RESUMEN
Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.
Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Histonas , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Histonas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5/metabolismo , Lactato Deshidrogenasa 5/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Pronóstico , Regulación hacia Arriba/genéticaRESUMEN
BRD7 was identified as a tumor suppressor in nasopharyngeal carcinoma (NPC). Circular RNAs (CircRNAs) are involved in the occurrence and development of NPC as oncogenes or tumor suppressors. However, the function and mechanism of the circular RNA forms derived from BRD7 in NPC are not well understood. In this study, we first identified that circBRD7 was a novel circRNA derived from BRD7 that inhibited cell proliferation, migration, invasion of NPC cells, as well as the xenograft tumor growth and metastasis in vivo. Mechanistically, circBRD7 promoted the transcriptional activation and expression of BRD7 by enhancing the enrichment of histone 3 lysine 27 acetylation (H3K27ac) in the promoter region of its host gene BRD7, and BRD7 promoted the formation of circBRD7. Therefore, circBRD7 formed a positive feedback loop with BRD7 to inhibit NPC development and progression. Moreover, restoration of BRD7 expression rescued the inhibitory effect of circBRD7 on the malignant progression of NPC. In addition, circBRD7 demonstrated low expression in NPC tissues, which was positively correlated with BRD7 expression and negatively correlated with the clinical stage of NPC patients. Taken together, circBRD7 attenuates the tumor growth and metastasis of NPC by forming a positive feedback loop with its host gene BRD7, and targeting the circBRD7/BRD7 axis is a promising strategy for the clinical diagnosis and treatment of NPC.
Asunto(s)
MicroARNs , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Regiones Promotoras Genéticas , Proliferación Celular/genética , Neoplasias Nasofaríngeas/patología , Epigénesis Genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , MicroARNs/genética , Proteínas que Contienen BromodominioRESUMEN
BACKGROUND: Oesophageal squamous cell carcinoma is one of the most commonly diagnosed carcinomas in China, and postoperative radiotherapy plays an important role in improving the prognosis of patients. Carcinomas in different locations of the oesophagus could have different patterns of lymph node metastasis after surgery. METHODS: In this multicentric retrospective study, we enrolled patients with middle thoracic oesophageal squamous cell carcinomas from 3 cancer centres, and none of the patients underwent radiotherapy before or after surgery. We analysed the lymph node recurrence rates in different stations to explore the postoperative lymphatic recurrence pattern. RESULTS: From January 1st, 2014, to December 31st, 2019, 132 patients met the criteria, and were included in this study. The lymphatic recurrence rate was 62.1%. Pathological stage (P = 0.032) and lymphadenectomy method (P = 0.006) were significant predictive factors of lymph node recurrence. The recurrence rates in the supraclavicular, upper and lower paratracheal stations of lymph nodes were 32.6%, 28.8% and 16.7%, respectively, showing a high incidence. The recurrence rate of the subcarinal node station was 9.8%, while 8.3% (upper, middle and lower) thoracic para-oesophageal nodes had recurrences. CONCLUSIONS: We recommend including the supraclavicular, upper and lower paratracheal stations of lymph nodes in the postoperative radiation field in middle thoracic oesophageal carcinomas. Subcarinal station is also potentially high-risk, while whether to include thoracic para-oesophageal or abdominal nodes needs careful consideration.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Escisión del Ganglio Linfático , Ganglios Linfáticos , Metástasis Linfática , Recurrencia Local de Neoplasia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/cirugía , Estudios Retrospectivos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Anciano , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/radioterapia , Esofagectomía , Adulto , Pronóstico , China/epidemiología , Estadificación de NeoplasiasRESUMEN
BACKGROUND: HSP60 is a heat shock proteins (HSPs) family member and help mitochondrial protein to fold correctly. Survivin is one of the inhibitors of apoptosis protein family member, which plays a significant part in cancer progression. They were capable of forming HSP60-survivin complexes and involved in the development of various tumors. METHODS: The Cancer Genome Atlas (TCGA) database demonstrated that HSP60 and survivin and their correlation on mRNA expression level with OSCC patients. Besides, expression of HSP60 and survivin proteins was studied utilizing immunohistochemistry in tissue microarrays (TMA) in OSCC and in adjacent non-cancerous squamous epithelium (Non-CCSE) tissues. RESULTS: Significantly increased levels of HSP60 and survivin in most cancers compared to normal tissue by pan-cancer analysis. HSP60 and survivin proved a significantly increased expression in OSCC samples compared to Non-CCSE both on mRNA and protein (both P < 0.05). Additionally, elevated HSP60 displayed a positive correlation with survivin in terms of mRNA and protein expression levels (all P < 0.001). Patients with OSCC who had advanced clinical stage or lymph node metastasis (LNM) showed higher HSP60 expression (P = 0.004, P = 0.006, respectively). Higher levels of the proteins HSP60 and survivin were significantly inversely correlated relationship with OSCC patients' overall survival rates in multivariate survival analysis (P = 0.018, P = 0.040). From the above results, overexpression of HSP60 and survivin protein may serve as independent biomarkers predicting poor prognosis in OSCC. CONCLUSIONS: Elevated HSP60 and survivin might be served as novel poor prognosis biomarkers for surgically resected OSCC patients.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Survivin , PronósticoRESUMEN
Dermatomyositis (DM) is an autoimmune disease often complicated with malignant tumors. More than 50% of DM patients have myositis specific autoantibodies in their bodies. DM specific autoantibodies [including anti-migration inhibitory factor (Mi)-2 antibody, anti-nuclear matrix protein (NXP)-2 antibody, anti-transcription intermediary factor (TIF) 1-γ antibody, and anti-small ubiquitin like modifier activating enzyme (SAE) antibody] play important roles in the pathogenesis of malignancy associated DM. Revealing the role of DM specific autoantibodies in the development of malignant tumors in DM patients can provide important evidence for accurately assessing the risk of developing malignant tumors in DM patients, and also provide new ideas for clinical diagnosis of DM and precise treatment.
Asunto(s)
Enfermedades Autoinmunes , Dermatomiositis , Neoplasias , Humanos , Autoanticuerpos , Neoplasias/complicacionesRESUMEN
BACKGROUND: Ribosomal protein S6 (S6), a downstream effect media of the AKT/mTOR pathway, not only is a part of 40S small subunit of eukaryotic ribosome, but also involves in protein synthesis and cell proliferation during cancer development. METHODS: In present study, we explore the association between phosphorylated S6 (p-S6) protein expression and clinicopathological features as well as prognostic implications in NSCLC. P-S6 was detected in tissue microarrays (TMAs) containing 350 NSCLC, 53 non-cancerous lung tissues (Non-CLT), and 88 cases of matched metastatic lymph node lesions via immunohistochemistry (IHC). Transwell assays and wound healing assay were used to assess the effects of p-S6 inhibition on NSCLC cell metastasis. RESULTS: The p-S6 expression in NSCLC was more evident than that in Non-CLT (p < 0.05). Compared to NSCLC patients who have no lymph node metastasis (LNM), those with LNM had higher p-S6 expression (p = 0.001). Regardless of lung squamous cell carcinoma (SCC) or adenocarcinoma (ADC), p-S6 was increased obviously in metastatic lymph nodes compared with matched primary cancers (p = 0.001, p = 0.022, respectively). Inhibition of p-S6 decreased the metastasis ability of NSCLC cells. In addition, p-S6 was an independent predicted marker for LNM in patients with NSCLC (p < 0.001). According to survival analysis, patients with highly expressed p-S6 had a lower survival rate compared with that with lower expression (p = 0.013). P-S6 is an unfavorable independent prognostic factor for NSCLC patients (p = 0.011). CONCLUSION: Increased expression of p-S6 is not only a novel predictive biomarker of LNM but also poor prognosis in NSCLC.
Asunto(s)
Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma/patología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Estadificación de Neoplasias , PronósticoRESUMEN
Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.
Asunto(s)
MicroARNs/biosíntesis , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Neoplásico/biosíntesis , Transcripción Genética , Proteínas Supresoras de Tumor/metabolismo , Factor de Transcripción YY1/metabolismo , Adulto , Línea Celular Tumoral , Femenino , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Proteínas Proto-Oncogénicas c-myc/genética , ARN Neoplásico/genética , Proteínas Supresoras de Tumor/genética , Factor de Transcripción YY1/genéticaRESUMEN
BACKGROUND: The major clinical obstacle that limits the long-term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor-mutant non-small cell lung cancer is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance. METHODS: Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V-positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/Cas9 technique. RESULTS: The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinib-resistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib-resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib-resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib-resistant cells. Knockout of Bim in osimertinib-resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib-resistant cells for this combination. CONCLUSIONS: The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic.
Asunto(s)
Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Panobinostat/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Quimioterapia Combinada , Receptores ErbB/genética , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Neoplasias Pulmonares/metabolismo , Panobinostat/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
Nasopharyngeal carcinoma (NPC) has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. We have previously shown that high cyclooxygenase-2 (COX-2) expression is associated with a poor prognosis of patients with NPC and inhibits chemotherapy-induced senescence in NPC cells. In this study, we found that COX-2 was upregulated in cancer-associated fibroblasts (CAFs) derived from NPC by RNA-Seq. Furthermore, elevated COX-2 expression in CAF was detected in NPC patients with poor survival and distant metastasis by using immunohistochemistry. Then, we identified that COX-2 is highly expressed in CAF at the distant metastasis site in seven paired NPC patients. High expression of COX-2 and secretion of prostaglandin E2, a major product catalyzed by COX-2 in fibroblasts, promotes migration and invasiveness of NPC cells in vitro. On the contrary, inhibition of COX-2 has the opposite effect in vitro as well as in the COX-2-/- mouse with the lung metastasis model in vivo. Mechanistically, we discovered that COX-2 elevates tumor necrosis factor-α expression in CAF to promote NPC cell migration and invasiveness. Overall, our results identified a novel target in CAF promoting NPC metastasis. Our findings suggested that high expression of COX-2 in CAF may serve as a new prognostic indicator for NPC metastasis and provide the possibility of targeting CAF for treating advanced NPC.
Asunto(s)
Fibroblastos Asociados al Cáncer/patología , Ciclooxigenasa 2/genética , Regulación Neoplásica de la Expresión Génica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Animales , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Pronóstico , Regulación hacia ArribaRESUMEN
AIMS: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly documented rare tumour type. Its molecular pathological features have thus far been very little studied. METHODS AND RESULTS: There were 13 PRNRP cases including 3 The Cancer Genome Atlas (TCGA) cases and our 10 cases in this study. The 3 TCGA cases were found by a combined analysis of GATA3 mRNA expression levels and digital slides from the TCGA papillary renal cell carcinoma project. KRAS codon 12 mutations were identified in the three PRNRPs from TCGA. Of our 10 PRNRP cases, the mutations were also discovered using Sanger sequencing in seven (77.8%) of nine cases with available DNA, where KRAS p.G12V (n = 3), p.G12D (n = 2), p.G12R (n = 1) and p.G12C (n = 1) alterations were found. PRNRP shared similar gene expression profiles with renal distal tubules via an interprofile correlation analysis. Gene set enrichment analysis revealed that genes involved in 'KEGG aldosterone regulated sodium reabsorption' or 'hallmark apical surface' were enriched in PRNRP. Moreover, polarised immunostaining patterns for L1CAM and EMA in the distal tubule were maintained in PRNRP. CONCLUSIONS: These results imply that the tumour potentially originates from the distal tubule, especially from the cortical collecting duct, and probably retains its cell polarity, except for nuclear inversion. We therefore propose that oncocytic papillary renal neoplasm with inverted nuclei (OPRNIN) is a better name for this tumour type. OPRNIN is a kidney site-specific KRAS mutation neoplasm different from conventional papillary renal cell carcinoma.
Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenoma Oxifílico/genética , Adenoma Oxifílico/patología , Adulto , Anciano , Núcleo Celular/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large-scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down-regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease-free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all-trans-RA (ATRA), we found that APLNR was significantly up-regulated in NPC cell lines (5-8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA-induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound-healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial-mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K-protein kinase B-mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.-Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang, Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng, Z., Xiong, W., Tan, M., Li, G., Zhang, W. APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.
Asunto(s)
Receptores de Apelina/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Transferasas/metabolismo , Tretinoina/uso terapéutico , Antineoplásicos/uso terapéutico , Receptores de Apelina/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Many cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT). METHODS: Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples. RESULTS: Our data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. CONCLUSIONS: Here, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT. Video abstract.
Asunto(s)
Antígeno B7-H1/metabolismo , Proteolisis , Ubiquitina Tiolesterasa/metabolismo , Animales , Complejo del Señalosoma COP9/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Citotoxicidad Inmunológica , Células HEK293 , Humanos , Terapia de Inmunosupresión , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Ratones , Péptido Hidrolasas/metabolismo , Unión Proteica , Estabilidad Proteica , Linfocitos T/inmunología , UbiquitinaciónRESUMEN
BACKGROUND: Cyclin D1 is an essential part of oncogenic transformation. We previously proved that cyclin D1 was upregulated in nasopharyngeal carcinoma (NPC) and promoted the NPC cell proliferation. But the association between cyclin D1 and the clinical outcome of NPC has not yet been determined. The study explores the possible relevance between the cyclin D1 expression and clinical parameters and its predictive value of prognosis in NPC patients. METHODS: We analyzed the clinical data from 379 NPC patients and 112 non-NPC patients in our previous study, which made further statistics. Receiver operating curve (ROC) was applied to select the optimal cutoff points. By analyzing the clinical data from 101 NPC patients using Chi-squared test, we estimated the relationship between the cyclin D1 expression level and clinicopathological parameters. We also used Kaplan-Meier method and log-rank test assess and compared the disease-free survival (DFS) rate and overall survival (OS) rate. The Cox proportional hazards model was adopted to perform the univariate and multivariate analyses. RESULT: Receiver operating curve analysis reported that cyclin D1 was used to differentiate between NPC patients and non-NPC patients (P < .001, sensitivity: 53.6%, specificity: 85.7%, AUC = 0.752). Cyclin D1 was positively correlated with lymph node metastasis (P = .015). A survival analysis of the 101 NPC patients indicated that the positive expression of cyclin D1 was predictive of a good prognosis (DFS: P = .010, OS: P = .019). Multivariate analysis showed that cyclin D1 could be used independently to predict NPC patients' prognosis (DFS: P = .038). CONCLUSION: The overexpression of cyclin D1 is a good prognostic marker for NPC.
Asunto(s)
Ciclina D1 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ciclina D1/análisis , Ciclina D1/genética , Ciclina D1/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Pronóstico , Análisis de Supervivencia , Regulación hacia Arriba/genética , Adulto JovenRESUMEN
Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos , Etopósido/farmacología , Neoplasias Pulmonares/metabolismo , Proteína Proto-Oncogénica c-ets-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN , Humanos , Neoplasias Pulmonares/genética , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Hidrolasas Diéster Fosfóricas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
OBJECTIVES: To explore the expression of programmed death ligand-1 (PD-L1) as well as the correlation between the expression and the clinicopathological features or prognosis in non-small cell lung cancer (NSCLC). METHODS: The expression of PD-L1 protein in 254 cases of surgically resected lung adenocarcinoma (L-ADC), 228 cases of surgically resected lung squamous cell cancer (L-SCC), and 99 cases of non-cancerous control lung tissues was detected with immunohistochemical SP method. The correlation between the PD-L1 expression and clinicopathological features was analyzed. Kaplan-Meier univariate and Cox multivariate regression analyses were performed to assess the prognosis of patients with L-ADC and L-SCC, respectively. RESULTS: Positive percentage of PD-L1 protein expression was higher in the tissues of L-ADC and L-SCC than that in the non-cancerous control lung tissues respectively (both P<0.05). Positive percentage of PD-L1 protein expression was higher in the tissues of L-SCC than that in the tissues of L-ADC (P<0.05). However, there were no correlation between the expression of PD-L1 and age, gender, pathological grades, clinical stages, and lymph node metastasis in L-ADC and L-SCC respectively (all P>0.05). Overall survival rate was evidently lower in the L-ADC patients with positive expression of PD-L1 protein compared to the patients with negative staining of PD-L1 (P<0.01). Multivariate Cox regression analysis further identified that the L-ADC patients of positive expression of PD-L1 protein had a poor prognosis (P<0.01). CONCLUSIONS: The positive percentage of PD-L1 protein expression is higher in the L-SCC patients than that in the L-ADC patients. Positive expression of PD-L1 protein can be served as an independent prognostic factor of poor prognosis in the patients with L-ADC.
Asunto(s)
Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma del Pulmón , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Neoplasias Pulmonares/cirugía , Pacientes , PronósticoRESUMEN
Tumor suppressor p53 is a master regulator of apoptosis and plays key roles in cell cycle checkpoints. p53 responds to metabolic changes and alters metabolism through several mechanisms in cancer. Lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, is highly expressed in a variety of tumors and catalyzes pyruvate to lactate. In the present study, we first analyzed the association and clinical significance of p53 and LDHA in breast cancer expressing wild-type p53 (wt-p53) and found that LDHA mRNA levels are negatively correlated with wt-p53 but not with mutation p53 mRNA levels, and low p53 and high LDHA expression are significantly associated with poor overall survival rates. Furthermore, p53 negatively regulates LDHA expression by directly binding its promoter region. Moreover, a series of LDHA gain-of-function and rescore experiments were carried out in breast cancer MCF7 cells expressing endogenous wt-p53, showing that ectopic expression of p53 decreases aerobic glycolysis, cell proliferation, migration, invasion and tumor formation of breast cancer cells and that restoration of the expression of LDHA in p53-overexpressing cells could abolish the suppressive effect of p53 on aerobic glycolysis and other malignant phenotypes. In conclusion, our findings showed that repression of LDHA induced by wt-p53 blocks tumor growth and invasion through downregulation of aerobic glycolysis in breast cancer, providing new insights into the mechanism by which p53 contributes to the development and progression of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Glucólisis/genética , L-Lactato Deshidrogenasa/genética , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Células MCF-7 , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , ARN Mensajero/genética , Tasa de SupervivenciaRESUMEN
AIMS: HSP90, as a molecular chaperone, has numerous substrate proteins, including HIF-1α and p-AKT, but the relationships among HSP90, HIF-1α and p-AKT have not been investigated in NPC. We examined and analysed the correlation between expression of HSP90, HIF-1α and p-AKT and clinicopathological features of NPC. METHODS: We collected 445 cases of NPC and 54 cases of non-cancerous nasopharyngeal epithelia tissues, detected expression of HSP90, HIF-1α and p-AKT proteins in these tissues by immunohistochemistry. RESULTS: The results indicated that overexpression of HSP90, HIF-1α and p-AKT in NPC was significantly higher than that in non-cancerous nasopharyngeal epithelia (P < 0.05). The overexpression of HIF-1α in primary NPC was significantly lower than that in matched lymph node metastatic NPC (P = 0.024) or recurrent NPC (P = 0.039). The overexpression of HSP90 (P < 0.001) and HIF-1α (P = 0.031) was evidently higher in late stage NPC. NPC patients with lymph node metastasis (LNM) had a higher overexpression rate of HSP90 (P < 0.001) than those without LNM. Increased HSP90 expression was positively associated with HIF-1α expression (r = 0.367, P < 0.001) and p-AKT (r = 0.142, P = 0.003) expression in NPC. Furthermore, HIF-1α was also related to p-AKT expression (r = 0.114, P = 0.017). The overall survival rate for NPC patients with up-regulated HSP90 was significantly lower than those with down-regulated HSP90 (P < 0.001), as was found with raised HIF-1α (P = 0.036) and increased p-AKT (P = 0.044). Multivariate Cox regression analysis further identified that HSP90 and HIF-1α were independent poor prognostic factors for NPC. CONCLUSIONS: Taken together, elevated HSP90 was associated with expression of HIF-1α and p-AKT in NPC. Furthermore, high expression of HSP90 and HIF-1α could be used as a novel independent poor prognostic biomarker for patients with NPC.
Asunto(s)
Biomarcadores de Tumor/análisis , Proteínas HSP90 de Choque Térmico/biosíntesis , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Adulto , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/mortalidad , Neoplasias Nasofaríngeas/mortalidad , Pronóstico , Proteínas Proto-Oncogénicas c-akt/biosíntesisRESUMEN
Wilms tumor is extremely rare in adults. There is no standard treatment for Wilms tumor in adults, and the therapy protocols are based on those used in children. Here, we report a case of Wilms tumor in a 24-year-old woman who was effectively treated with apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2. The favorable outcome suggested that antiangiogenic therapy might be effective in treating adults with Wilms tumors. Starting with this case, we reviewed the features of Wilms tumors in adults and its treatment with antiangiogenic therapy. The information in this review could provide a novel approach to treating adults with Wilms tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Piridinas/uso terapéutico , Tumor de Wilms/tratamiento farmacológico , Adulto , Femenino , Humanos , Neoplasias Renales/patología , Pronóstico , Tumor de Wilms/patología , Adulto JovenRESUMEN
The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1ß in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1ß. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA-treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Inflamasomas/inmunología , Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/mortalidad , Lesión Pulmonar/inmunología , Inmunidad Adaptativa , Animales , Caspasa 1/genética , Caspasa 1/inmunología , Caspasa 1/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Humanos , Gripe Humana/fisiopatología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Lesión Pulmonar/fisiopatología , Lesión Pulmonar/virología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/virología , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/fisiopatología , Infecciones por Orthomyxoviridae/virología , ARN Interferente Pequeño/genética , Carga Viral/inmunologíaRESUMEN
BACKGROUND: Atypical manifestations, such as elevated serum immunoglobulin-G4 (IgG4) and extra-pulmonary IgG4 positive plasmacyte infiltration, have been described in patients with eosinophilic granulomatosis with polyangiitis (EGPA), such complicated situation might not be readily differentiated from IgG4-related disease. CASE PRESENTATION: Here, we report an interesting and rare case of EGPA in a 41 year-old male with negative anti-neutrophil cytoplasmic antibodies (ANCAs), which showed abundant pulmonary IgG4-positive plasma cells infiltration and markedly elevated serum IgG4 levels without extra-pulmonary lesions of IgG4-related disease. The clinical characteristics hesitated us whether the diagnosis as EGPA overlapping with IgG4-related lung disease should be concluded because of the absence of storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration. The patient's systemic symptoms, pulmonary lesions, blood eosinophils count / percentage, and serum IgG4 levels were significantly improved with immunosuppressive therapy. CONCLUSIONS: We consider that the overlapping pathogenesis exists in the disease course of EGPA and IgG4-related disease, which may lead to interaction during the course of the diseases. And the utilization of diagnostic criteria for IgG4-related lung disease with the careful differentiation is needed in such cases.