RESUMO
Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15â¯% of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.
Assuntos
RNA Helicases DEAD-box , Desoxicitidina , Gencitabina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , RNA Longo não Codificante , Animais , Humanos , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ubiquitinação/efeitos dos fármacosRESUMO
The profound influence of microbiota in cancer initiation and progression has been under the spotlight for years, leading to numerous researches on cancer microbiome entering clinical evaluation. As promising biomarkers and therapeutic targets, the critical involvement of microbiota in cancer clinical practice has been increasingly appreciated. Here, recent progress in this field is reviewed. We describe the potential of tumor-associated microbiota as effective diagnostic and prognostic biomarkers, respectively. In addition, we highlight the relationship between microbiota and the therapeutic efficacy, toxicity, or side effects of commonly utilized treatments for cancer, including chemotherapy, radiotherapy, and immunotherapy. Given that microbial factors influence the cancer treatment outcome, we further summarize some dominating microbial interventions and discuss the hidden risks of these strategies. This review aims to provide an overview of the applications and advancements of microbes in cancer clinical relevance.
Assuntos
Microbiota , Neoplasias , Humanos , Relevância Clínica , Neoplasias/terapia , Neoplasias/diagnóstico , Biomarcadores , ImunoterapiaRESUMO
The microbiota of solid tumors was identified >100 years ago; however, heterogeneous composition and diversity have been revealed only recently. Growing evidence has suggested that several functional mechanisms of the intratumoral microbiota affect tumorigenesis and progression, suggesting that the intratumoral microbiota is a promising biomarker for multiple cancers. The low biomass of the intratumoral microbiota poses a major challenge to related research, thus necessitating the use of a multiple-modality integrated framework to resolve this dilemma. Advanced techniques such as single-cell sequencing provide significant clues, and the gradual optimization of functional experiments and culture-based methods enables deeper investigation of the underlying mechanisms involved. In this review, we outline the current state of research on the intratumoral microbiota and describe the challenges and comprehensive strategies for future research.
Assuntos
Microbiota , Neoplasias , Humanos , Neoplasias/microbiologia , Carcinogênese , Animais , Análise de Célula Única/métodosRESUMO
The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.
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Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Assuntos
Docetaxel , Resistencia a Medicamentos Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Piroptose , Ubiquitina-Proteína Ligases , Ubiquitinação , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dinaminas/metabolismo , Dinaminas/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Gasderminas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosforilação/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Piroptose/genética , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.
Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Docetaxel/uso terapêutico , Neoplasias Nasofaríngeas/patologia , Fatores de Transcrição/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/uso terapêutico , Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ubiquitina TiolesteraseRESUMO
An increasing number of studies have found that long non-coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non-protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras-related protein Rab-1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation-associated 2G4 (PA2G4) and stromal cell-derived factor 4 (SDF4; also known as 45-kDa calcium-binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173-knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173-RAB1B-PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients.
Assuntos
Neoplasias Nasofaríngeas , RNA Longo não Codificante , Proteínas de Ligação a RNA , Proteínas rab1 de Ligação ao GTP , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas rab1 de Ligação ao GTP/genética , Proteínas rab1 de Ligação ao GTP/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismoRESUMO
Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments.
Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Transição Epitelial-Mesenquimal/genética , Transdução de Sinais , Movimento Celular/genética , Neoplasias Nasofaríngeas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Proteínas de Choque Térmico HSP40/metabolismoRESUMO
Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8+ T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.
Assuntos
DNA Mitocondrial , Neoplasias Nasofaríngeas , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/metabolismo , Recidiva Local de Neoplasia , UbiquitinaçãoRESUMO
The tumor microbiome is believed to have a profound impact on tumor progression owing to its local colonization in the tumor microenvironment (TME). Using the Cancer Microbiome Atlas (TCMA), a database of curated, decontaminated microbial profiles for 3,689 oropharyngeal, esophageal, gastrointestinal, and colorectal tissue samples from 1,772 patients, we conducted a comprehensive multi-omics analysis to reveal microbial signatures among various cancers and the potential mechanisms involved in tumor progression of head and neck squamous cell carcinoma (HNSC). We found that compared with other cancer types, the tumor-resident microbiome of HNSC accounted for the highest bacterial abundance and strongest association with host TME signatures. Fusobacterium was found to be enriched in HNSC tissues, which was associated with an increased inflammatory effect and inferior prognosis. Moreover, we revealed that the microbiota-associated inflammatory TME was attributed to the competing endogenouse RNA (ceRNA) network and chromatin accessibility. IMPORTANCE Studies on revealing the composition and potential mechanisms of the tumor microbiome are still at an initial stage. We uncovered the potential contribution of the tumor-resident microbiota on the immunosuppressive microenvironment in HNSC, which will provide a new perspective for tumor microbiome research and yield valuable insights into the clinical management of HNSC.
Assuntos
Neoplasias de Cabeça e Pescoço , Fusobacterium , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral/genéticaRESUMO
Epitranscriptomic remodeling such as N6 -methyladenosine (m6 A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6 A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6 A hypomethylation in metastatic NPC tissues. The m6 A-modified CBX1 mRNA transcript is recognized and destabilized by the m6 A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.
Assuntos
Heterocromatina , Neoplasias Nasofaríngeas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Epigênese Genética/genética , Heterocromatina/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT1/genéticaRESUMO
Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hypermethylated in NPC, which results in its downregulation. USP44 enhances the sensitivity of NPC cells to radiotherapy in vitro and in vivo. USP44 recruits and stabilizes the E3 ubiquitin ligase TRIM25 by removing its K48-linked polyubiquitin chains at Lys439, which further facilitates the degradation of Ku80 and inhibits its recruitment to DNA double-strand breaks (DSBs), thus enhancing DNA damage and inhibiting DNA repair via non-homologous end joining (NHEJ). Knockout of TRIM25 reverses the radiotherapy sensitization effect of USP44. Clinically, low expression of USP44 indicates a poor prognosis and facilitates tumour relapse in NPC patients. This study suggests the USP44-TRIM25-Ku80 axis provides potential therapeutic targets for NPC patients.
Assuntos
Carcinogênese/genética , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Ubiquitina Tiolesterase/genética , Apoptose/genética , Apoptose/efeitos da radiação , Carcinogênese/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Metilação de DNA , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Regiões Promotoras Genéticas/genética , Tolerância a Radiação/genética , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Importance: Microbiota-tumor interactions have qualified microbiota as a promising prognostic biomarker in various types of cancers. Although the nasopharynx acts as a crucial niche of the upper respiratory tract microbiome, whether the intratumoral microbiota exists and its clinical significance in nasopharyngeal carcinoma (NPC) remain uncertain. Objective: To evaluate the clinical significance of intratumoral microbiota for individual prognostication in patients with NPC. Design, Setting, and Participants: This retrospective cohort study included NPC biopsy samples from 2 hospitals: Sun Yat-sen University Cancer Center (Guangzhou, China) and Zhejiang Cancer Hospital (Hangzhou, China) between January 2004 and November 2016, with follow-up through November 2020. A total of 802 patients were included according to the following criteria: with histologically proven NPC, without distant metastasis at initial diagnosis, had not received antitumor treatment before biopsy sampling, aged between 18 and 70 years, with complete medical records and regular follow-up, without a history of cancer, and successfully extracted enough DNA for experiments. Main Outcomes and Measures: The primary end point was disease-free survival, and the secondary end points included distant metastasis-free survival and overall survival. To assess the existence and load of intratumoral microbiota in 96 patients with NPC with or without tumor relapse, 16S rRNA sequencing and quantitative polymerase chain reaction were used. The associations between intratumoral bacterial load and clinical outcome were evaluated in 241 fresh-frozen NPC samples (training cohort) and validated in paraffin-embedded NPC samples of internal (n = 233) and external (n = 232) validation cohorts. Metagenomic and transcriptome analyses were performed to ascertain the origin and underlying mechanism of intratumoral bacteria. Results: A total of 802 patients with NPC (mean [SD] age, 46.2 [10.6] years; 594 [74.1%] male) were enrolled. Microbiota presented within NPC tumor tissues, among which Corynebacterium and Staphylococcus predominated. Patients with a high bacterial load in the training cohort had inferior rates of disease-free survival (hazard ratio [HR], 2.90; 95% CI, 1.72-4.90; P < .001), distant metastasis-free survival (HR, 3.18; 95% CI, 1.58-6.39; P < .001), and overall survival (HR, 3.41; 95% CI, 1.90-6.11, P < .001) than those with a low bacterial load, a finding that was validated by the internal and external validation cohorts. Single-nucleotide variant analysis revealed that the nasopharyngeal microbiota was the main origin of NPC intratumoral bacteria. Transcriptome and digital pathology analyses demonstrated that a higher intratumoral bacterial load was negatively associated with T-lymphocyte infiltration. Conclusions and Relevance: Intratumoral bacterial load was a robust prognostic tool for patients with NPC in this cohort study, indicating potential guidance for treatment decisions in patients at different levels of risk of malignant progression.
Assuntos
Microbiota , Neoplasias Nasofaríngeas , Adolescente , Adulto , Idoso , Biomarcadores , China/epidemiologia , Estudos de Coortes , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Nucleotídeos , Prognóstico , RNA Ribossômico 16S , Estudos Retrospectivos , Adulto JovemRESUMO
Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT-qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.
Assuntos
Neoplasias Nasofaríngeas , RNA Longo não Codificante , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/patologia , RNA Longo não Codificante/genéticaRESUMO
OBJECTIVE: Metabolic syndrome has been identified as a prognostic predictor in multiple cancers. This study aimed to evaluate the impact of metabolic syndrome on the clinical outcome of patients with nasopharyngeal carcinoma (NPC) and its mechanism. METHODS: A cohort of 2003 NPC patients with a median follow-up time of 96.3 months (range: 4.1-120.0 months) were enrolled in this analysis. Kaplan-Meier curves and the Log rank test were used to determine the differences in progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS). Univariate and multivariable analyses were used to identify independent prognostic predictors. Untargeted metabolomics (LC-HRMS) was used to detect the serum metabolic profiles of 10 well-matched patients with or without metabolic syndrome. Differential metabolite-based enrichment analysis and pathway analysis were performed to identify the potential mechanism of metabolic syndrome in NPC. RESULTS: A total of 171/2003 (8.5%) patients were diagnosed with metabolic syndrome, and these patients tended to be male (P < 0.001) and older (P = 0.003). Patients with metabolic syndrome had poorer PFS (P = 0.011), CSS (P = 0.003) and OS (P = 0.001) than those without metabolic syndrome. Univariate and multivariable analyses showed that metabolic syndrome was a statistically significant and independent predictor for PFS (HR: 1.34, 95% CI: 1.03-1.75, P = 0.032), CSS (HR: 1.53, 95% CI: 1.12-2.08, P = 0.008), and OS (HR: 1.50, 95% CI: 1.13-2.00, P = 0.006). The serum metabolic profile of patients with metabolic syndrome was distinct from that of patients without metabolic syndrome. A total of 319 differential metabolites [log2(FC)>1 or log2 (FC)<-1] were identified and were significantly involved in D-glutamine and D-glutamate metabolism, and valine, leucine and isoleucine biosynthesis. CONCLUSION: Metabolic syndrome can serve as a prognostic predictor and guide a more personalized therapy for NPC patients.
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PURPOSE: Serum cystatin C has been considered as a significant prognostic factor for various malignancies. This study aimed to evaluate the relationship between serum cystatin C level before antitumor treatment and the prognosis of nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: A cohort of 2077 NPC patients were enrolled between April 2009 and September 2012. The Kaplan-Meier curves and log rank tests were used to determine the differences of overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox regression analyses were used to determine independent prognostic factors. RESULTS: Overall, 362/2077 (17.4%) patients had high serum cystatin C level, and they were older and more male (both P<0.001), and they had higher TNM stage (all P<0.05). Kaplan-Meier analysis revealed that patients with high serum cystatin C had worse OS (P<0.001) and DFS (P<0.001). Univariate and multivariate Cox regression analysis showed that high serum cystatin C level was an independent prognostic predictor of OS (HR: 1.56, 95%CI: 1.25-1.95) and DFS (HR: 1.38, 95%CI: 1.13-1.68). Subgroup analysis based on TNM stage revealed that advanced-stage NPC patients with high serum cystatin C had poorer OS (P<0.001) and DFS (P<0.001). CONCLUSION: Our results revealed that high serum cystatin C level before antitumor treatment can predict clinical outcomes of NPC patients treated with IMRT, and it can guide clinicians to formulate more personalized therapy for NPC patients.
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PURPOSE: The prognostic value of serum calcium levels in nasopharyngeal carcinoma (NPC) remains unknown. This study aimed to evaluate the prognostic value of serum calcium levels in patients with NPC. PATIENTS AND METHODS: A total of 2094 patients diagnosed with NPC between April 2009 and September 2012 were enrolled in this retrospective analysis. The median follow-up time was 96.3 months (range: 4.1-120.0 months). Univariate and multivariable Cox proportional hazards models were used to identify significant and independent prognostic predictors of overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and relapse-free survival (RFS). RESULTS: Overall, low serum calcium levels were detected in 1109/2094 (53.00%) patients and tended to be more frequently detected in older (P<0.001) and female (P=0.001) patients. Patients with low serum calcium levels had poorer OS (P=0.011), DFS (P=0.012) and DMFS (P=0.004) than those with high serum calcium levels, but serum calcium levels had no significant effect on RFS (P=0.376). In univariate and multivariable analyses, low serum calcium levels were a statistically significant and independent prognostic factor for OS, DFS, and DMFS but had no prognostic value for RFS. CONCLUSION: Serum calcium levels can serve as a prognostic predictor and guide more individualized treatment for NPC patients.