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1.
Cell Death Dis ; 15(4): 294, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664379

RESUMO

Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/ß-catenin signaling pathway. PICK1 restrained the nuclear accumulation of ß-catenin and accelerated the degradation of ß-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/ß-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC.


Assuntos
Biomarcadores Tumorais , Proteínas de Transporte , Proliferação de Células , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteínas Nucleares , Via de Sinalização Wnt , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/metabolismo , Prognóstico , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Animais , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , beta Catenina/metabolismo , Camundongos Nus , Masculino , Feminino , Camundongos , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Mutação/genética
2.
Cells ; 13(7)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38606998

RESUMO

Nasopharyngeal carcinoma (NPC) is a type of cancer that originates from the mucosal lining of the nasopharynx and can invade and spread. Although contemporary chemoradiotherapy effectively manages the disease locally, there are still challenges with locoregional recurrence and distant failure. Therefore, it is crucial to have a deeper understanding of the molecular basis of NPC cell movement in order to develop a more effective treatment and to improve patient survival rates. Cancer cell line models are invaluable in studying health and disease and it is not surprising that they play a critical role in NPC research. Consequently, scientists have established around 80 immortalized human NPC lines that are commonly used as in vitro models. However, over the years, it has been observed that many cell lines are misidentified or contaminated by other cells. This cross-contamination leads to the creation of false cell lines that no longer match the original donor. In this commentary, we discuss the impact of misidentified NPC cell lines on the scientific literature. We found 1159 articles from 2000 to 2023 that used NPC cell lines contaminated with HeLa cells. Alarmingly, the number of publications and citations using these contaminated cell lines continued to increase, even after information about the contamination was officially published. These articles were most commonly published in the fields of oncology, pharmacology, and experimental medicine research. These findings highlight the importance of science policy and support the need for journals to require authentication testing before publication.


Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/metabolismo , Células HeLa , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Recidiva Local de Neoplasia/metabolismo , Nasofaringe/metabolismo , Nasofaringe/patologia
3.
J Exp Clin Cancer Res ; 43(1): 122, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654320

RESUMO

BACKGROUND: Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. METHODS: RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. RESULTS: We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5'-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. CONCLUSIONS: These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.


Assuntos
Carcinoma Nasofaríngeo , Rad51 Recombinase , Tolerância a Radiação , Reparo de DNA por Recombinação , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Rad51 Recombinase/metabolismo , Rad51 Recombinase/genética , Camundongos , Animais , Tolerância a Radiação/genética , RNA Circular/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Linhagem Celular Tumoral , Feminino , Masculino , Prognóstico , Camundongos Nus
4.
Cell Biochem Funct ; 42(2): e3939, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38454810

RESUMO

We aimed to explore the effects of NOP16 on the pathogenesis of nasopharyngeal carcinoma (NPC) and the related mechanism. In this study, the expression level of NOP16 in NPC tissues and adjacent tissues was measured by qRT-polymerase chain reaction (PCR) and immunohistochemistry (IHC) tests. In the in vitro study, the expression levels of NOP16 and RhoA/phosphatidylinositol 3-kinase (PI3K)/Akt/c-Myc and IKK/IKB/NF-κB signalling pathway-related proteins in NPC cells were measured by qRT-PCR and Western blot (WB). CCK8 assays and colony formation assays were used to detect cell proliferation. Transwell assays were used to detect the migration and invasion ability of NPC cells. Flow cytometry and WB were used to measure the level of apoptosis. For the in vivo study, NPC xenograft models were established in nude mice, and tumour weight and volume were recorded. The expression levels of NOP16 and RhoA/PI3K/Akt/c-Myc signalling pathway-related proteins and mRNAs were measured by immunofluorescence, qRT-PCR and WB experiments. In clinical samples, the results of qRT-PCR and IHC experiments showed that the expression level of NOP16 was significantly increased in NPC tissues. In the in vitro study, the results of qRT-PCR and WB experiments showed that NOP16 was significantly increased in NPC cells. The CCK8 assay, colony formation assay, transwell assay and flow cytometry results showed that knocking out NOP16 inhibited the proliferation, migration and invasion of NPC cells and increased apoptosis. WB results showed that knocking out NOP16 inhibited the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB signalling pathways. These effects were reversed by 740Y-P (PI3K activator). In the in vivo study, knockdown of NOP16 reduced tumour volume and weight and inhibited the RhoA/PI3K/Akt/c-Myc signalling pathway. In conclusion, knockdown of NOP16 inhibited the proliferation, migration and invasion of NPC cells and induced apoptosis by inhibiting the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB pathways, leading to the malignant phenotype of NPC.


Assuntos
Neoplasias Nasofaríngeas , Fragmentos de Peptídeos , Proteínas Proto-Oncogênicas c-akt , Receptores do Fator de Crescimento Derivado de Plaquetas , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , NF-kappa B , Camundongos Nus , Linhagem Celular Tumoral , Apoptose/genética , Proliferação de Células/genética , Movimento Celular/genética
5.
Sci Rep ; 14(1): 6681, 2024 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509141

RESUMO

Improving drug sensitivity is an important strategy in chemotherapy of cancer and accumulating evidence indicates that miRNAs are involved in the regulation of drug sensitivity, but the specific mechanism is still unclear. Our previous study has found that miR-296-5p was significantly downregulated in nasopharyngeal carcinoma (NPC). Here, we aim to explore whether miR-296-5p is involved in regulating cisplatin sensitivity in NPC by regulating STAT3/KLF4 signaling axis. The cell proliferation and clonogenic capacity of NPC cells were evaluated by CCK8 Assay and plate colony assay, respectively. The Annexin V-FITC staining kit was used to determine and quantify the apoptotic cells using flow cytometry. The drug efflux ability of NPC cells were determined by Rhodamine 123 efflux experiment. The expression of miR-296-5p, apoptosis-related genes and protein in NPC cell lines were detected by qPCR and Western blot, respectively. Animal study was used to evaluate the sensitivity of NPC cells to DDP treatment in vivo. Our results showed that elevated miR-296-5p expression obviously promoted the sensitivity of NPC cells to DDP by inhibiting cell proliferation and clonogenic capacity, and inducing apoptosis. In addition, we found that miR-296-5p inhibited the expression of STAT3 and KLF4 in NPC cells, while overexpression of exogenous STAT3 reversed miR-296-5p-mediated enhancement in cell death of DDP-treated NPC cells. In vivo studies further confirmed that miR-296-5p promotes the sensitivity of NPC cells to DDP treatment. miRNA-296-5p enhances the drug sensitivity of nasopharyngeal carcinoma cells to cisplatin via STAT3/KLF4 signaling pathway.


Assuntos
MicroRNAs , Neoplasias Nasofaríngeas , Animais , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Cisplatino/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Resistencia a Medicamentos Antineoplásicos/genética
6.
Neoplasia ; 50: 100980, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38382442

RESUMO

Nasopharyngeal carcinoma (NPC) and oropharyngeal carcinoma (OPC) are subtypes of head and neck cancer with different treatment effects due to the heterogeneity of tumor microenvironments. This study was to investigate the distinctive tumor microenvironments of NPC and OPC. Analyzing single-cell data from 10 cases of each subtype, we reveal significant differences in cellular composition, with NPC microenvironment dominated by T/NK and B cells, and OPC characterized by prevalent epithelial cells and fibroblasts. Dynamic transitions of CD8 T cells are observed in both tumor types, involving shifts from naivety to cytotoxicity, proliferation, and eventual exhaustion/exhausted states. Additionally, Tregs exhibit heightened proliferative abilities in later developmental stages, concomitant with exhaustion. These highly proliferative T cells and Tregs manifest elevated glycolysis and lactate metabolism activities. Furthermore, we explore intercellular communication between glycolytic malignant epithelial cells and these proliferative T cells. These findings offer comprehensive insights into the heterogeneity of tumor microenvironments and provide a solid foundation for future therapeutic strategies and targeted interventions.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Carcinoma Nasofaríngeo , Células Epiteliais/metabolismo , Análise de Célula Única , Microambiente Tumoral
7.
Cell Biochem Funct ; 42(2): e3945, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38362935

RESUMO

MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFß/SMAD, RAS/MAPK, Wnt/ß-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.


Assuntos
Carcinoma , MicroRNAs , Neoplasias Nasofaríngeas , Humanos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , beta Catenina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Transdução de Sinais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Movimento Celular/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo
8.
Int J Biol Sci ; 20(1): 182-199, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164179

RESUMO

Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or persistence of cancer after radiotherapy is still inevitable, highlighting the need to identify therapeutic resistance factors and develop effective methods for NPC treatment. Herein, we found that TRAF4 is overexpressed in NPC cells and tissues. Knockdown TRAF4 significantly increased the radiosensitivity of NPC cells, possibly by inhibiting the Akt/Wee1/CDK1 axis, thereby suppressing survivin phosphorylation and promoting its degradation by FBXL7. TRAF4 is positively correlated with p-Akt and survivin in NPC tissues. High protein levels of TRAF4 were observed in acquired radioresistant NPC cells, and knockdown of TRAF4 overcomes radioresistant in vitro and the xenograft mouse model. Altogether, our study highlights the TRAF4-survivin axis as a potential therapeutic target for radiosensitization in NPC.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Animais , Camundongos , Carcinoma/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Survivina/genética , Survivina/metabolismo , Fator 4 Associado a Receptor de TNF/metabolismo , Transdução de Sinais , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Ubiquitinação/genética
9.
Anticancer Drugs ; 35(4): 317-324, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38215016

RESUMO

The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Nasofaríngeas , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/metabolismo , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Tigeciclina/farmacologia , Tigeciclina/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Mitocôndrias , Neoplasias Nasofaríngeas/metabolismo
10.
J Adv Res ; 56: 69-86, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37061217

RESUMO

INTRODUCTION: The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. OBJECTIVES: To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T-cells and response to chemotherapy. METHODS: In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T-cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T-cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. RESULTS: NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. CONCLUSION: Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T-cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy.


Assuntos
Cisplatino , Neoplasias Nasofaríngeas , Humanos , Animais , Camundongos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Células T de Memória , Linhagem Celular Tumoral , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Microambiente Tumoral
11.
Curr Cancer Drug Targets ; 24(2): 127-141, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37183458

RESUMO

EBV promotes many cancers such as lymphoma, nasopharyngeal carcinoma, and gastric; Latent Membrane Protein 1 (LMP1) is considered to be a major oncogenic protein encoded by Epstein- Barr virus (EBV). LMP1 functions as a carcinogen in lymphoma and nasopharyngeal carcinoma, and LMP1 may also promote gastric cancer. The expression level of LMP1 in host cells is a key determinant in tumorigenesis and maintenance of virus specificity. By promoting cell immortalization and cell transformation, promoting cell proliferation, affecting immunity, and regulating cell apoptosis, LMP1 plays a crucial tumorigenic role in epithelial cancers. However, very little is currently known about LMP1 in Epstein-Barr virus-associated gastric cancer (EBVaGC); the main reason is that the expression level of LMP1 in EBVaGC is comparatively lower than other EBV-encoded proteins, such as The Latent Membrane Protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and BamHI-A rightward frame 1 (BARF1), to date, there are few studies related to LMP1 in EBVaGC. Recent studies have demonstrated that LMP1 promotes EBVaGC by affecting The phosphatidylinositol 3-kinase- Akt (PI3K-Akt), Nuclear factor-kappa B (NF-κB), and other signaling pathways to regulate many downstream targets such as Forkhead box class O (FOXO), C-X-C-motif chemokine receptor (CXCR), COX-2 (Cyclooxygenase-2); moreover, the gene methylation induced by LMP1 in EBVaGC has become one of the characteristics that distinguish this gastric cancer (GC) from other types of gastric cancer and LMP1 also promotes the formation of the tumor microenvironment (TME) of EBVaGC in several ways. This review synthesizes previous relevant literature, aiming to highlight the latest findings on the mechanism of action of LMP1 in EBVaGC, summarize the function of LMP1 in EBVaGC, lay the theoretical foundation for subsequent new research on LMP1 in EBVaGC, and contribute to the development of novel LMP1-targeted drugs.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma , Neoplasias Nasofaríngeas , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Neoplasias Gástricas/metabolismo , Carcinoma Nasofaríngeo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Membrana/metabolismo , Microambiente Tumoral , Proteínas Virais/metabolismo
12.
J Biochem Mol Toxicol ; 38(1): e23590, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38037286

RESUMO

Polo-like kinase 1 (PLK1) inhibitor NMS-P937 is a targeted therapeutic agent with good preclinical efficacy in various human cancers, and its therapeutic effect on nasopharyngeal carcinoma (NPC) remains to be determined. Here, to explore biological activity of NMS-P937 in NPC, multiple types of NPC cells were utilized. We tested IC50 values, carried out flow cytometry, western blot analysis analysis, immunofluorescence, and constructed subcutaneous xenograft mouse models. We found that treatment with NMS-P937 increased the proportion of G2/M phase NPC cells, where CyclinB1 expression was upregulated and CyclinE1 expression was downregulated. Besides, NMS-P937 treatment-induced NPC cell apoptosis with increased cleavage of PARP and caspase-3. Mechanistically, NMS-P937 treatment led to aberrant mitosis, causing increased reactive oxygen species (ROS) levels. ROS scavenger N-acetylcysteine partially reversed ROS levels induced by NMS-P937. Furthermore, NMS-P937 administration restrained NPC xenografts growth in nude mice. Overall, NMS-P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS-P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma.


Assuntos
Neoplasias Nasofaríngeas , Pirazóis , Quinazolinas , Humanos , Camundongos , Animais , Carcinoma Nasofaríngeo/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Nasofaríngeas/metabolismo , Apoptose
13.
Environ Toxicol ; 39(3): 1631-1640, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38018881

RESUMO

BACKGROUND: N6-methyladenosine (m6A) modification interacting microRNAs (miRNAs) have been confirmed to participate in nasopharyngeal carcinoma (NPC) progression. This research investigated miR-1908-5p's function and regulatory mechanism in the tumorigenesis of NPC via m6A modification and targeting a key gene. METHODS: The levels of miR-1908-5p, homeodomain-only protein homeobox (HOPX), and methyltransferase-like 3 (METTL3) expressions were detected via RT-qPCR. The correlation between miR-1908-5p and the HOPX/METTL3 axis, as well as their regulatory mechanism, was investigated by dual luciferase reporter, western blotting, and MeRIP assays. Moreover, the bio-functions of miR-1908-5p, HOPX, and METTL3 in NPC were explored through CCK8, transwell, caspase-3 activity, and xenograft tumor assays. RESULTS: RT-qPCR results indicated a miR-1908-5p upregulation in NPC. Knocking down miR-1908-5p diminished the NPC cell viability and migration in vitro. In vivo, downregulating miR-1908-5p repressed NPC cell tumor growth. Moreover, HOPX was specifically targeted by miR-1908-5p, and HOPX downregulation led to reversal of the anti-tumor impact of the miR-1908-5p inhibitor against NPC cell malignancy. Also, METTL3 could mediate the m6A modification of miR-1908-5p to regulate its influence on NPC cells. CONCLUSION: This study demonstrated that the METTL3-mediated m6A modification of miR-1908-5p enhanced the tumorigenesis of NPC by targeting HOPX. These findings propose new insights for NPC diagnosis and therapy.


Assuntos
Adenina , Metiltransferases , MicroRNAs , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Adenina/análogos & derivados , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Genes Homeobox , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia
14.
Cell Oncol (Dordr) ; 47(1): 283-301, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37782406

RESUMO

PURPOSE: Nasopharyngeal carcinoma (NPC) has characteristics of high invasion and early metastasis. Most NPC patients present with locoregionally advanced illness when first diagnosed. Therefore, it is urgent to discover NPC biomarkers. Fibroblast growth Factor 19 (FGF19) plays a role in various physiological or pathological processes, including cancer. In this research, we discovered the importance of FGF19 in NPC, and clarified its role in tumour angiogenesis. METHODS: Western blotting, immunohistochemistry and ELISA were used to investigate FGF19 expression in NPC. Then we took CCK8, colony formation, Transwell and wound healing assays to identify the influence of FGF19 on NPC malignant behaviours. The proliferative and metastatic capacity of FGF19 were evaluated in nude mice and zebrafish. The role of FGF19 in angiogenesis was investigated by tube formation and Matrigel plug angiogenesis assays. We then evaluated the variation in Annexin A2(ANXA2) levels with the treatment of FGF19. Lastly, co-immunoprecipitation and ubiquitination assays were performed to identify the mechanisms involved. RESULTS: FGF19 levels were elevated in tissues and serum of NPC patients and were associated with poor clinical stages. High expression of FGF19 promoted NPC malignant behaviours. In particular, FGF19 expression was correlated with microvessel density in tissues and NPC-derived FGF19 could accelerate angiogenesis in vitro and in vivo. Mechanistically, FGF19 influenced ANXA2 expression to promote angiogenesis. Moreover, tripartite motif-containing 21(TRIM21) interacted with ANXA2 and was responsible for ANXA2 ubiquitination. CONCLUSION: FGF19 promoted NPC angiogenesis by inhibiting TRIM21-mediated ANXA2 ubiquitination. It may serve as a noninvasive biomarker for NPC and provides new insights for therapy.


Assuntos
Anexina A2 , Fatores de Crescimento de Fibroblastos , Neoplasias Nasofaríngeas , Ribonucleoproteínas , Animais , Humanos , Camundongos , Anexina A2/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Peixe-Zebra/metabolismo , Ribonucleoproteínas/metabolismo
15.
Autophagy ; 20(2): 329-348, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37776538

RESUMO

Chemotherapeutic resistance is one of the most common reasons for poor prognosis of patients with nasopharyngeal carcinoma (NPC). We found that CENPN can promote the growth, proliferation and apoptosis resistance of NPC cells, but its relationship with chemotherapeutic resistance in NPC is unclear. Here we verified that the CENPN expression level in NPC patients was positively correlated with the degree of paclitaxel (PTX) resistance and a poor prognosis through analysis of clinical cases. VAMP8 expression was significantly increased after knockdown of CENPN by transcriptome sequencing. We found in cell experiments that CENPN inhibited macroautophagy/autophagy and VAMP8 expression and significantly increased PTX resistance. Overexpression of CENPN reduced the inhibitory effects of PTX on survival, cell proliferation, cell cycle progression and apoptosis resistance in NPC cells by inhibiting autophagy. In turn, knockdown of CENPN can affect the phenotype of NPC cells by increasing autophagy to achieve PTX sensitization. Sequential knockdown of CENPN and VAMP8 reversed the PTX-sensitizing effect of CENPN knockdown alone. Experiments in nude mice confirmed that knockdown of CENPN can increase VAMP8 expression, enhance autophagy and increase the sensitivity of NPC cells to PTX. Mechanistic studies showed that CENPN inhibited the translocation of p-CREB into the nucleus of NPC cells, resulting in the decreased binding of p-CREB to the VAMP8 promoter, thereby inhibiting the transcription of VAMP8. These results demonstrate that CENPN may be a marker for predicting chemotherapeutic efficacy and a potential target for inducing chemosensitization to agents such as PTX.Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; CENPN: centromere protein N; CQ: chloroquine; CREB: cAMP responsive element binding protein; ChIP: chromatin immunoprecipitation assay; IC50: half-maximal inhibitory concentration; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPC: nasopharyngeal carcinoma; NPG: nasopharyngitis; oeCENPN: overexpressed CENPN; PTX: paclitaxel; RAPA: rapamycin; RNA-seq: transcriptome sequencing; shCENPN: small hairpin RNA expression vector targeting the human CENPN gene; shCENPN-shVAMP8: sequential knockdown targeting the human CENPN gene and VAMP8 gene; shVAMP8: small hairpin RNA expression vector targeting the human VAMP8 gene; TEM: transmission electron microscopy; TIR: tumor inhibitory rate; VAMP8: vesicle associated membrane protein 8.


Assuntos
Neoplasias Nasofaríngeas , Paclitaxel , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Camundongos Nus , Autofagia/genética , Linhagem Celular Tumoral , RNA Interferente Pequeno/farmacologia , Proteínas R-SNARE/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/farmacologia
16.
Chem Biol Drug Des ; 103(1): e14411, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38073436

RESUMO

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the nasopharyngeal epithelium with a high incidence in southern China and parts of Southeast Asia. The current treatment methods are mainly radiotherapy and chemotherapy. However, they often have side effects and are not suitable for long-term exposure. Natural products have received more and more attention in cancer prevention and treatment because of their its high efficiency, low toxic side effects, and low toxicity. Natural products can serve as a viable alternative, and this study aimed to review the efficacy and mechanisms of natural products in the treatment of NPC by examining previous literature. Most natural products act by inhibiting cell proliferation, metastasis, inducing cell cycle arrest, and apoptosis. Although further research is needed to verify their effectiveness and safety, natural products can significantly improve the treatment of NPC.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proliferação de Células , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral
17.
Cancer Gene Ther ; 31(3): 454-463, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38135697

RESUMO

Nasopharyngeal carcinoma (NPC) originates in the epithelial cells of the nasopharynx and is a common malignant tumor in southern China and Southeast Asia. Metastasis of NPC remains the main cause of death for NPC patients even though the tumor is sensitive to radiotherapy and chemotherapy. Here, we found that the transmembrane protein tetraspanin1 (TSPAN1) potently inhibited the in vitro migration and invasion, as well as, the in vivo metastasis of NPC cells via interacting with the IKBB protein. In addition, TSPAN1 was essential in preventing the overactivation of the NF-kB pathway in TSPAN1 overexpressing NPC cells. Furthermore, reduced TSPAN1 expression was associated with NPC metastasis and the poor prognosis of NPC patients. These results uncovered the suppressive role of TSPAN1 against NF-kB signaling in NPC cells for preventing NPC metastasis. Its therapeutic value warrants further investigation.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Tetraspaninas/genética , Tetraspaninas/metabolismo
18.
Head Neck ; 46(1): 192-211, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37929674

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common malignancy occurring in the head and neck. Identification of immune-related methylated biomarkers might be helpful for NPC detection and prognostic evaluation. METHODS: A co-methylation network based on WGCNA was constructed to identify modules associated with NPC and immune cells. In combination with differentially expressed genes (DEGs) and immune-related genes from ImmPort database, the candidate immune-related methylated genes (IRMGs) were obtained. RESULTS: Our combined analysis identified 12 IRMGs. Among them, both the methylation and mRNA expression of CCL28, CSK, and PRKCB were correlated with the infiltration of B cells. CD1D, CR2, and GDF10 were favorable markers. Demethylation experiments validated that downregulation of GDF10, PRKCB, SLC40A1, and TGFBR3 in NPC resulted from promoter hypermethylation. Additionally, a diagnostic model was developed and exhibited high discriminative accuracy. CONCLUSIONS: These results provided a group of immune-related methylated biomarkers that may help with the diagnosis and prognosis of NPC.


Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Prognóstico , Metilação de DNA
19.
J Ethnopharmacol ; 323: 117667, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38159821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Stephania cephalantha Hayata is an important traditional medicinal plant widely used in traditional medicine to treat cancer. Cepharanthine (CEP) was extracted from the roots of Stephania cephalantha Hayata. It has been found to exhibit anticancer activity in different types of cancer cells. Nevertheless, the activity of CEP against nasopharyngeal carcinoma (NPC) and its underlying mechanism warrant further investigation. AIMS OF THE STUDY: NPC is an invasive and highly metastatic malignancy that affects the head and neck region. This research aimed to investigate the pharmacological properties and underlying mechanism of CEP against NPC, aiming to offer novel perspectives on treating NPC using CEP. MATERIALS AND METHODS: In vitro, the pharmacological activity of CEP against NPC was evaluated using the CCK-8 assay. To predict and elucidate the anticancer mechanism of CEP against NPC, we employed network pharmacology, conducted molecular docking analysis, and performed Western blot experiments. In vivo validation was performed through a nude mice xenograft model of human NPC, Western blot and immunohistochemical (IHC) assays to confirm pharmacological activity and the mechanism. RESULTS: In a dose-dependent manner, the proliferation and clonogenic capacity of NPC cells were significantly inhibited by CEP. Additionally, NPC cell migration was suppressed by CEP. The results obtained from network pharmacology experiments revealed that anti-NPC effect of CEP was associated with 8 core targets, including EGFR, AKT1, PIK3CA, and mTOR. By performing molecular docking, the binding capacity of CEP to the candidate core proteins (EGFR, AKT1, PIK3CA, and mTOR) was predicted, resulting in docking energies of -10.0 kcal/mol for EGFR, -12.4 kcal/mol for PIK3CA, -10.8 kcal/mol for AKT1, and -8.6 kcal/mol for mTOR. The Western blot analysis showed that CEP effectively suppressed the expression of EGFR and the phosphorylation levels of downstream signaling proteins, including PI3K, AKT, mTOR, and ERK. After CEP intervention, a noteworthy decrease in tumor size, without inducing any toxicity, was observed in NPC xenograft nude mice undergoing in vivo treatment. Additionally, IHC analysis demonstrated a significant reduction in the expression levels of EGFR and Ki-67 following CEP treatment. CONCLUSION: CEP exhibits significant pharmacological effects on NPC, and its mechanistic action involves restraining the activation of the EGFR/PI3K/AKT pathway. CEP represents a promising pharmaceutical agent for addressing and mitigating NPC.


Assuntos
Benzodioxóis , Benzilisoquinolinas , Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-akt , Stephania , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Simulação de Acoplamento Molecular , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Farmacologia em Rede , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Receptores ErbB
20.
J Extracell Vesicles ; 12(12): e12390, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38117000

RESUMO

Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.


Assuntos
Vesículas Extracelulares , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Células Dendríticas , Galectinas/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Microambiente Tumoral
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