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INTRODUCTION: Developing effective methods to enhance tumor radiosensitivity is crucial for improving the therapeutic efficacy of radiotherapy (RT). Due to its deep tissue penetration, excellent safety profile, and precise controllability, sonosensitizer- based sonodynamic therapy (SDT) has recently garnered significant attention as a promising combined approach with RT. METHOD: However, the limited reactive oxygen species (ROS) generation ability in the aggregated state and the absence of specific organelle targeting in sonosensitizers hinder their potential to augment RT. This study introduces a fundamental principle guiding the design of high-performance sonosensitizers employed in the aggregated state. Building upon these principles, we develop a mitochondria-targeted sonosensitizer molecule (TCSVP) with aggregation-induced emission (AIE) characteristics by organic synthesis. Then, we demonstrate the abilities of TCSVP to target mitochondria and produce ROS under ultrasound in H460 cancer cells using confocal laser scanning microscopy (CLSM) and fluorescence microscopy. Subsequently, we examine the effectiveness of enhancing tumor radiosensitivity by utilizing TCSVP and ultrasound in both H460 cells and H460 and 4T1 tumor-bearing mice. RESULTS: The results indicate that evoking non-lethal mitochondrial oxidative stress in tumors by TCSVP under ultrasound stimulation can significantly improve tumor radiosensitivity (p <0.05). Additionally, the in vivo safety profile of TCSVP is thoroughly confirmed by histopathological analysis. CONCLUSION: This work proposes strategies for designing efficient sonosensitizers and underscores that evoking non-lethal mitochondrial oxidative stress is an effective method to enhance tumor radiosensitivity.
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BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.
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Resistencia a Antineoplásicos , Indoles , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Sulfonamidas , Neoplasias de la Tiroides , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Humanos , Animales , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Indoles/farmacología , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sulfonamidas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Sorafenib/farmacología , Quinolinas/farmacología , Mutación , Antígenos/metabolismo , Proteoglicanos/metabolismo , Proteínas de la Membrana , Proteoglicanos Tipo Condroitín SulfatoRESUMEN
PURPOSE: The role of dual-specificity phosphatase-5 (DUSP5) in BRAF-mutant thyroid cancers remains unclear. The aims of this study are to investigate the role of DUSP5 in BRAF-mutant thyroid cancer cells, explore its value in the diagnosis and evaluate therapeutic potential of targeting DUSP5 combined with sorafenib for BRAF-mutant thyroid cancer patients. METHODS: The role of DUSP5 in thyroid cancer cells was determined by a series of in vitro and in vivo experiments. Underlying mechanisms were explored by western blotting analysis. The diagnostic value of combination detection of DUSP5 expression and BRAFV600E mutation was evaluated using ROC curve. RESULTS: Knocking down DUSP5 in BRAF-mutant thyroid cancer cells significantly inhibited colony formation, cell migration and invasion, meanwhile, induced cell cycle arrest and cell apoptosis. Moreover, inhibition of DUSP5 improved the anti-tumor efficacy of sorafenib both in vitro and in vivo. Besides, combination detection of DUSP5 expression and BRAFV600E mutation showed much more accuracy in preoperative diagnosis of thyroid cancer. CONCLUSIONS: Our data demonstrate an oncogenic role of DUSP5 in BRAF-mutant thyroid cancer cells, and combined analysis of its expression and BRAFV600E mutation can accurately diagnose thyroid cancer. In addition, inhibition of DUSP5 improves the response of BRAF-mutant thyroid cancer cells to sorafenib.
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Antineoplásicos , Proteínas Proto-Oncogénicas B-raf , Sorafenib , Neoplasias de la Tiroides , Sorafenib/farmacología , Sorafenib/uso terapéutico , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Animales , Mutación , Femenino , Masculino , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones , Persona de Mediana Edad , Proliferación Celular/efectos de los fármacos , FenotipoRESUMEN
Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/patología , Neoplasias Encefálicas/genética , Transformación Celular Neoplásica/genética , Oncogenes , Biomarcadores , Proliferación Celular , Proteína Elk-1 con Dominio ets/genética , ADN Helicasas/genéticaRESUMEN
Triple-negative breast cancer (TNBC) represents 10-20 % of all breast cancer (BC) cases and is characterized by poor prognosis. Given the urgent need to improve prognostication and develop specific therapies for TNBC, the identification of new molecular targets is of great importance. MicroRNA (miRNA) has been reported as a valuable and novel molecular target in the progression of TNBC. However, the expression and function of miRNAs in different tumors are heterogeneous. Herein, we first analyzed miRNA data from The Cancer Genome Atlas (TCGA) and surprisedly found that overexpressed miRNAs were associated with poor survival in all breast cancer patients, but the overexpressed miRNAs were associated with better survival in TNBC patients. Based on the heterogeneity of miRNA expression in TNBC, we conducted further analysis using univariate Cox proportional hazard regression models and identified 17 miRNAs with prognostic potential. Subsequently, a multivariate Cox model was employed to create a 3-miRNA prognostic model for predicting overall survival in TNBC patients. The diagnostic model exhibited an area under the curve (AUC) of 0.727, and multivariable Cox regression indicated that each covariate was associated with survival. These data indicate that this model is relatively accurate and robust for risk assessment, which have a certain value for clinical application. In order to explore the network behind the overexpressed miRNAs in TNBC, we established a novel network consisting of lncRNAs, miRNAs, and mRNAs through complete transcriptome data from matched samples in the TCGA database. In this network, IRS-1 appeared to be the top hub gene. Experimental results demonstrated that miR-15b-5p and miR-148a-3p effectively target IRS-1 in vitro, shedding light on the intricate regulatory mechanisms in TNBC mediated by the heterogeneous miRNAs. Besides, miR-148a-3p significantly inhibited cell migration and viability. Overall, this study may add valuable insights into the molecular landscape of TNBC based on miRNAs and have the potential to contribute to the development of targeted therapies and improved prognostic strategies of TNBC.
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MicroARNs , ARN Largo no Codificante , Neoplasias de la Mama Triple Negativas , Humanos , MicroARNs/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , ARN Largo no Codificante/genética , Pronóstico , ARN Mensajero/genética , Detección Precoz del Cáncer , Regulación Neoplásica de la Expresión Génica/genética , Biomarcadores de Tumor/genéticaRESUMEN
STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we found that STAG2 was frequently down-regulated in thyroid cancers compared with control subjects. By a series of in vitro and in vivo studies, we demonstrated that STAG2 knockdown virtually had no effect on malignant phenotypes of BRAF-mutant thyroid cancer cells such as cell proliferation, colony formation and tumorigenic ability in nude mice compared with the control. In addition, unlike melanoma, STAG2 knockdown also did not affect the sensitivity of these cells to MEK inhibitor. However, we surprisingly found that STAG2-knockdown cells exhibited more sensitive to glutamine deprivation or glutaminase inhibitor BPTES compared with control cells. Mechanistically, knocking down STAG2 in BRAF-mutant thyroid cancer cells decreases the protein stability of c-Myc via the ERK/AKT/GSK3ß feedback pathway, thereby impairing glutamine metabolism of thyroid cancer cells by down-regulating its downstream targets such as SCL1A5, GLS and GLS2. Our data, taken together, demonstrate that STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells, thereby improving their cellular response to glutaminase inhibitor. This study will provide a potential therapeutic strategy for BRAF-mutant thyroid cancers.
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Proteínas Proto-Oncogénicas B-raf , Neoplasias de la Tiroides , Animales , Humanos , Ratones , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Glutaminasa/metabolismo , Glutamina/genética , Melanoma/patología , Ratones Desnudos , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/genéticaRESUMEN
BRAFV600E mutation is one of the most therapeutic targets in thyroid cancers. However, its specific inhibitors have shown little clinical benefit because they can reactivate the MAPK/ERK and PI3K/AKT pathways by feedback upregulating the transcription of HER3. Peptidyl-prolyl cis/trans isomerase Pin1 has been proven to be closely associated with tumor progression. Here, we aimed to determine antitumor activity of Pin1 inhibitor API-1 in thyroid cancer and its effect on cellular response to BRAF inhibitors. The results showed that API-1 exhibited strong antitumor activity against thyroid cancer. Meanwhile, it improved the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4032 and there was a synergistic effect between them. Specially, a combination therapy of API-1 and PLX4032 significantly inhibited cell proliferation, colony formation, and the growth of xenograft tumors as well as induced cell apoptosis in BRAF-mutant thyroid cancer cells compared with API-1 or PLX4032 monotherapy. Similar results were also observed in transgenic mice with BrafV600E-driven thyroid cancer. Mechanistically, API-1 enhanced XPO5 ability to export pre-microRNA 20a (pre-miR-20a) from the nucleus to cytoplasm, thereby promoting the maturation of miR-20a-5p. Further studies showed that miR-20a-5p specifically targeted and down-regulated HER3, thereby blocking the reactivation of MAPK/ERK and PI3K/AKT signaling pathways caused by PLX4032. These results, taken together, demonstrate that Pin1 inhibitor API-1 significantly improves the sensitivity of BRAF-mutant thyroid cancer cells to PLX4032. Thus, this study not only determines the potential antitumor activity of Pin1 inhibitor API-1 in thyroid cancer but also offers an alternative therapeutic strategy for BRAF-mutant thyroid cancers by a combination of Pin1 inhibitor and BRAF kinase inhibitor.
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MicroARNs , Neoplasias de la Tiroides , Humanos , Ratones , Animales , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sulfonamidas/farmacología , Retroalimentación , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Línea Celular Tumoral , Mutación , CarioferinasRESUMEN
Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn2+); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression.
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Neoplasias Gástricas , Animales , Ratones , Quinasa de la Caseína II/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Sistema de Señalización de MAP Quinasas , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Zinc/metabolismo , HumanosRESUMEN
Background: Thyrotropin receptor (TSHR) plays a central role in maintaining thyroid function and TSHR impairment causes hypothyroidism, which is often associated with metabolic disarrangement. The most common type of hypothyroidism is autoimmune disease-related and the mechanism, particularly with respect to the role of microRNAs (miRNAs), has not been delineated. Methods: Serum from 30 patients with subclinical hypothyroidism (SCH) and 30 healthy individuals were collected and exosomal miR-146a (exo-miR-146a) was examined, followed by extensive mechanistic investigation using various molecular and cellular experimental approaches and genetic-knockout mouse models. Results: Our clinical investigation showed that exo-miR-146a was systemically elevated in the serum of patients with SCH (p = 0.04) compared with healthy individuals, prompting us to investigate the biological effects of miR-146a in cells. We found that miR-146a could target and down-regulate neuron-glial antigen 2 (Ng2), with consequent down-regulation of TSHR. We next generated a thyroid-specific Ng2 knockout (Thy-Ng2-/-) mouse model and found a significant down-regulation of TSHR in Thy-Ng2-/- mice, accompanied by the development of hypothyroidism and metabolic disorders. We further found that a decrease in NG2 resulted in decreased receptor tyrosine kinase-linked downstream signaling and down-regulation of c-Myc, consequently resulting in up-regulation of miR-142 and miR-146a in thyroid cells. Up-regulated miR-142 targeted the 3'-untranslated region (UTR) of TSHR messenger RNA (mRNA) and post-transcriptionally down-regulated TSHR, explaining the development of hypothyroidism above. Local up-regulation of miR-146a in thyroid cells augments the earlier cited processes initiated by systemically elevated miR-146a, thereby forming a feedback loop to propel the development and progression of hypothyroidism. Conclusions: This study has uncovered a self-augmenting molecular loop initiated by elevated exo-miR-146a to suppress TSHR through targeting and down-regulating NG2, thereby initiating and propelling the development and progression of hypothyroidism.
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Hipotiroidismo , MicroARNs , Animales , Ratones , Retroalimentación , Hipotiroidismo/genética , MicroARNs/genética , MicroARNs/metabolismo , Receptores de Tirotropina/genéticaRESUMEN
The classical oxidizing enzymatic activity of Ten Eleven Translocation 1 (TET1) and its tumor suppressor role are well known. Here, we find that high TET1 expression is associated with poor patient survival in solid cancers often having hypoxia, which is inconsistent with its tumor suppressor role. Through a series of in vitro and in vivo studies, using thyroid cancer as a model, we demonstrate that TET1 plays a tumor suppressor function in normoxia and, surprisingly, an oncogenic function in hypoxia. Mechanistically, TET1 mediates HIF1α-p300 interaction by acting as a co-activator of HIF1α to promote CK2B transcription under hypoxia, which is independent of its enzymatic activity; CK2 activates the AKT/GSK3ß signaling pathway to promote oncogenesis. Activated AKT/GSK3ß signaling in turn maintains HIF1α at elevated levels by preventing its K48-linked ubiquitination and degradation, creating a feedback loop to enhance the oncogenicity of TET1 in hypoxia. Thus, this study uncovers a novel oncogenic mechanism in which TET1 promotes oncogenesis and cancer progression through a non-enzymatic interaction between TET1 and HIF1α in hypoxia, providing novel therapeutic targeting implications for cancer.
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Carcinogénesis , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas , Humanos , Carcinogénesis/genética , Hipoxia de la Célula/genética , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipoxia/genética , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BRAFV600E, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Vemurafenib (PLX4032), a specific inhibitor of BRAFV600E kinase, exhibits antitumor activity in patients with BRAFV600E-mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to BRAF kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on BRAFV600E-mutated thyroid cancer cells and its effect on the response of these cells to BRAF kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRAFV600E-mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/AKT signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of BRAFV600E-mutated thyroid cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for BRAFV600E-mutated thyroid cancers.
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Proteínas Proto-Oncogénicas B-raf , Neoplasias de la Tiroides , Humanos , Vemurafenib/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Disulfiram/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Especies Reactivas de Oxígeno , Sulfonamidas/farmacología , Indoles/farmacología , Retroalimentación , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias de la Tiroides/patología , Línea Celular TumoralRESUMEN
Accumulating evidence supports evolutionary trait of drug resistance. Like resilience in other systems, most tumor cells experience drug-tolerant state before full resistance acquired. However, the underlying mechanism is still poorly understood. Here, we identify that EGF like domain multiple 7 (EGFL7) is a responsive gene to epidermal growth factor receptor (EGFR) kinase inhibition during a period when tumors are decimated. Moreover, our data reveal that the adaptive increase of EGFL7 during this process is controlled by the depression of nonsense-mediated mRNA decay (NMD) pathway. Upregulation of EGFL7 activates NOTCH signaling in lung cancer cells, which slows down the decrease of c-Myc caused by EGFR inhibition, thereby helping the survival of cancer cells. Our data, taken together, demonstrate that EGFL7 is a driver gene for resistance to EGFR kinase inhibition, and suggest that targeting EGFL7/NOTCH signaling may improve the clinical benefits of EGFR inhibitors in patients with EGFR mutant tumors.
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Factores de Crecimiento Endotelial , Neoplasias Pulmonares , Humanos , Familia de Proteínas EGF/metabolismo , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Proteínas de Unión al Calcio , Receptores ErbB/metabolismo , Factores de Transcripción/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Resistencia a Antineoplásicos/genética , Línea Celular TumoralRESUMEN
Background: Metastatic disease is a major cause of thyroid cancer-related death. However, the mechanisms responsible for thyroid cancer metastasis are unclear. Dipeptidyl peptidase-4 (DPP4) is a multifunctional cell surface glycoprotein that has been reported to be a negative prognostic factor in thyroid cancer. We explored the molecular mechanism of the role of DPP4 in thyroid cancer cell metastasis. Methods: The effects of DPP4 on thyroid cancer cell migration/invasion in vitro were assessed by transwell assays. A lung metastatic mouse model was also established to determine the effect of DPP4 on tumor metastasis in vivo. DPP4 inhibitor sitagliptin was used to test its effect on thyroid cancer cell metastasis. The mechanism of which DPP4 promotes thyroid cancer cell metastasis was explored by a series of molecular and biochemical experiments. Results: We observed that DPP4 was significantly upregulated in papillary thyroid cancers compared with control subjects, and its expression was positively associated with lymph node metastasis and BRAFV600E mutation. Functional studies showed that DPP4 knockdown significantly inhibited metastatic potential of thyroid cancer cells, and vice versa. However, DPP4 inhibitor sitagliptin did not affect the metastatic ability of thyroid cancer cells, indicating that the promoting effect of DPP4 on tumor metastasis was independent of its enzymatic activity. Mechanistically, DPP4 interacted with the α4 and ß1 integrin subunits, and stabilized the formation of integrin α4ß1 complex. DPP4-mediated integrin signal activation promoted the nuclear localization of c-Jun through the FAK/AKT pathway, thereby inducing the transcription of transforming growth factor-beta 1 (TGFB1 coding for protein TGF-ß1). TGF-ß1 then facilitated tumor metastasis by inducing the epithelial-mesenchymal transition. Conclusions: DPP4 promotes thyroid cancer cell metastasis through the integrins/FAK/AKT/c-Jun/TGF-ß1 signaling axis. These findings may have implications for an alternative therapeutic strategy for thyroid cancer.
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Inhibidores de la Dipeptidil-Peptidasa IV , Neoplasias de la Tiroides , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/farmacología , Integrina alfa4beta1 , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Transición Epitelial-Mesenquimal , Movimiento Celular , Fosfato de Sitagliptina/farmacología , Transducción de Señal , Factores de Crecimiento Transformadores/farmacología , Línea Celular TumoralRESUMEN
Breast cancer is the most common female tumors arising worldwide, and genetic and epigenetic events are constantly accumulated in breast tumorigenesis. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel, mainly maintaining Zn2+, Ca2+ and Mg2+ homeostasis. It is also involved in regulating proliferation and migration in various cancers including breast cancer. However, epigenetic alterations (such as promoter methylation) of TRPM7 and their correlation with clinical outcomes in breast cancer patients remain largely unclear. In this study, we found that TRPM7 was highly expressed in the luminal A subtype of breast cancers but no other subtypes compared with GTEx (Genotype-Tissue Expression Rad) or normal samples by analyzing the TCGA database. Correspondingly, TRPM7 was methylated in 42.7% (93 of 219) of breast cancers. Further studies found that promoter methylation of TRPM7 were significantly associated with better clinical outcomes in breast cancer patients, especially in the Luminal A subtype. Besides, methylated TRPM7 was correlated with less number of metastatic lymph nodes and longer local failure free survival time in this subtype. In summary, our data indicate that promoter methylation of TRPM7 may predict poor prognosis in patients with luminal A breast cancer.
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Neoplasias de la Mama , Canales Catiónicos TRPM , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Metilación de ADN , Femenino , Humanos , Pronóstico , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/genética , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismoRESUMEN
RAD21 plays multiple roles in numerous cancers. In breast cancer (BC), a high level of RAD21 correlates with poor disease outcomes and resistance to chemotherapy. However, data regarding RAD21 promoter methylation in BC tissue and its correlation with clinical outcomes in patients with BC remain limited. Here, we investigated the clinicopathological features associated with the methylation status of RAD21 in BC to figure out its possible role in pathogenesis and the formation of breast carcinogenesis. The methylation status of the RAD21 gene was significantly associated with better clinical outcomes in patients with BC.
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Neoplasias de la Mama , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona , Metilación de ADN , Proteínas de Unión al ADN/genética , Femenino , Humanos , Pronóstico , Regiones Promotoras Genéticas , CohesinasRESUMEN
BACKGROUND: Mannose, a natural hexose existing in daily food, has been demonstrated to preferentially inhibit the progression of tumors with low expression of phosphate mannose isomerase (PMI). However, its function in thyroid cancer still remains elusive. METHODS: MTT, colony formation and flow cytometry assays were performed to determine the response of thyroid cancer cells to mannose. Meanwhile, mouse models of subcutaneous xenograft and primary papillary thyroid cancer were established to determine in vivo anti-tumor activity of mannose. The underlying mechanism of mannose selectively killing thyroid cancer cells was clarified by a series of molecular and biochemical experiments. RESULTS: Our data demonstrated that mannose selectively suppressed the growth of thyroid cancer cells, and found that enzyme activity of PMI rather than its protein expression was negatively associated with the response of thyroid cancer cells to mannose. Besides, our data showed that zinc ion (Zn2+) chelator TPEN clearly increased the response of mannose-insensitive cells to mannose by inhibiting enzyme activity of PMI, while Zn2+ supplement could effectively reverse this effect. Further studies found that the expression of zinc transport protein ZIP10, which transport Zn2+ from extracellular area into cells, was negatively related to the response of thyroid cancer cells to mannose. Knocking down ZIP10 in mannose-insensitive cells significantly inhibited in vitro and in vivo growth of these cells by decreasing intracellular Zn2+ concentration and enzyme activity of PMI. Moreover, ectopic expression of ZIP10 in mannose-sensitive cells decrease their cellular response to mannose. Mechanistically, mannose exerted its anti-tumor effect by inhibiting cellular glycolysis; however, this effect was highly dependent on expression status of ZIP10. CONCLUSION: The present study demonstrate that mannose selectively kills thyroid cancer cells dependent on enzyme activity of PMI rather than its expression, and provide a mechanistic rationale for exploring clinical use of mannose in thyroid cancer therapy.
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Isomerasas Aldosa-Cetosa/metabolismo , Proteínas de Transporte de Catión/metabolismo , Fosfatos/metabolismo , Neoplasias de la Tiroides/genética , Animales , Línea Celular Tumoral , Femenino , Humanos , RatonesRESUMEN
Glucocorticoids (GCs) are widely used in the treatment of various autoimmune and inflammatory diseases, including inflammatory bowel disease (IBD). However, the effect of GCs on the progression of colitis-associated colorectal cancer (CAC) has not been well explored. In this study, we first established a colorectal cancer model induced by azoxymethane and dextran sulfate sodium (AOM/DSS) and a colitis model induced by DSS in mice. Dexamethasone (DEX) was then administered at different periods of time to determine its effect on tumorigenesis and tumor progression. Meanwhile, body weight, stool property and fecal blood of mice were recorded. At the end of this study, the number and load of tumors were evaluated, and the expression of proteins associated with cell proliferation was analyzed. To evaluate the inflammation in colon, we detected the level of pro-inflammatory cytokine TNFα, and the mucosal infiltration of inflammatory cells. Our results revealed that AOM injection followed by three cycles of drinking water containing 1.5% DSS successfully induced multiple tumor formation in mouse colon and rectum. Both early and late DEX intervention suppressed tumor growth in mouse colorectum, and downregulated the expression of PCNA and cyclin D1. Moreover, DEX treatment significantly inhibited TNFα production, mucosal infiltration of inflammatory cells, and the activity of MAPK/JNK pathway, particularly early DEX intervention. However, we also found that DEX treatment deteriorated the general state of mouse manifested by greater loss of body weight and rectal bleeding. In summary, both early and late DEX interventions significantly ameliorate colonic inflammation and inhibit the progression of AOM/DSS-induced colorectal cancer, at least partly due to the inhibition of MAPK/JNK pathway. It is noteworthy that the deleterious effect on the general condition of mouse may limit the duration of GCs treatment.
RESUMEN
BACKGROUND: Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. METHODS: We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. RESULTS: Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. CONCLUSIONS: Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.
Asunto(s)
Atovacuona , Nanopartículas/química , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Animales , Atovacuona/química , Atovacuona/farmacología , Línea Celular Tumoral , Células Cultivadas , Portadores de Fármacos/química , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Ratones SCID , SmegmamorphaRESUMEN
Gliomas are the most malignant and common tumors of the human brain, and the prognosis of glioma patients is extremely poor. MicroRNAs (miRNAs or miRs) play critical roles in different types of cancer by performing posttranscriptional regulation of gene expression. Although miR218 has been demonstrated to be decreased in gliomas, its role in gliomas remains largely unknown. miR218 expression was analyzed in gliomas and normal brain tissues (control subjects) using a dataset from The Cancer Genome Atlas. A series of in vitro and in vivo studies were performed to determine the biological roles of miR218 in glioma cells. Potential targets of miR218 were identified using a dualluciferase reporter system. Western blot and dualluciferase reporter system experiments were performed to evaluate the regulatory effect of miR218 on the tenascin C (TNC)/AKT/activator protein 1 (AP1)/transforming growth factor ß1 (TGFß1) pathway. It was demonstrated that miR218 was significantly downregulated in gliomas compared with control subjects, and played potent tumor suppressor roles in glioma cells by inhibiting cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, as well as inducing cell cycle arrest and apoptosis. Mechanistically, miR218 inhibited malignant phenotypes of glioma cells by binding to the 3'untranslated region of its target TNC and subsequently suppressing its expression. As a result, miR218 could reduce AKT phosphorylation and subsequently inhibit transcriptional activity of AP1 by reducing JNK phosphorylation, downregulating the expression of TGFß1, while TGFß1 was able to, in turn, activate the TNC/AKT/AP1 signaling axis. Our data revealed a previously unknown tumor suppressor role of miR218 by blocking the TNC/AKT/AP1/TGFß1positive feedback loop in glioma.
Asunto(s)
Retroalimentación Fisiológica , Glioma/genética , Glioma/patología , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tenascina/metabolismo , Factor de Transcripción AP-1/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Masculino , Ratones , MicroARNs/genética , Fenotipo , Transducción de SeñalRESUMEN
Neurofibromatosis type 1 (NF1), an autosomal dominant and multisystem disorder, is generally considered to be caused by NF1 inactivation. However, there are also numerous studies showing that Neurofibromatosis type 1-like phenotype can be caused by the abnormalities in the other genes. Through targeted parallel sequencing, whole-exome sequencing, de novo genomic sequencing, and RNA isoform sequencing, we identified a germline V2097M variation in CSPG4 gene probably increased susceptibility to a NF1-like phenotype family. Besides, a series of in vitro functional studies revealed that this variant promoted cell proliferation by activating the MAPK/ERK signaling pathway via hindering ectodomain cleavage of CSPG4. Our data demonstrate that a germline variation in the CSPG4 gene might be a high risk to cause NF1-like phenotype. To our knowledge, this is the first report of mutations in the CSPG4 gene in human diseases.