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Prostate cancer (PCa) is a high-mortality cancer. Docetaxel (DCT) combined with second-generation anti-androgens is considered the golden standard therapy for PCa, whose application is limited for DCT resistance (DR). Therefore, exploring the mechanism of DR is of great importance. In this study, PCa cell lines of PC3 and DU145 were employed, and DR cells were constructed by treatment with graded DCT. CircSLC4A7, miR-1205, and microtubule-associated protein tau (MAPT) transfections were established. Cell counting kit-8 assay was performed to evaluate the cell activity and IC50 of DCT. After being treated with DCT, DR was assessed by colony formation assay, flow cytometry analysis, and terminal transferase-mediated UTP nick end-labeling assay. Real-time quantitative PCR and western blotting analysis evaluated the expression levels of genes. The dual-luciferase reporter gene assay verified the miR-1205 binding sites with circSLC4A7 and MAPT. An animal experiment was performed to assess the tumor growth influenced by circSLC4A7. After conducting DR cells and isolated exosomes, we found that not only co-culture with DR cells but also treatment with DR cells' exosomes would promote the DR of normal cells. Moreover, circSLC4A7 was highly expressed in DR cells and their exosomes. CircSLC4A7 overexpression enhanced DR, represented as raised IC50 of DCT, increased colony formation, and decreased cell apoptosis after DCT treatment, while circSLC4A7 knockdown had the opposite effect. MiR-1205 was confirmed as a circSLC4A7-sponged miRNA and miR-1205 inhibitor reversed the effect of sh-circSLC4A7. MAPT was further identified as a target of miR-1205 and had a similar effect with circSLC4A7. The effect of circSLC4A7 on DR was also confirmed by xenograft experiments. Collectively, circSLC4A7 in resistant-cells-derived exosomes promotes DCT resistance of PCa via miR-1205/MAPT axis, which may provide a new treatment strategy for DR of PCa.
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Background: Neoadjuvant therapy has become a mainstay of treatment for locally advanced resectable esophageal cancer. The objective of this research was to investigate the effectiveness and safety of neoadjuvant immunotherapy combined with chemotherapy in treating surgically removable esophageal squamous cell carcinoma (ESCC). Methods: From January 1, 2016 to April 1, 2023, we conducted a retrospective analysis of patients diagnosed with resectable esophageal cancer who underwent neoadjuvant immunotherapy combined with chemotherapy at The First Affiliated Hospital of Nanchang University. The primary endpoints of this study were pathologic complete response (pCR), major pathologic response (MPR) and disease-free survival (DFS). The secondary endpoints of this study were overall survival (OS), objective response rate (ORR) and safety. Results: A total of 122 patients with ESCC receiving neoadjuvant immune-chemotherapy (nICT) were included. Fifty-four patients achieved partial response (PR) and two patients achieved complete response (CR), with an ORR of 45.9%. Of the 106 patients who underwent surgery, a total of 28 patients achieved pCR (26.4%) and a total of 37 patients achieved MPR (34.9%). Grade 3 or higher adverse events occurred in 26 patients (21.3%). The most common postoperative complication was pneumonitis (25.5%). Conclusions: Neoadjuvant immunotherapy combined with chemotherapy demonstrates satisfactory efficacy in the treatment of locally advanced ESCC, with manageable treatment-related adverse events and postoperative complications.
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BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Cisplatino , Desoxicitidina , Gemcitabina , Medición de Resultados Informados por el Paciente , Humanos , Cisplatino/administración & dosificación , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Femenino , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/mortalidad , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Persona de Mediana Edad , Anticuerpos Monoclonales/administración & dosificación , Anciano , Adulto , Calidad de VidaRESUMEN
PURPOSE: This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65 years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). RESULTS: A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2 months (95% CI: 5.1-7.3), and the median OS was 15.3 months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. CONCLUSION: The study demonstrated that individuals older than 65 years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Puntos de Control Inmunológico , Supervivencia sin Progresión , Humanos , Anciano , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tasa de SupervivenciaRESUMEN
OBJECTIVE: The study aimed to explore the clinical and pathological characteristics, survival outcomes, and prognostic factors of colorectal hepatoid adenocarcinoma. METHODS: We performed two cases of colorectal hepatoid adenocarcinoma treated at the Oncology Department of the First Affiliated Hospital of Nanchang University. We also reviewed literature up to the present and performed a retrospective study of colorectal hepatoid adenocarcinoma. RESULTS: Among the 39 patients included in this study, 28 had primary tumors in the colon, 9 in the rectum, and 2 in the rectosigmoid junction. The median age was 52 years (range 31-75 years); 28 patients (71.8%) were male. Out of the 32 patients for whom survival data were available, 24 patients succumbed to disease-related causes. The median overall survival of 32 patients was 8 months, with 1-year and 2-year overall survival rates of 31.0% and 16.0%, respectively. Univariate analysis revealed that depth of infiltration, presence of liver metastases, TNM stage, and the completeness of surgical resection were significantly associated with the overall survival period of colorectal hepatoid adenocarcinoma. CONCLUSION: Colorectal hepatoid adenocarcinoma exhibits a high degree of aggressiveness and poor prognosis. The major strategy for early-stage HAC was radical surgery and chemoradiotherapy demonstrates limited efficacy for extending survival.
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Adenocarcinoma , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Femenino , Estudios Retrospectivos , Adenocarcinoma/patología , Neoplasias Hepáticas/secundario , Recto/patologíaRESUMEN
To explore the clinicopathological characteristics, survival outcomes, and prognosis of very young gastric cancer (GC). From January 1, 2011 to January 1, 2021, GC patients under 30 years old treated in three tertiary hospitals were enrolled. Clinicopathological characteristics were summarized, prognostic factors and survival outcomes including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were retrospectively analyzed. One hundred patients were finally included, with a median age of 23 years.73 (73.0%) were female. Most patients had initial symptoms of abdominal pain (66.0%). The most common tumor locations were gastric antrum (38.0%) and gastric body (37.0%). The main histological types were diffuse (81.0%) and poorly differentiated (91.0%). Most patients presented with stage III-IV disease (82.0%) at diagnosis and the common sites of metastasis were ovary (39.5%) and peritoneum (27.6%). The mOS of the whole group was 23.3 months (95% CI 17.2-29.4). Moreover, the mOS of patients at stage I-II was not reached. The mOS of patients at stage III and stage IV was 40.6 months (95% CI 10.2-70.9) and 10.3 months (95% CI 8.9-11.6), respectively. The mDFS of stage I-III patients was 28.5 months (95% CI 14.7-42.3), and the mPFS of the metastatic patients was 4.5 months (95% CI 4.0-5.0). TNM stage (P = 0.005) and radical surgery (P = 0.001) were independent prognostic factors of overall survival. The very young GC were predominantly female, diffuse type, and advanced diagnosis. TNM stage and radical surgery were independent prognosis factors for overall survival.
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Neoplasias Gástricas , Humanos , Femenino , Adulto Joven , Adulto , Masculino , Pronóstico , Neoplasias Gástricas/patología , Estadificación de Neoplasias , Estudios Retrospectivos , GastrectomíaRESUMEN
Limonoids are considered the effective part in Meliaceae plants that exert anti-inflammatory effects. Gedunin-type limonoids specifically have anti-inflammatory effects. However, the role of gedunin-type limonoids in the inflammatory diseases mediated by NLRP3 inflammasome remains to be explored. We found that deacetylgudunin (DAG), a gedunin-type limonoid from Toona sinensis, had similar anti-inflammatory effects and lower toxicity than gedunin. Further studies showed that DAG down-regulated the NF-κB pathway, inhibited K+ efflux and ROS release, inhibited ASC oligomerization, and significantly weakened the interaction of NLRP3 with ASC and NEK7. Furthermore, DAG could not further inhibit IL-1ß secretion and K+ efflux when combined with the P2X7 inhibitor A438079. In conclusion, our research revealed that DAG exerted an anti-inflammatory effect by inhibiting the P2X7/NLRP3 signaling pathway and enriched the application of gedunin-type limonoids in inflammatory diseases driven by the NLRP3 inflammasome.
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Inflamasomas , Limoninas , Antiinflamatorios/farmacología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Limoninas/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , ToonaRESUMEN
The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.
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Neoplasias Gástricas , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Retroalimentación , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Musculares/metabolismo , Neoplasias Gástricas/patología , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) regulate tumor development and metastasis in several types of cancers through various molecular mechanisms. However, the biological role of most lncRNAs in pancreatic cancer (PC) remains unclear. Here, we explored the expression, biological functions, and molecular mechanism of LINC01128 in PC. METHODS: Quantitive reverse transcription PCR was used to detect the expression level of LINC01128 in PC tissues and different PC cell lines. A loss-of-function and gain-of-function experiment was used to explore the biological effects of LINC01128 on PC carcinogenesis in vitro and in vivo. Western blot analysis, subcellular fractionation experiment, luciferase reporter gene assay, and MS2-RNA immunoprecipitation experiment were used to study the potential molecular mechanism of LINC01128 during carcinogenesis. RESULTS: The expression of LINC01128 was upregulated in PC tissues and cell lines, and overexpression of LINC01128 was significantly related to the poor prognosis of patients with PC. Furthermore, silencing LINC01128 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of PC cells in vitro and tumor growth in vivo, while LINC01128 overexpression promoted these processes. Further research showed that LINC01128 acted as a sponge for microRNA miR-561-5p, and lactate dehydrogenase A (LDHA) was the downstream target gene of miR-561-5p. It was also revealed that the expression of miR-561-5p in PC was decreased, and a negative correlation between miR-561-5p and LINC01128 was revealed. Based on rescue experiments, LDHA overexpression partially restored the inhibitory effect of LINC01128 knockdown on proliferation, migration, and invasion of PC cells. CONCLUSIONS: LINC01128 promotes the proliferation, migration, invasion, and EMT of PC by regulating the miR-561-5p/LDHA axis, suggesting LINC01128 may be a new prognostic marker and therapeutic target in PC.
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F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC). However, the effects and molecular mechanisms of FBXW5 in GC remain unexplored. To elucidate the clinical significance of FBXW5, immunohistochemistry was conducted to reveal the positive correlation between FBXW5 expression and lymph node metastasis (p < 0.001) and TNM stage (training cohort: p = 0.018; validation cohort: p = 0.001). Further, patients with high FBXW5 expression were found to have poor prognosis (training cohort: log-rank p = 0.020; validation cohort: log-rank p = 0.025). Cell experiments revealed the promoting effects of FBXW5 on the proliferation, invasion, metastasis, and chemoresistance of GC cells. Blocking LATS1-YAP1 leads to the loss of FBXW5-mediated regulation of the Hippo pathway and partial functions. Further, co-immunoprecipitation and in vivo ubiquitination assays revealed the interaction between FBXW5 and LATS1, which promoted the ubiquitination and degradation of LATS1. Based on mouse xenograft assays, FBXW5 silencing attenuated the growth of subcutaneous tumor xenografts. Altogether, FBXW5 was found to inactivate the Hippo signaling pathway by enhancing LATS1 ubiquitination and degradation, which promoted the invasion, metastasis, and drug resistance of GC cells.
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Our study aimed to investigate the clinical significance and biological functions of Spindlin1 (SPIN1) in colorectal cancer (CRC) tumorigenesis and progression, as well as the mechanism underlying its upregulation. The expression of SPIN1 was detected by immunohistochemistry and western blotting assays. Bioinformatics prediction and dual-luciferase reporter assays were used to determine whether microRNA-381 (miR-381) could target SPIN1. A series of cell functional experiments were performed to investigate whether the miR-381-mediated regulation of SPIN1 is involved in the progression and aggressiveness of CRC cells via the Wnt/ß-catenin pathway. Our results showed that SPIN1 is frequently overexpressed in CRC tissues and cell lines, and its upregulation is positively correlated with disease progression and lymph node metastasis. Moreover, SPIN1 depletion suppresses cell growth, migration, and invasion through inactivation of the Wnt/ß-catenin signaling pathway, which recapitulates the effects of miR-381 upregulation. Moreover, SPIN1 is a target gene of miR-381, and miR-381 is downregulated in CRC. Furthermore, the reintroduction of SPIN1 partially abolished the miR-381-mediated inhibitory effects in CRC cells. In summary, our data revealed that the miR-381/SPIN1 axis greatly contributes to CRC tumorigenesis by orchestrating the Wnt/ß-catenin pathway, thereby representing actionable therapeutic targets for colorectal cancer patients.
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Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MicroARNs/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Vía de Señalización Wnt , Secuencia de Bases , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Invasividad Neoplásica , Fosfoproteínas/genética , Regulación hacia Arriba/genética , Vía de Señalización Wnt/genéticaRESUMEN
Copious evidence reveals that long non-coding RNAs (lncRNAs) exert great regulatory functions in various human cancers. LINC01224 is a novel lncRNA, identified as a cancer regulator of HCC. However, the underlying mechanisms and clinical significance of LINC01224 in other types of cancers need further researches to explore. In this study, we aimed to elucidate the biological role of LINC01224 in NSCLC progression. Presently, LINNC01224 expression was elevated and miR-2467 expression was down-regulated in NSCLC, compared with standard control. Then we described the reciprocal correlation between LINC01224 and miR 2467. Afterward, the dual-luciferase reporter assay, RIP assay and RNA pull-down assay validated the base-pair interaction between LINC01224 and miR-2467. Moreover, our findings demonstrated that the silence of LINC01224 inhibited cell proliferation and invasion in NSCLC and enhanced cisplatin (CDDP) sensitivity in vitro. Besides, rescue assays verified that miR-2467 inhibitor could reverse the effects on cell biological activities and CDDP resistance caused by knockdown of LINC01224. Finally, in vivo experiments implicated that knockdown of LINC01224 could inhibit NSCLC tumor growth. To sum up, LINC01224 can promote tumor progression and CDDP resistance in NSCLC via sponging miR-2467, suggesting a promising therapeutic target for better diagnosis and prognosis of NSCLC patients.
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Resistencia a Antineoplásicos , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MicroARNs/genética , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: Monoclonal antibodies that target the PD-1 receptor are emerging as promising therapeutic candidates for the treatment of biliary tract cancers (BTCs). The purpose of the current study was to assess the combination of the camrelizumab with chemotherapy as a first-line treatment for metastatic BTCs. METHODS: We conducted a prospective single-arm pilot study of PD-1 antibody (camrelizumab 3 mg/kg d1, Q2 W or Q3 W) combined with different chemotherapy regimens as first-line treatment for BTCs. Efficacy endpoints were objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Treatment-related adverse events (TRAEs) were also evaluated. RESULTS: Fourteen patients with histologically confirmed BTCs were evaluated. The ORR was 14.3% (95% CI: 1.8 to 42.8) and the DCR was 64.3% (95%CI: 41.7 to 86.9). The median PFS was 6.5 months (95% CI: 3.8 to 9.2), and the 6- and 12-month PFS rates were 61.6% and 12.3%, respectively. The median OS was 9.9 months (95% CI: 7.6 to 12.2), and the 6-and 12-month OS rates were 74.5% and 26.6%, respectively. All patients displayed at least 1 TRAE., and Grade 3 or 4 TRAEs occurred in 6 (42.86%) patients. CONCLUSIONS: Camrelizumab combined with chemotherapy as first-line treatment for metastatic BTCs demonstrated acceptable safety and efficacy in our pilot study. These findings warrant prospective controlled clinical trials comparing combinations of camrelizumab and chemotherapy to standard regimens.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/patología , Supervivencia sin Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Resultado del TratamientoRESUMEN
[This corrects the article DOI: 10.3389/fonc.2020.591698.].
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Long non-coding RNAs (lncRNAs) are a novel class of regulators in multiple cancer biological processes. However, the functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. In this study, we identified PWAR6 as a frequently down-regulated lncRNA in PDAC samples as well as a panel of pancreatic cancer cell lines. Down-regulated PWAR6 was associated with multiple clinical outcomes, including advanced tumour stage, distant metastasis, and overall survival of PDAC patients. In our cell-based assays, ectopic expression of PWAR6 dramatically repressed PDAC cells proliferation, invasion and migration, accelerated apoptosis, and induced cell cycle arrest at G0/G1 phase. In contrast, depletion of PWAR6 mediated by siRNA exhibited opposite effects on PDAC cell behaviours. In vivo study further validated the anti-tumour role of PWAR6 in PDAC. By taking advantage of available online sources, we also identified YAP1 as a potential PWAR6 target gene. Negative correlation between YAP1 and PWAR6 expressions were observed in both online database and our PDAC samples. Notably, rescue experiments further indicated that YAP1 is an important downstream effector involved in PWAR6-mediated functions. Mechanistically, PWAR6 could bind to methyltransferase EZH2, a core component of Polycomb Repressive Complex 2 (PRC2) in regulating gene expression, and scaffold EZH2 to the promoter region of YAP1, resulting in epigenetic repression of YAP1. In conclusion, our data manifest the vital roles of PWAR6 in PDAC tumorigenesis and underscore the potential of PWAR6 as a promising target for PDAC diagnosis and therapy.
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Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/patología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , Factores de Transcripción/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pronóstico , Tasa de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAPRESUMEN
Low-density lipoprotein receptor class A domain containing 2 (LDLRAD2) acts as a protein-coding gene in a large number of human diseases. However, the potential roles and underlying mechanism in pancreatic cancer remains unclear. Therefore, this study was conducted to address this question. Herein, we found that the expression of LDLRAD2 was elevated in pancreatic cancer tissues and cell lines. LDLRAD2 knockdown inhibited pancreatic cancer cell proliferation, migration, and invasion in vitro. Besides, silencing LDLRAD2 impaired tumor growth and metastasis in vivo and up-regulated the E-Cadherin level, whereas down-regulated the expression of N-Cadherin and Vimentin levels, which indicating that LDLRAD2 knockdown suppresses EMT. Additionally, LDLRAD2 knockdown decreased the Warburg effect and glycolytic enzymes expression. Pathway scan assay and western blotting assay indicated that LDLRAD2 knockdown significantly down-regulated the expression of phosphorylation of Akt and phosphorylation of mTOR, which suggested that knockdown of LDLRAD2 inhibits Akt/mTOR signaling pathway. Taken together, these findings suggested that LDLRAD2 may be an oncogene in pancreatic cancer via modulating Akt/mTOR signaling pathway.
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Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de la Membrana/genética , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Regulación hacia Arriba/genética , Efecto Warburg en OncologíaRESUMEN
BACKGROUND: Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated. METHODS: The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real-time quantitative PCR (RT-qPCR) were used to analyze protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates were analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA), and LinkedOmics database. RESULTS: The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC. CONCLUSIONS: The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks, and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC.
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Proteínas Relacionadas con la Folistatina , Neoplasias Gástricas , Biomarcadores , Proteínas Relacionadas con la Folistatina/genética , Humanos , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunologíaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. The long noncoding RNA (lncRNA) DUXAP8 has been reported to play an important role in CRC. This study investigated the mechanism by which this lncRNA regulates CRC progression. METHODS: The levels of lncRNA DUXAP8 in CRC tissues and cell lines were detected by qRT-PCR. We then knocked down or forced overexpression of DUXAP8, and the resultant effect on cell proliferation was determined by the Edu assay and a cell cycle analysis, and the effect on cell apoptosis was determined by flow cytometry. The cell invasion/migration ability and the epithelial-to-mesenchymal transition (EMT) markers were determined by Transwell/wound healing assays and Western blotting. CHIP and RNA pull-down assays were performed to determine the binding of Zeste gene enhancer 2 (EZH2) and trimethylated histone H3 to Lys27 (H3K27me3) in the E-cadherin promoter regions, or to DUXAP8. RESULTS: The levels of lncRNA DUXAP8 were significantly increased in CRC tissues and CRC cell lines. Knockdown of lncRNA DUXAP8 inhibited cell proliferation and the EMT process, and increased cell apoptosis, and overexpression of lncRNA DUXAP8 had an opposite effect. Both ChIP and RNA pull-down assays showed that the E-cadherin promoter region was bound by H3K27me3 and EZH2, which restrained E-cadherin expression. However, that binding was suppressed and E-cadherin expression was markedly induced by lncRNA DUXAP8 knockdown. Furthermore, lncRNA DUXAP8 could interact with EZH2 and H3K27me3. CONCLUSION: Our data indicated that lncRNA DUXAP8 could induce the progression of CRC by negatively regulating E-cadherin via interaction with EZH2 and H3K27me3. These findings suggest lncRNA DUXAP8 as target for treating CRC.
RESUMEN
Acylglycerol kinase (AGK) uses adenosine triphosphate (ATP) and acylglycerol to generate adenosine diphosphate (ADP) and acyl-sn-glycerol 3-phosphate in cells. Recent evidence has demonstrated that dysregulated AGK expression is associated with the development of various human cancers. This study investigated the effects of AGK on gastric cancer cell proliferation and carcinogenesis and explored the underlying molecular events. AGK expression was up-regulated in gastric cancer and was associated with poor prognosis in gastric cancer patients. AGK overexpression increased gastric cancer proliferation, invasion capacity and the expression of the epithelial-mesenchymal transition markers in vitro. Conversely, the knockdown of AGK expression reduced gastric cancer cell proliferation in vitro and in nude mouse tumour cell xenografts. Importantly, AGK expression was associated with the YAP1 expression in gastric cancer cells and tissues. YAP1 expression also transcriptionally induced AGK expression through the binding of TEAD to the AGK gene promoter. However, AGK expression inhibited the activation of the Hippo pathway proteins and induced YAP1 nuclear localization to enhance the transcription activity of YAP1/TEADs. In conclusion, the study demonstrates that AGK is not only a novel target of the Hippo-YAP1 pathway, but that it also positively regulates YAP1 expression, thus forming a YAP1-AGK-positive feedback loop.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Enzimológica de la Expresión Génica , Células HEK293 , Humanos , Ratones Desnudos , Invasividad Neoplásica , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Neoplasias Gástricas/patología , Transcripción Genética , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Pancreatic cancer (PC) is one of the most aggressive cancers and has an extremely poor prognosis worldwide. Long noncoding RNA (lncRNA) has been reported to be a potential prognostic biomarker in the initiation and prognosis of PC. Nevertheless, the biological functions and the detailed molecular mechanism of LINC00514 in PC remain unclear. METHODS: We measured the expression level of LINC00514 in PC tissues and cell lines by quantitative real-time PCR. Gain- and loss-of-function experiments were performed to explore the bioeffects of LINC00514 on PC development both in vitro and in vivo. Subcellular fractionation, luciferase reporter assay, RNA immunoprecipitation assay, pull-down assay and western blotting were performed to investigate the oncogenic molecular mechanisms of LINC00514. RESULTS: In this study, LINC00514 was shown to be upregulated in PC tissues and cell lines. Increased LINC00514 expression was significantly associated with the clinical progression and prognosis of PC patients. In addition, silencing LINC00514 inhibited PC cell proliferation, migration and invasion, while LINC00514 overexpression promoted these processes. Moreover, LINC00514 knockdown remarkably inhibited PC development and metastasis in vivo. Deeper investigations indicated that LINC00514 acted as a sponge for microRNA-28-5p (miR-28-5p) in PC and that Rap1b was a downstream target of miR-28-5p. Furthermore, the positive correlation of LINC00514 and Rap1b and the negative correlation between miR-28-5p and LINC00514 (or Rap1b) were revealed. Based on the rescue assays, Rap1b inhibition partially suppressed the oncogenic effect of LINC00514 overexpression on PC cell proliferation, migration and invasion. CONCLUSIONS: This study is the first to characterize the oncogenic function of the long noncoding RNA LINC00514 in pancreatic cancer progression by acting as a competing endogenous RNA (ceRNA) of miR-28-5p to upregulate Rap1b expression. Understanding this molecular mechanism might contribute to further discoveries of better diagnostic and therapeutic options for pancreatic cancer.