-YAP protein expression (1.157±0.076 vs 0.479±0.038, t=37.120, P<0.05), the increase of YAP protein expression in the nucleus (0.143±0.012 vs 0.425±0.031, t=29.181, P<0.05), the reduced proportion of cells in G0/G1 phase [(72.494±3.309)% vs (58.747±2.865)%, t=17.265, P<0.05], and the decrease of apoptosis ratio [(53.158±3.376)% vs (29.621±2.713)%, t=28.584, P<0.05]. Conclusion: Hinokiol can arrest the cell cycle and induce the cell apoptosis of CNE1 cells via Hippo/YAP signaling pathway.
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Apoptosis , Compuestos de Bifenilo , Ciclo Celular , Vía de Señalización Hippo , Lignanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Transducción de Señal , Humanos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Carcinoma Nasofaríngeo/metabolismo , Ciclo Celular/efectos de los fármacos , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Lignanos/farmacología , Compuestos de Bifenilo/farmacología , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP , Proteínas Serina-Treonina Quinasas/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclina D1/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismoRESUMEN
BACKGROUND/AIM: Although photobiomodulation therapy (PBMt) is available to alleviate post-operative side effects of malignant diseases, its application is still controversial due to some potential of cancer recurrence and occurrence of a secondary malignancy. We investigated effect of PBMt on mitochondrial function in HT29 colon cancer cells. METHODS: HT29 cell proliferation was determined with MTT assay after PBMt. Immunofluorescent staining was performed to determine mitochondrial biogenesis and reactive oxygen species (ROS). Mitochondrial membrane potential was measured with Mitotracker. Western blotting was executed to determine expression of fission, fusion, UCP2, and cyclin B1 and D1 proteins. In vivo study was performed by subcutaneously inoculating cancer cells into nude mice and immunohistochemistry was done to determine expression of FIS1, MFN2, UCP2, and p-AKT. RESULTS: The proliferation and migration of HT29 cells reached maximum with PBMt (670 nm, light emitting diode, LED) at 2.0 J/cm2 compared to control (P < 0.05) with more expression of cyclin B1 and cyclin D1 (P < 0.05). Immunofluorescent staining showed that ROS and mitochondrial membrane potential were enhanced after PBMt compared to control. ATP synthesis of mitochondria was also higher in the PBMt group than in the control (P < 0.05). Expression levels of fission and fusion proteins were significantly increased in the PBMt group than in the control (P < 0.05). Electron microscopy revealed that the percentage of mitochondria showing fission was not significantly different between the two groups. Oncometabolites including D-2-hydoxyglutamate in the supernatant of cell culture were higher in the PBMt group than in the control with increased UCP2 expression (P < 0.05). Both tumor size and weight of xenograft in nude mice model were bigger and heavier in the PBMt group than in the control (P < 0.05). Immunohistologically, mitochondrial biogenesis proteins UCP2 and p-AKT in xenograft of nude mice were expressed more in the PBMt group than in the control (P < 0.05). CONCLUSIONS: Treatment with PBM using red light LED may induce proliferation and progression of HT29 cancer cells by increasing mitochondrial activity and fission.
Asunto(s)
Proliferación Celular , Neoplasias del Colon , Potencial de la Membrana Mitocondrial , Ratones Desnudos , Mitocondrias , Especies Reactivas de Oxígeno , Humanos , Células HT29 , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Animales , Proliferación Celular/efectos de la radiación , Ratones , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Neoplasias del Colon/metabolismo , Potencial de la Membrana Mitocondrial/efectos de la radiación , Terapia por Luz de Baja Intensidad , Movimiento Celular/efectos de la radiación , Ciclina B1/metabolismo , Dinámicas Mitocondriales/efectos de la radiación , Ciclina D1/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Cancer neuroscience is an emerging field of cancer biology focused on defining the interactions and relationships between the nervous system, developing malignancies, and their environments. Our previous work demonstrates that small extracellular vesicles (sEVs) released by head and neck squamous cell carcinomas (HNSCCs) recruit loco-regional nerves to the tumor. sEVs contain a diverse collection of biological cargo, including microRNAs (miRNAs). Here, we asked whether two genes commonly amplified in HNSCC, CCND1, and PIK3CA, impact the sEV miRNA cargo and, subsequently, sEV-mediated tumor innervation. To test this, we individually overexpressed these genes in a syngeneic murine HNSCC cell line, purified their sEVs, and tested their neurite outgrowth activity on dorsal root ganglia (DRG) neurons in vitro. sEVs purified from Ccnd1-overexpressing cells significantly increased neurite outgrowth of DRG compared to sEVs from parental or Pik3ca over-expressing cells. When implanted into C57BL/6 mice, Ccnd1 over-expressing tumor cells promoted significantly more tumor innervation in vivo. qPCR analysis of sEVs shows that increased expression of Ccnd1 altered the packaging of miRNAs (miR-15-5p, miR-17-5p, and miR-21-5p), many of which target transcripts important in regulating axonogenesis. These data indicate that genetic amplifications harbored by malignancies impose changes in sEV miRNA cargo, which can influence tumorc innervation.
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Fosfatidilinositol 3-Quinasa Clase I , Vesículas Extracelulares , Neoplasias de Cabeza y Cuello , Ratones Endogámicos C57BL , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Ratones , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Línea Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Ganglios Espinales/metabolismo , Humanos , Amplificación de Genes , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
Thyroid cancer (TC) is one of the most common endocrine malignancies worldwide. Increasing evidence suggests that vitamin D (VD) has potential benefits in the treatment of TC. However, evidence regarding the targets and molecular mechanisms of VD in TC remains limited. In this study, we conducted network pharmacology, molecular docking, and experimental evaluation to explore the target genes, biological functions, and signaling pathways involved in this process. Network analysis revealed 77 potential target genes of VD against TC, and four hub target genes were identified: ESR1, KIT, CCND1, and PGR. Furthermore, we identified the biological processes (BP) and signaling pathways involving these potential target genes, and then determined the possible interaction between the hub targets and VD through molecular docking. Finally, through in vitro experiments, we found that VD effectively inhibits the proliferation of TC cells and downregulates the expression of the ESR1 gene. In conclusion, the effects of VD against TC involve multiple biological targets, BP, and signaling pathways. These findings provide scientific evidence for the application of VD in the treatment of TC.
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Proliferación Celular , Simulación del Acoplamiento Molecular , Transducción de Señal , Neoplasias de la Tiroides , Vitamina D , Humanos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Vitamina D/farmacología , Vitamina D/metabolismo , Vitamina D/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Farmacología en Red , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Ciclina D1/metabolismo , Ciclina D1/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
This study investigated the regulatory impact of Toll-like receptor 4 (TLR4) gene on glioma cell proliferation and apoptosis, elucidating the molecular mechanisms underlying TLR4-induced growth inhibition in vivo. U-87MG-Sh and U-87MG-NC cells, with silenced TLR4 and negative control plasmid respectively, were established. Eighteen nude mice, divided into transfection, negative control, and blank control groups, were inoculated with corresponding cells. Over four weeks, the transfection group exhibited significantly reduced tumor growth rates, smaller mass and volume, and lower growth activity compared to controls. Histological analysis revealed sparse tumor cells, increased fibrous connective tissue, and slower angiogenesis in the transfection group. Flow cytometry demonstrated a lower proliferation index and increased G0/1 cell count in the transfection group. mRNA levels of TLR4, NF-κB, and CyclinD1 were significantly lower in the transfection group. TLR4 silencing correlated with U-87MG cell proliferation regulation, growth inhibition, NF-κB and CyclinD1 modulation, and induction of cell cycle arrest and apoptosis. These findings suggest TLR4 as a potential gene therapy target for glioma.
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Apoptosis , Proliferación Celular , Ciclina D1 , Silenciador del Gen , Glioma , Ratones Desnudos , FN-kappa B , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Glioma/patología , Glioma/genética , Glioma/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Apoptosis/genética , Humanos , FN-kappa B/metabolismo , Ciclina D1/metabolismo , Ciclina D1/genética , Ratones , Puntos de Control del Ciclo Celular/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB CRESUMEN
Quadruple-hit lymphomas are extremely rare non-Hodgkin lymphomas with a reported dismal prognosis in the few reported cases. A "quadruple hit" has been defined by the presence of concurrent MYC, BCL2, BCL6, and CCND1 chromosomal rearrangements. We report a new case of a quadruple hit lymphoma in a 73-year-old Hispanic man who presented with an enlarging left-sided neck mass. Computed tomography showed a 1.9-cm mass in left the tonsil with bulky cervical lymphadenopathy. The presence of all four chromosomal rearrangements can reportedly occur with disease progression in both diffuse large B-cell lymphomas and mantle cell lymphomas. Further characterization of the tumor by next-generation sequencing may be of benefit to delineate between these two possibilities. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing were used to confirm and classify the diagnosis. Histologic sections of the cervical lymph node demonstrated an atypical lymphoid infiltrate with large and pleomorphic cells, which were positive for CD20, CD10, BCL1 (Cyclin D1), BCL2, BCL6, and cMYC and negative for CD5 and SOX11 on immunohistochemistry with a Ki-67 proliferative index of 70%. FISH demonstrated MYC, BCL2, BCL6, and CCND1 rearrangements and the diagnosis of high-grade B-cell lymphoma with MYC, BCL2, BCL6, and CCND1 was rendered. Our patient was treated with dose adjusted etoposide, doxorubicin, cyclophosphamide, prednisone, and rituximab chemotherapy and has been in remission for 20 months.
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Ciclina D1 , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-bcl-6 , Humanos , Masculino , Proteínas Proto-Oncogénicas c-bcl-6/genética , Anciano , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Reordenamiento Génico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B/diagnóstico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/uso terapéutico , Prednisona/uso terapéutico , Clasificación del Tumor , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Rituximab/uso terapéutico , Hibridación Fluorescente in Situ , Etopósido/uso terapéutico , Etopósido/administración & dosificaciónRESUMEN
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, for which targeted therapy regimens are lacking. The traditional Chinese medicine Menispermum dauricum DC (M. dauricum) and its compounds have been reported to have antitumor activity against various cancers; however, their anti-TNBC activity is unknown. In this work, dauricine and N-desmethyldauricine from M. dauricum were separated and identified to have anti-TNBC via a multi-component bioactivity and structure-guided method. The cell counting kit 8 assay showed that dauricine and N-desmethyldauricine inhibited the proliferation of four tested TNBC cell lines, with half maximal inhibitory concentration values ranging from 5.01 µM to 13.16 µM. Further research suggested that N-desmethyldauricine induced cell apoptosis, arrested cell cycle progression in the G0/G1 phase, and inhibited cell migration. Western blot analysis revealed that the proapoptotic protein cleaved-poly-ADP-ribose polymerase 1 was upregulated, and the G0/G1 phase-related proteins cyclin-dependent kinase 2 and cyclin D1 and the migration-related protein matrix metallopeptidase 9 were downregulated. Furthermore, N-desmethyldauricine decreased the protein expression of p65, an important subunit of nuclear factor kappa-beta (NF-κB). Moreover, an antiproliferation assay of three-dimensional (3D) tumor spheroids showed that N-desmethyldauricine diminished cellâcell adhesion and suppressed the growth of TNBC 3D spheroids. Taken together, these findings indicate that N-desmethyldauricine inhibited the proliferation of TNBC cells and decreased the expression of p65 in the NF-κB pathway.
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Apoptosis , Bencilisoquinolinas , Proliferación Celular , Regulación hacia Abajo , Menispermum , FN-kappa B , Transducción de Señal , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/química , Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Menispermum/química , Movimiento Celular/efectos de los fármacos , Femenino , Ciclina D1/metabolismo , TetrahidroisoquinolinasRESUMEN
OBJECTIVE: Molecular docking is a key tool in structural molecular biology and computer-assisted drug design. Oral carcinogenesis is a complex, multistep process in which genetic events within signal transduction pathways governing normal cellular physiology are quantitatively or qualitatively altered. There are various molecular targets like Cyclin D and PI3k- alpha Ras Binding Domain receptor protein involved in the pathogenesis of Oral Squamous Cell Carcinoma. The aim of the study is to demonstrate the computer aided drug design to identify a potent natural molecule for targeting cyclin D4 and PI3K RAS binding protein. MATERIALS AND METHODS: Target selection (Cyclin D1 and PI3K-alpha Ras Binding Domain receptor) was done and structures were derived from protein data bank. Ligands (Apigenin, Chrysoeriol and Luteolin) selection was done and structure derived. Final docking was performed by Autodock. RESULTS: From the docking results it can be seen that luteolin has the highest binding energy (-5.45) with the Cyclin D receptor molecule followed by Chrysoeriol (-4.99) and Apigenin (-4.96). The binding energies of the ligands against PI3K-alpha Ras Binding Domain receptors were Apigenin (-4.51), Chrysoeriol (-4.6) and Luteolin (-4.56). CONCLUSION: The study concludes that all the three selected ligands possess high binding energy with both the target proteins involved in carcinogenesis with highest binding energy possessed by Luteolin against the Cyclin D receptor and by Chrysoeriol against PI3K-RAS binding protein. Thus their activity can be utilized to derive potential Anti-cancer therapeutic drugs.