transforming-growth-factor-beta and Nasopharyngeal-Neoplasms

Diaminodichoroplatinum (DDP) resistance of tumor cells is the culprit of nasopharyngeal carcinoma (NPC) treatment failure. MicroRNA-577 is lowly expressed in NPC tissues, but relevant mechanism is poorly studied. Therefore, this study investigated the role of microRNA-577 in NPC cells with DDP resistance and its mechanism. DDP-resistant NPC cells were established by treatment with DDP at increased concentrations (2, 4, 6, 8, or 10 μg/mL). MicroRNA-577 and EIF5A2 mRNA expressions were detected by qRT-PCR. Cell biological behaviors were assessed via cell function experiments. Expressions of epithelial mesenchymal transformation (EMT)-related proteins were quantified by western blot. The targeting relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and microRNA-577 was verified through dual-luciferase reporter assay. The tumor volume and weight were measured after subcutaneous tumorigenesis in mice. As observed from the results, microRNA-577 expression was reduced in NPC cells and DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the malignant behaviors and EMT of DDP-resistant NPC cells, and facilitated cell apoptosis. MicroRNA-577 targeted EIF5A2, and overexpressed EIF5A2 reversed the above effects of up-regulated microRNA-577 on DDP-resistant NPC cells. Besides, EIF5A2 positively regulated TGF-β signaling pathway, and TGF-β treatment offset the promoting effects of EIF5A2 silencing on apoptosis of DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the proliferation of DDP-resistant NPC cells, and down-regulated the levels of EIF5A2 and TGF-β as well as EMT in vivo. Collectively, microRNA-577/EIF5A2 axis hinders the EMT progression through the blockage of TGF-β signaling pathway, so as to inhibit the proliferation of DDP-resistant NPC.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Eukaryotic Translation Initiation Factor 5A; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Signal Transduction; Transforming Growth Factor beta

Growth differentiation factor-10 (GDF10) belongs to a member of the transforming growth factor-β (TGF-β) superfamily. Dysfunction of the TGF-β pathway can lead to carcinoma progression. Previous studies have shown that GDF10 acts as a tumor suppressor gene in some cancers. However, the molecular mechanisms of the association between GDF10 and cell functions in nasopharyngeal carcinoma (NPC) remain unclear. In this study, the expression and methylation levels of GDF10 were studied in human subjects and cell lines. Furthermore, overexpression of GDF10 was used to explore its biological function and potential mechanism in NPC cell lines. GDF10 was downregulated in NPC owing to its aberrant promoter methylation. After treatment with 5-aza-2'-deoxycytidine, the expression of GDF10 in NPC cells was reversed. We also confirmed that the overexpression of GDF10 significantly inhibited cell proliferation and tumor growth both in vitro and in vivo, respectively. Additionally, GDF10 overexpression in NPC cells attenuated migration and invasion and inhibited epithelial-to-mesenchymal transition with a decrease in nuclear Smad2 and NF-κB protein accumulation. GDF10 was silenced owing to its promoter hypermethylation, and it might originally act as a functional tumor suppressor via TGF-β/Smad and NF-κB signaling pathways in NPC.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 10; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; NF-kappa B; Transforming Growth Factor beta

Reliable predictors are urgently needed to identify stage II nasopharyngeal carcinoma (NPC) patients who could benefit from concurrent chemoradiotherapy (CCRT). We aimed to develop a nomogram integrating MRI-identified multidimensional features of lymph nodes to predict survival and assist the decision-making of CCRT for stage II NPC.. This retrospective study enrolled 242 stage II NPC patients treated from January 2007 to December 2017. Overall survival (OS) was the primary endpoint. Performance of nomogram was evaluated using calibration curves, Harrell Concordance Index (C-index), area under the curve (AUC) and decision curves analysis (DCA) and was compared with TNM staging. According to the individualized nomogram score, patients were classified into two risk cohorts and therapeutic efficacy of CCRT were evaluated in each cohort.. Three independent prognostic factors for OS: age, number and location of positive lymph nodes were included into the final nomogram. T stage was also incorporated due to its importance in clinical decision-making. Calibration plots demonstrated a good match between the predicted and our observed OS rates. C-index for nomogram was 0.726 compared with 0.537 for TNM staging (. This lymph node features-based nomogram demonstrated excellent discrimination and predictive accuracy for stage II patients and could identify patients who can benefit from CCRT.

Topics: Chemoradiotherapy; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nomograms; Retrospective Studies; Transforming Growth Factor beta

Macrophage migration inhibitory factor (MIF), originally reported as an inflammation regulating molecule, is elevated in various cancer cells, which may promote carcinogenesis. Meanwhile, ISO-1 is a potent small molecular inhibitor of MIF, which has not been investigated in nasopharyngeal carcinoma (NPC), hence the impact of ISO-1 on NPC cells remains to be illustrated.. This study intended to explore the biological function of ISO-1 in NPC cells in vitro and prove a possibility of ISO-1 being a novel agent in NPC treatments.. Gene expression of MIF in Head and Neck squamous cell carcinoma was obtained from The Cancer Genome Atlas (TCGA) database. Nasal pharyngeal tissues were collected from adult patients undergoing nasopharyngeal biopsy for MIF level detection. Proliferation of NPC cell lines 5-8B and 6-10B was studied using Cell Counting Kit-8 (CCK-8) assay and plate-colony-formation assay, apoptosis was determined by flow cytometry and TUNEL staining, migration and invasion capacities were measured by wound-healing assay and transwell assay, all to explore the function of ISO-1 in NPC cells in vitro. Epithelial-to-mesenchymal transition (EMT) level of NPC cells was determined by Western blot analysis and immunofluorescence assay.. Transcript level of MIF was significantly higher in head and neck squamous cell carcinoma. Protein MIF was overexpressed in human NPC tissues compared to non-cancerous ones, and its expression could be compromised by ISO-1 in vitro. 100μM ISO-1 significantly hindered NPC cells' migration and invasion capacitiesin vitro but acted relatively poorly on proliferation and apoptosis. Immunofluorescence assay and Western blotting implied a downregulated EMT level through TGF-β/Smad4 axis in ISO-1 treated NPC cells compared to the vehicle.. This study indicated that MIF antagonist ISO-1 holds an impact on NPC progression by influencing the migration and invasion of NPC cells ISO-1 inhibits the EMT process of NPC cells through TGF-β/Smad4 axis, supporting that prudent application of ISO-1 may be a potential adjuvant treatment for NPC.

Topics: Acetates; Adult; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Isoxazoles; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Smad4 Protein; Squamous Cell Carcinoma of Head and Neck; Transforming Growth Factor beta

To explore the effect of miR-296-5p on the metastasis of nasopharyngeal carcinoma (NPC) cells and investigate the underlying mechanism.. The expressions of miR-296-5p in NPC tissues and cells were determined using GSE32920 database analysis and real-time PCR and miRNA microarray assays. An miR-296-5p mimic and inhibitor were transfected into NPC cells. Then, immunofluorescence imaging, scratch wound-healing, transwell migration and invasion assays were used to observe the effects of miR-296-5p on cell metastasis and invasion. Real-time PCR and western blotting were carried out to detect the expressions of genes and proteins related to epithelial-mesenchymal transition (EMT). A dual luciferase reporter assay was used to identify whether TGF-β is the target gene of miR-296-5p. Finally, TGF-β expression plasmids were transfected into NPC cells to verify the role of TGF-β in the miR-296-5p-mediated inhibition of nasopharyngeal carcinoma cell metastasis.. Our results show that miR-296-5p inhibits the migratory and invasive capacities of NPC cells by targeting TGF-β, which suppresses EMT. Importantly, the miR-296-5p level was significantly lower in human NPC tissues than in adjacent normal tissues. It also negatively correlated with TGF-β and was significantly associated with the lymph node metastasis of patients with NPC.. Our findings show that miR-296-5p represses the EMT-related metastasis of NPC by targeting TGF-β. This provides new insight into the role of miR-296-5p in regulating NPC metastasis and invasiveness.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Transforming Growth Factor beta

Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck squamous carcinoma that is notorious for its high metastatic potential. In this study, we reported that FOXA1 protein was decreased in NPC cells. Loss of FOXA1 is associated with lymph node metastasis and poor prognosis. Silencing FOXA1 in NP69 and C666-1 NPC cells accelerated cell proliferation and migration, while re-expression of FOXA1 has opposite effects. Microarray and RNA-seq analysis revealed that re-expression of FOXA1 in NPC cells reprogrammed the TGF-β-stimulated transcription program, which is characterized by promotion of TGF-β-inducible tumor-suppressive targets but repression of TGF-β-inducible oncogenes expression in NPC cells, leading to restoration of NPC cell sensitivity to TGF-β's growth-inhibitory effect. BAMBI, a TGF-β responsive tumor suppressor, was induced by FOXA1 in NPC cells. FOXA1 binding on the BAMBI gene facilitated SMAD2/3 binding to the BAMBI promoter via increasing BAMBI associated H3K4me1 and H3K27ac modification. Enforced expression of BAMBI in NPC cells suppressed cell proliferation and invasiveness. Our data suggested that FOXA1 is a master factor in controlling the TGF-β-stimulated transcriptome and a regulator of TGF-β biological functions in NPC oncogenesis.

Topics: Acetylation; Animals; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular Reprogramming; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha; Histones; Humans; Membrane Proteins; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Promoter Regions, Genetic; Signal Transduction; Smad2 Protein; Smad3 Protein; Transcriptional Activation; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein-Barr virus (EBV). We envisioned that in-depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty-three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep-sequenced (>1000×) with respect to a panel of 409 cancer-related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF-κB, and TGF-β pathways. In addition, patients harbored CNV among 409 cancer-related genes and missense mutations in TGF-β/SMAD signaling were associated with poor overall survival and poor recurrence-free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD-dependent TGF-β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF-β-mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF-β signaling contributes to exacerbating the NPC pathogenesis.

Topics: Biomarkers, Tumor; DNA Copy Number Variations; Female; Gene Expression; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Oncogenes; Protein Binding; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta

Transforming growth factor beta (TGF-?), a pleiotropic cytokine, promotes cell proliferation and migration in multiple cancers, including nasopharyngeal carcinoma (NPC). microRNA-124 (miR-124) becomes downregulated in NPC and inhibits the tumorigenesis of this disease. However, the role of miR-124 in TGF-?-induced NPC development remains unknown. In this study, constant TGF-? stimulation repressed miR-124 expression, whereas miR-124 overexpression antagonized TGF-?-promoted NPC cell growth and migration. miR-124 overexpression decreased p-SMAD2/3, SMAD4, and p-ERK levels, indicating that ectopic miR-124 overexpression inhibited SMAD and non-SMAD pathways. Pro-oncogenic lncRNA MALAT1 was targeted by miR-124 that regulated ERK/MAPK by targeting MALAT1 independent of the SMAD signaling pathway. In conclusion, our work clarified the significant role of miR-124 in TGF-? signaling pathways independent of the SMAD signaling pathway and showed the potential of miR-124 as a new therapeutic target against NPC.

Topics: Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; MicroRNAs; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; RNA, Long Noncoding; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Transforming Growth Factor beta

Epithelial-mesenchymal transition (EMT) is considered a prerequisite for tumor invasion and metastasis in many cancers. However, the mechanisms underlying EMT in nasopharyngeal carcinoma (NPC) is largely unknown. In this study, we found that transforming growth factor-β (TGF-β), which reportedly promotes EMT in multiple cancers, can trigger EMT and increase the invasive and migratory capacities of NPC cells. Conversely, the downregulation of SMAD4, a vital member of the canonical TGF-β pathway, reversed the TGF-β-induced EMT, invasion, and migration. Further experiments revealed that SMAD4 was the target of miRNA-34a, which was downregulated in NPC tissues and suppressed NPC cell metastasis in vivo. miRNA-34a overexpression also antagonized the TGF-β-induced EMT progression, invasion, and migration through SMAD4 inhibition. However, the restoration of SMAD4 expression rescued the inhibitory effects of miRNA-34a on tumorigenesis. All these results confirmed that miRNA-34a suppressed the TGF-β-induced EMT, invasion, and migration of NPC cells by directly targeting SMAD4, which indicated the potential of miR-34a as a therapeutic target against NPC.

Topics: Animals; Carcinoma; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta

Inhibin B (INHBB), a heterodimer of a common α-subunit and a βB-subunit, is a glycoprotein belonging to the transforming growth factor-β (TGF-β) family. In this study, we observed INHBB expression was reduced in nasopharyngeal carcinoma (NPC) tissues compared to non-tumor nasopharyngeal epithelium tissues, and INHBB was associated with lymph node metastasis, stage of disease, and clinical progress. Positive expression of INHBB in NPC predicted a better prognosis (overall survival, P = 0.038). However, the molecular mechanisms of INHBB have not been addressed in NPC. We induced anoikis-resistant cells in NPC cell lines under anchorage-independent conditions, then found epithelial-mesenchymal transition markers changed, cell apoptosis decreased, cell cycle was modified, and invasion strengthened in anoikis-resistant NPC cells. These anoikis-resistant NPC cells showed decreased expression of INHBB compared with adhesion cells. Furthermore, INHBB was found to influence the above-mentioned changes. In the anoikis-resistant NPC cells with INHBB overexpression, apoptotic cells increased, S phase cells weakened, vimentin, matrix metallopeptidase-9, and vascular endothelial growth factor A expression were downregulated, and E-cadherin expression was upregulated, and vice versa in knockdown of INHBB (INHBB shRNA) anoikis-resistant NPC cells. Diminished INHBB expression could activate the TGF-β pathway to phosphorylate Smad2/3 and form complexes in the nucleus, which resulted in the above changes. Thus, our results revealed for the first time that INHBB could suppress anoikis resistance and migration of NPC cells by the TGF-β signaling pathway, decrease p53 overexpression, and could serve as a potential biomarker for NPC metastasis and prognosis as well as a therapeutic application.

Topics: Adolescent; Adult; Aged; Anoikis; Carcinoma; Cell Line, Tumor; Cell Movement; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibin-beta Subunits; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Prognosis; Signal Transduction; Transforming Growth Factor beta; Tumor Suppressor Protein p53; Young Adult

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (

Topics: Adult; Aged; Carcinoma; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genome, Human; Genomics; Herpesvirus 4, Human; Humans; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Mutation; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; NF-kappa B; Prognosis; Transforming Growth Factor beta; Tumor Microenvironment; Wnt Signaling Pathway

The objective of the present study was to evaluate the role of the TGFβ/PDCD4/AP-1 pathway in nasopharyngeal carcinoma (NPC) and its relationship to NPC prognosis.. NPC tissues collected from 66 NPC patients were compared to 17 nasopharyngeal mucosa biopsy specimens collected as normal tissues. Immunohistochemical staining was performed to assess expression of transforming growth factor-β receptor I (TGFβRI), programmed cell death 4 (PDCD4) and activator protein-1 (AP-1). The Kaplan-Meier method was applied to evaluate NPC patient overall survival (OS) and progression-free-survival (PFS). Cox regression analysis was used to estimate independent prognostic factors for NPC. The human NPC cell line CNE2 was selected and treated with SB431542, an inhibitor of TGFβRI; expression of TGFβRI and PDCD4 in CNE2 cells was determined by western blotting. NPC tissues showed higher expression of TGFβRI and AP-1 but lower expression of PDCD4 than normal tissues (all P < 0.05).. The results of Kaplan-Meier analysis showed that TGFβRI-positive patients and AP-1-positive patients had shorter OS and PFS than TGFβRI-negative patients and AP-1-negative patients; additionally, PDCD4-positive patients had higher OS and PFS than PDCD4-negative patients. Cox regression analysis revealed that advanced tumor stage, overexpression of TGFβRI and AP-1, and low expression of PDCD4 were unfavorable factors influencing OS and PFS in NPC patients. Compared with the control group, expression of TGFβRI decreased and that of PDCD4 increased significantly in CNE2 cells treated with the inhibitor (all P < 0.05). These findings indicate that the TGFβ/PDCD4/AP-1 pathway may be associated with NPC development and progression.. High expression of TGFβRI and AP-1 and low expression of PDCD4 may be unfavorable prognostic factors for NPC.

Topics: Adult; Aged; Apoptosis Regulatory Proteins; Carcinoma; Cell Line, Tumor; Disease-Free Survival; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Prognosis; RNA-Binding Proteins; Signal Transduction; Transcription Factor AP-1; Transforming Growth Factor beta

Metastasis is the main cause of cancer-related deaths. Nasopharyngeal carcinoma (NPC) is characterized by severe local invasion and high incidence of regional lymph node metastasis, which represents poor prognosis. However, the underlying mechanism that induces lymph node metastasis of NPC remains largely unknown. Herein, we report that flotillin-1 (FLOT1), a component of lipid raft, which was reported to be involved in tumor progression, was robustly upregulated in the NPC samples with lymph node metastasis. High FLOT1 expression was significantly associated with N classification as well as poorer overall and disease-free survivals in 169 archived clinical NPC samples. Overexpression of FLOT1 enhanced the migratory and invasive abilities of NPC cells in vitro, and more importantly, promoted invasion into the surrounding tissues and metastasis to lymph nodes in vivo. Whereas silencing of endogenous FLOT1 in NPC cells decreased the local invasion and metastasis to lymph nodes. Furthermore, FLOT1 induced the expression and secretion of TGF-β1, facilitated the activation of TGF-β/Smad3 signaling to effectuate epithelial-mesenchymal transition. Our findings present new evidence that FLOT1 plays an important role in promoting aggressive behavior of NPC and provide new insights into the regulatory mechanism of TGF-β signaling.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Signal Transduction; Transforming Growth Factor beta; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Approximately 20% of global cancer incidence is causally linked to an infectious agent. Epstein-Barr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifies novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1's ability to induce the expression of the extracellular matrix protein, fibronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its effects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fibronectin induction. LMP1 also induces the expression and activation of the major fibronectin receptor, α5β1 integrin, an effect that is accompanied by increased focal adhesion formation and turnover. Taken together, these findings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells.

Topics: Activins; Carcinoma; Cell Adhesion; Cell Line; Epithelial Cells; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Integrin beta1; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta; Viral Matrix Proteins

Epithelial-mesenchymal transition (EMT) is associated with invasion and metastasis of cancer cells. High-mobility group AT-hook 2 (HMGA2) has been found to play a critical role in EMT in a number of malignant tumors. However, whether HMGA2 regulates the EMT in human nasopharyngeal carcinoma (NPC) is unclear.. The aim of this study was to investigate the effect and mechanism of HMGA2 in inducing invasion and migration in NPC.. In NPC tissues samples, the association of HMGA2 mRNA expression with clinicopathological characteristics were estimated by real-time quantitative RT-PCR(qRT-PCR). In vitro, following the silencing of HMGA2 in CNE-1 and CNE-2 cell lines, the viability and metastatic ability were analyzed using Cell Counting Kit-8 (CCK8), colony formation assay, and transwell assay. EMT and transforming growth factor-beta (TGFβ)/Smad3 signaling pathway-related protein expression changes were evaluated using western blot.. HMGA2 was upregulated in NPC cell lines and clinical specimens (P < 0.01), and HMGA2 expression correlated significantly with metastasis (P = 0.02) and disease-free survival of NPC (hazard ratio: 3.52; 95% confidence interval: 1.34-7.79; P = 0.01). In addition, following in vitro knockdown of HMGA2, the aggressiveness of cells was markedly inhibited, Vimentin and Snail level was downregulated and E-cadherin expression was upregulated. Moreover, the expression of key proteins TGFβRII and p-Smad3 of the TGFβ/Smad3 signaling pathway was inhibited by the downregulation of HMGA2.. HMGA2 might maintain EMT-induced invasion and migration through the TGFβ/Smad3 signaling pathway in NPC cell lines.

Topics: Carcinoma; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; HMGA2 Protein; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nasopharynx; Neoplasm Invasiveness; RNA Interference; RNA, Small Interfering; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation

Nasopharyngeal carcinoma (NPC) is commonly diagnosed in southern Asia. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. Increasing evidence suggests that the dysregulation of miRNAs promotes NPC tumorigenesis. Epstein-Barr virus (EBV) infection and EBV-encoded miRNAs are also associated with the development of NPC. However, it is unclear how cellular and EBV miRNAs jointly regulate target genes and signaling pathways in NPC. In the present study, we analyzed the differential cellular and EBV miRNA expression profiles in 20 pooled NPC tissues using microarrays. We found that 19 cellular miRNAs and 9 EBV miRNAs were upregulated and 31 cellular miRNAs were downregulated in NPC tissues. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the 19 upregulated miRNAs target mainly the p53 signaling pathway in cancer, whereas the downregulated miRNAs regulate pathways related to cancer, focal adhesion and Erb, and MAPK signaling. In contrast, the upregulated EBV miRNAs target primarily the TGF-β and Wnt signaling pathways. Data also suggested that cellular miR-34b, miR-34c, miR-18a, miR‑200a/b, miR-449a, miR-31 and let-7 may be dysregulated in NPCs, and that the aberrant activation of their target genes in the p53 pathway and cell cycle enhance NPC cell survival and proliferation. In addition, EBV-miRNAs such as BART3 and BART5 target genes in the p53, TGF-β and Wnt signaling pathways to modulate NPC apoptosis and transformation. To better elucidate the interaction between miRNAs and target genes, we constructed an anti-correlated cellular and EBV miRNA/target gene regulatory network. The current findings may help dissect the roles played by cellular and EBV miRNAs during NPC tumorigenesis, and also provide useful biomarkers for the diagnosis and treatment of NPCs.

Topics: Carcinoma; Cell Cycle; Cell Proliferation; Epstein-Barr Virus Infections; Focal Adhesions; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Herpesvirus 4, Human; Humans; MAP Kinase Signaling System; MicroRNAs; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Oligonucleotide Array Sequence Analysis; RNA, Viral; Transforming Growth Factor beta; Tumor Suppressor Protein p53; Wnt Signaling Pathway

The aim of this study is to investigate whether IL-6, IL-10 and TGF-β are able to confer resistance to apoptosis in nasopharyngeal carcinoma cells by upregulating the expression of survivin.. The human nasopharyngeal carcinoma cell line TW01 (WHO NPC Type I) was cultured in DMEM-F12 Ham medium containing 10% FBS in a humidified atmosphere of 5% CO(2) and 37°C and treated with different concentrations of IL-6, IL-10 and TGF-β. Survivin mRNA expression was measured by real-time quantitative PCR and Western blot. Apoptosis was determined based on the assay for caspase-3 activity.. Of all the cytokines tested, only TGF-β (10 pg/mL) induced the over-expression of survivin at a significant level and this correlated with resistance to apoptosis (p ≤ 0.05). To confirm if survivin is responsible for resistance to apoptosis, YM155 which is a survivin inhibitor was used and the results showed that YM155 abrogated the protective effect of TGF-β. Interestingly, IL-10 did not significantly alter the expression of survivin.. We conclude that TGF-β up-regulates the expression of survivin leading to the resistance to apoptosis in NPC TW01 cells.

Topics: Apoptosis; Blotting, Western; Cell Culture Techniques; Cell Line, Tumor; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Interleukin-10; Interleukin-6; Naphthoquinones; Nasopharyngeal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Survivin; Transforming Growth Factor beta

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular and locally invasive tumor that exclusively affects male adolescents. Sex hormones are first discussed to clarify the etiology of JNA. Recently with the advances in the field of cell biology angiogenetic markers, proliferation markers and growth factors are investigated to identify the molecular basis of JNA as all neoplasm. In this study we tried to evaluate the expression of proliferation, angiogenesis and hormonal markers in JNA.. Immunohistochemical analysis were performed on paraffin-embedded 27 JNA samples which were obtained from the patients operated at University of Hacettepe Department of Otorhinolaryngology, a tertiary care center. Estrogen receptor (ER), progesterone receptor (PR), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) specific antibodies were used and evaluated by light microscopy. Two of 27 cases were ER positive. Nine of 27 cases were positive for PR. All of the cases were stained with PCNA. Twenty-four of 27 cases stained with VEGF. TGF-beta was positive in 14 of 27 cases. All recurrent cases were stained with PCNA and VEGF; just three of them were stained with TGF-beta.. Hormonal markers ER and PR did not seem to play a role in pathogenesis of JNA. PCNA, VEGF and TGF-beta may play a role in the pathogenesis of JNA by promoting angiogenesis and proliferation, but this role did not seem to have a relation with hormonal markers.

Topics: Adolescent; Adult; Angiofibroma; Child; Female; Humans; Immunohistochemistry; Male; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Proliferating Cell Nuclear Antigen; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Nasopharyngeal carcinoma (NPC) is a common epithelial neoplasm among the Chinese populations in Southern China and South East Asia. Epstein-Barr virus (EBV) is known to be an important etiologic agent of NPC and the viral gene products are frequently detected in NPC tissues along with elevated antibody titres to the viral proteins (VCA and EA) in a majority of patients. Elevated plasma EBV DNA load is regarded as an important marker for the presence of the disease and for the monitoring of disease progression. However, other serum/plasma parameters such as the levels of certain interleukins and growth factors have also been implicated in NPC. The objectives of the present study are, 1) to investigate the correlations between plasma EBV DNA load and the levels of interleukin (IL)-6, IL-10, TGF-beta1 and SCF (steel factor) and 2) to relate these parameters to the stages of NPC and the effect of treatment.. A total of 78 untreated NPC patients were enrolled in this study. Of these, 51 were followed-up after treatment. The remaining patients had irregular or were lost to follow-up. Plasma EBV DNA was quantified using real-time quantitative PCR. The levels of plasma interleukins and growth factors were quantified using ELISA.. A significant decrease in EBV DNA load was detected in plasma of untreated NPC patients (1669 +/- 637 copies/mL; n = 51) following treatment (57 +/- 37 copies/mL, p < 0.05); n = 51). Plasma EBV DNA load was shown to be a good prognosticator for disease progression and clinical outcome in five of the follow-up patients. A significant difference in IL-6 levels was noted between the untreated patients (164 +/- 37 pg/mL; n = 51) and following treatment (58 +/- 16 pg/mL, p < 0.05; n = 51). Positive correlations between EBV DNA load and IL-10 (r(49) = 0.535, p < 0.01), between IL6 and IL-10 (r(49) = 0.474, p < 0.01) and between TGF and SCF (r(49) = 0.464, p < 0.01) were observed in patients following treatment. None of the parameters tested including IgA-VCA were associated with tumour stages.. We conclude that among the parameters investigated, EBV DNA load and IL-6 levels were promising markers for the presence of NPC and for the assessment of treatment outcome.

Topics: Antibodies, Viral; Antigens, Viral; Capsid Proteins; Carcinoma; DNA, Viral; Female; Growth Substances; Herpesvirus 4, Human; Humans; Immunoglobulin A; Interleukin-10; Interleukin-6; Male; Nasopharyngeal Neoplasms; Neoplasm Staging; Prognosis; Stem Cell Factor; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viral Load

Our aim was to study the correlation between plasma transforming growth factor (TGF)-beta1 level and radiation-induced mucositis and dermatitis in nasopharyngeal carcinoma (NPC) patients.. Blood samples obtained from patients treated with concurrent chemo-radiotherapy (CCRT) were divided into two groups according to the pre-treatment plasma TGF-beta1 level (> or =7.5 ng/ml as group 1 and < 7.5 ng/ml as group 2). Enzyme-linked immunosorbent assay (ELISA) was used for the measurement of the TGF-beta1 level. Radiation toxicity was evaluated according to Radiation Treatment Oncology Group criteria. Data were analyzed by the generalized estimation equation method.. TGF-beta1 levels of group 1 patients were decreased significantly (P = 0.002) at the end of the treatment. The rate of decrease was 0.12 ng/ml per fraction (P = 0.02). The average TGF-beta1 level in patients who suffered acute radiation morbidity (grade > or =2) was significantly higher (P = 0.0057) than that of those who suffered less (grade < 2).. A lower pre-treatment plasma TGF-beta1 level and the grade of radiation toxicity both appeared to contribute to the elevated plasma TGF-beta1 after CCRT.

Topics: Antineoplastic Agents; Combined Modality Therapy; Dermatitis; Humans; Mouth Mucosa; Nasopharyngeal Neoplasms; Radiation Injuries; Radiotherapy; Stomatitis; Transforming Growth Factor beta; Transforming Growth Factor beta1

The molecular mechanisms leading to development of nasopharyngeal carcinoma (NPC) are not well understood. To delineate the features of NPC, we tried to identify unique expression of cellular genes in the tumor biopsy specimens.. By use of a combination of differential display and cDNA microarray analysis, we found two genes, 3E5 and 4A5, to show unique expression in the NPC biopsy specimens compared with nontumor nasopharyngeal tissues. Expression of 3E5, the osteoblast-specific factor-2 (OSF-2) gene, was detected at significantly higher levels in NPC biopsy specimens than that in control tissues, a finding confirmed using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). A correlation between expression of OSF-2 and its regulatory cytokine transforming growth factor-beta was observed in nontumor tissues but not in NPC biopsy specimens. On the other hand, expression of 4A5, whose sequences represent the 3' untranslated region of the polymeric immunoglobulin receptor (pIgR) gene, was detected rarely in NPC specimens but frequently in nontumor controls. The expression of pIgR in normal epithelial cells, but not in NPC tumor cells, was verified by RT-PCR and immunohistochemical staining.. NPC shows significant upregulation of OSF-2 and downregulation of pIgR. Expression of OSF-2 is likely to play a role in the pathogenesis of NPC. In addition, expression of OSF-2 and pIgR is disassociated with the expression of their regulatory cytokines in NPC biopsy specimens, suggesting that the tumors may have altered responses to certain cytokines.

Topics: Cell Adhesion Molecules; Gene Expression Regulation, Neoplastic; Humans; Nasopharyngeal Neoplasms; Oligonucleotide Array Sequence Analysis; Receptors, Polymeric Immunoglobulin; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Juvenile nasopharyngeal angiofibroma is a rare nasopharyngeal tumor that occurs exclusively in adolescent boys. It is a histologically benign but locally persistent growth of stromal and vascular tissue. Although male hormones and some growth factors, such as transforming growth factor beta1 (TGF-beta1), insulin-like growth factor II (IGF-II), and, lately, the proto-oncogene beta-catenin, have been implicated in the histogenesis of the tumor, the biologic signaling pathways that drive this peculiar fibrovascular proliferation are still nuclear.. To evaluate immunoexpressions of beta-catenin, c-Kit, p130Cas, TGF-beta3, bone morphogenic protein 4, nerve growth factor (NGF), and the IGF receptor (IGF-1R) in a series of juvenile nasopharyngeal angiofibromas and to compare to that of a group of nasal polyps.. A standard immunohistochemical technique was used on paraffin sections of 12 sporadic juvenile nasopharyngeal angiofibromas and 15 nasal polyps with microwave or steam antigen retrieval. Immunoreactivity was analyzed semiquantitatively in stromal cells and endothelial cells of each case.. The expressions of beta-catenin (nuclear), c-Kit (cytoplasmic), and NGF (cytoplasmic) were higher and more frequent in stromal cells of juvenile nasopharyngeal angiofibromas than those of nasal polyps. Both juvenile nasopharyngeal angiofibromas and nasal polyps showed similarly frequent and strong immunoreactivity for p130Cas and TGF-beta3 and weak immunoreactivity for bone morphogenic protein 4 in both stromal cells and endothelial cells. No IGF-1R immunoreactivity was detected in any case of either group.. Our results support the role of beta-catenin in juvenile nasopharyngeal angiofibromas and suggest a potential involvement of c-Kit and NGF signaling pathways in the juvenile nasopharyngeal angiofibromas. Although the biologic significance of c-Kit in juvenile nasopharyngeal angiofibromas has yet to be defined, the finding of frequent and high c-Kit expression might have therapeutic importance for patients with juvenile nasopharyngeal angiofibromas.

Topics: Adolescent; Adult; Angiofibroma; Antigens, Surface; Bone Morphogenetic Proteins; Child; Crk-Associated Substrate Protein; Growth Substances; Humans; Immunohistochemistry; Male; Nasal Polyps; Nasopharyngeal Neoplasms; Nerve Growth Factor; Paraffin Embedding; Phosphoproteins; Proteins; Proto-Oncogene Mas; Proto-Oncogene Proteins c-kit; Receptor, IGF Type 1; Receptors, Progesterone; Retinoblastoma Protein; Retinoblastoma-Like Protein p130; Transforming Growth Factor beta; Transforming Growth Factor beta3

We had proved that different latent membrane protein 1 (LMP1) variants of Epstein-Barr virus (EBV) had different effects upon growth characteristics of a human well-differentiated nasopharyngeal carcinoma (NPC) cell strain CNE1. This study was designed to investigate the possible effects of different LMP1 variants on resistance of CNE1 to TGFbeta1 and the related mechanism(s) so as to further elucidate the intrinsic mechanisms of their growth-promoting effects upon CNE1.. The plasmids including J124 (served as a control plasmid),124-B95-8 (carried LMP1 gene cloned from B95-8 lymphocytes,B95-8-LMP1), and J124- CAO-5 (carried LMP1 gene cloned from NPC tissues,CAO-LMP1) were introduced into CNE1 by liposomal transfection. The transfected cell strains were named CNE1-V,CNE1-B,and CNE1-C,respectively. Gene and protein expression of LMP1 in CNE1 were identified by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis,respectively. Then growth inhibition assay using MTT colorimetric method and flow cytometry were conducted to investigate different effects of the two LMP1 variants on resistance of CNE1 to TGFbeta1. Meanwhile,TGFbetaRI,TGFbetaRII, and cyclin D1 were detected by Western blot analysis and p15 mRNA was examined by semi-quantitative RT-PCR.. Two transfected cell strains (CNE1-B and CNE1-C) stably expressing different LMP1 variants were established successfully. When the treating concentration of TGFbeta1 was 5 ng/ml, the growth inhibitory rates of CNE1, CNE1-V,CNE1-B,and CNE1-C were 31.8%, 27.9%, 10.94%, and -4.26%, respectively, and the proliferation index (PI) were (24.55+/-2.55)%, (25.43+/-2.18)%, (46.78+/-2.56)%, and (54.70+/-3.84)%, respectively. CAO-LMP1 induced complete TGFbeta1 resistance in CNE1, whereas B95-8-LMP1 induced partial resistance. Neither of the two LMP1 variants had effects on TGFbetaRI and TGFbetaRII protein expression in CEN1,whereas both of them induced cyclin D1 expression significantly. CAO-LMP1 induced higher level of cyclin D1 than B95-8-LMP1 did (P< 0.05). B95-8-LMP1 had no significant effect on p15 mRNA expression (P >0.05), whereas CAO-LMP1 down-regulated p15 mRNA level obviously (P< 0.05).. B95-8-LMP1 could induce partial resistance of CNE1 to TGFbeta1 and the main mechanism was correlated with up-regulation of cyclin D1 protein, whereas CAO-LMP1 could induce complete resistance to TGFbeta1 and the mechanisms were correlated with up-regulation of cyclin D1 protein as well as down-regulation of p15 mRNA.

Topics: Cell Division; Cell Transformation, Viral; Drug Resistance, Neoplasm; Genetic Variation; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Viral Matrix Proteins

To find reliable diagnostic immunological indicators in peripheral blood for nasopharyngeal carcinoma, and to evaluate the possibility of cancer screening and early diagnosis of the malignancies in the future.. Plasma samples were obtained from 83 patients with nasopharyngeal carcinoma and from 105 patients with benign diseases. Nine cytokines were selected as the candidates for the indicators and their quantity in the plasma samples determined by enzyme-linked immunosorbent assay, the result of which was analyzed statistically.. Interleukin (IL)-4 level was obviously increased, while IL-6, IL-12, transforming growth factor (TGF)-beta, interferon (IFN)-gamma levels significantly reduced (P<0.05) in the plasma from patients with nasopharyngeal carcinoma.. These cytokins may serve as the indicators in the diagnosis of nasopharyngeal carcinoma.

Topics: Biomarkers, Tumor; Cytokines; Enzyme-Linked Immunosorbent Assay; Humans; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-6; Nasopharyngeal Neoplasms; Transforming Growth Factor beta

Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, especially in southern China. One of the most striking features of this disease is its close relationship with Epstein-Barr Virus (EBV). However, to date there is no direct study on the mechanisms involved in the role of EBV in the tumorigenesis of NPC, largely due to lack of an experimental model. Available hypotheses on the association between EBV and NPC are generated from non-nasopharyngeal epithelial cell systems such as human keratinocytes or mouse epithelial cells, which may not truly represent the biological properties of nasopharyngeal epithelial (NP) cells. In this study, we report the establishment of two immortalized NP cell lines, NP69SV40T and NP39E6/E7, using SV40T and HPV16E6/E7 oncogenes. We found that NP60SV40T and NP39E6/E7 cell lines not only maintained many characteristics of normal NP cells (i.e. keratin profile and responsive to TGFbeta inhibition) but also highly responsive to one of the EBV encoded genes, LMP1. Comparative genome hybridization (CGH) analysis showed that these two cell lines contained multiple genetic alterations, some of which have been described in NPC. The immortalized NP cell lines are non-tumorigenic and exhibit anchorage-dependent growth. These cell lines may provide a possible cell model system for studying the mechanisms involved in the tumorigenesis of NPC.

Topics: Antigens, Polyomavirus Transforming; Cell Division; Cell Line, Transformed; Chromosomes, Human; Enzyme Activation; Epithelial Cells; Genes, Viral; Herpesvirus 4, Human; Humans; Models, Biological; Nasopharyngeal Neoplasms; Nasopharynx; Nucleic Acid Hybridization; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Repressor Proteins; Simian virus 40; Telomerase; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viral Matrix Proteins

Juvenile nasopharyngeal angiofibroma (JNA) is a histologically benign, locally aggressive neoplasm of the nasopharynx that exclusively affects male adolescents. It is known to be sensitive to androgens, but there are likely intermediary cytokines and/or growth factors that mediate aggressive stromal cell proliferation and angiogenesis. Transforming growth factor beta1 (TGF-beta1) is a polypeptide that is secreted in an inactive form, cleaved to produce an active form, and then deactivated in the tissues. It activates fibroblast proliferation and is known to induce angiogenesis.. To evaluate the presence of activated TGF-beta1 within the stroma of JNA specimens and to quantify the percentage of JNA specimens expressing the active growth factor.. Immunohistochemical analysis was performed on 19 specimens of JNA using a unique antibody that identifies only the activated form of TGF-beta1. The percentage of cells staining positively for activated TGF-beta1 was determined semiquantitatively by visual methods.. Of 19 cases stained, all 19 (100%) showed strong positive staining (2 cases with 33%-66% of cells staining and 17 with 66%-100% of cells staining). Activated TGF-beta1 was identified in stromal cell nuclei and cytoplasm and in the endothelium of the capillaries within all specimens of JNA.. The localization of activated TGF-beta1 to the fibroblasts and endothelial cells within JNA tumors suggests that TGF-beta1 may play a role in the stromal cell proliferation and angiogenesis associated with JNA. Additional receptor studies and more quantitative methods of analysis are needed to further define the role of TGF-beta1 in the pathogenesis of JNA.

Topics: Adolescent; Angiofibroma; Humans; Immunohistochemistry; Male; Nasopharyngeal Neoplasms; Transforming Growth Factor beta

To study the expression of transforming growth factor(TGF) beta s, their receptors and TGF beta-receptor interacting protein-1 (TRIP-1) in nasopharygneal carcinoma.. Immunohistochemical technology and in situ hybridization methods were adopted to detect the TRIP-1 mRNA and 3 kinds of TGF beta isoforms and 2 kinds of TGF beta receptors protein in the same biopsy specimen.. The positive expression of TGF beta 1, TGF beta 2, TGF beta 3, TGF beta R I and TGF beta R II was stronger in the tumor adjacent epithelium than in the tumor itself, which were 65.79%, 66.67%, 55.26%, 48.57% and 63.16% higher than those in the tumor itself respectively(P < 0.01). The level of TRIP-1mRNA measured in the epithelial cells was also higher than that in the tumor cells (19.32 +/- 10.70 versus 11.96 +/- 5.85, P < 0.05).. The signal transmission of TGF beta family is diminished in the poorly differentiated squamous cell carcinoma of nasopharynx. It may be a factor for the development of nasopharygneal carcinoma.

Topics: Carcinoma, Squamous Cell; Eukaryotic Initiation Factor-3; Humans; Immunohistochemistry; In Situ Hybridization; Nasopharyngeal Neoplasms; Protein Biosynthesis; Proteins; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta

Nasopharyngeal carcinomas (NPCs) of non-keratinizing type are strongly associated with Epstein-Barr virus (EBV). EBV and its gene products induce the synthesis and/or release of transforming growth factor beta1 (TGF-beta1) from human cells and platelets. TGF-beta1 is an immunosuppressive cytokine, and many tumors are known to secrete it, to counter the host immune response. To determine the potential role of this cytokine in the pathogenesis of NPC, 53 serum samples from patients with EBV-associated NPC and 20 from healthy donors were analyzed for total and active TGF-beta content using ELISA. Serum samples for TGF-beta content were also analyzed from NPC patients at different clinical stages of the tumors. Significantly higher (p < 0.01) levels of active and total TGF-beta were found in the sera of NPC patients than in control sera. The ratio of active:total TGF-beta was also significantly (p < 0.01) increased in the NPC sera. Levels of this cytokine were also significantly higher (p < 0.05) in the sera of patients with advanced stages of tumor compared to patients with earlier stages. Furthermore, higher levels were seen in patients with relapsing than with remitting tumors; even higher levels were observed in NPC patients who died of the tumor. Our data suggest a role of this cytokine in the pathogenesis of NPC; therefore, it may prove to be a valuable biomarker molecule for the diagnosis and prognosis of NPC. Int. J. Cancer (Pred. Oncol.) 84:396-399, 1999.

Topics: Biomarkers, Tumor; Enzyme-Linked Immunosorbent Assay; Herpesvirus 4, Human; Humans; Lymphatic Metastasis; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Predictive Value of Tests; Recurrence; Survival Analysis; Transforming Growth Factor beta

The mechanism of growth inhibition by transforming growth factor (TGF)-beta 1 was investigated. We examined the growth inhibitory effects of TGF-beta 1 on human nasopharyngeal carcinoma (KB) cells which constitutively expressed p53. TGF-beta 1 suppressed the DNA synthesis of KB cells in a dose-dependent manner. It had minimal effect on adenovirus-2-transduced KB cells expressing either adenovirus early region 1B (E1B) or 1A (E1A) product, which respectively binds to p53 or Rb product and inhibits its function, and no growth inhibition at all was observed with KB cells expressing both E1B and E1A products. Dephosphorylation of the p53 was promoted by TGF-beta 1 stimulation in KB cells, but not in E1B-producing KB cells, which sequestrate the function of p53. The growth inhibition of KB cells by TGF-beta 1 was significantly reduced by treatment with okadaic acid. These results suggest that p53 transduces the antiproliferative signal of TGF-beta 1 possibly through its dephosphorylation.

Topics: Adenovirus E1A Proteins; Adenovirus E1B Proteins; Blotting, Western; Cell Division; DNA, Viral; Dose-Response Relationship, Drug; Ethers, Cyclic; Genes, p53; Humans; Nasopharyngeal Neoplasms; Okadaic Acid; Phosphorylation; Transduction, Genetic; Transforming Growth Factor beta; Tumor Cells, Cultured