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Long non-coding RNAs (lncRNAs) play an important role in breast cancer progression, but the function of lncRNAs in regulating tumor-associated macrophages (TAMs) remains unclear. As carriers of lncRNAs, exosomes play an important role as mediators in the communication between cancer cells and the tumor microenvironment. In this study, we found that lncRNA HAGLROS was highly expressed in breast cancer tissues and plasma exosomes, and its high expression was related to the poor prognosis of breast cancer patients. Functionally, breast cancer cell-derived exosomal lncRNA HAGLROS promotes breast cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT) process and angiogenesis by inducing TAM/M2 polarization. Mechanistically, lncRNA HAGLROS competitively binds to miR-135-3p to prevent the degradation of its target gene COL10A1. Collectively, these results indicated that the lncRNA HAGLROS/miR-135b-3p/COL10A1 axis promoted breast cancer progression, and revealed the interactive communication mechanism between breast cancer cells and TAMs, suggesting that lncRNA HAGLROS may be a potential biomarker and therapeutic target for breast cancer.
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Neoplasias de la Mama , Exosomas , MicroARNs , ARN Largo no Codificante , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Exosomas/metabolismo , Exosomas/genética , Regulación Neoplásica de la Expresión Génica , Macrófagos/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patologíaRESUMEN
Prostate cancer (PC) is a major global health concern affecting male individuals. Among its variants, androgen-independent prostate cancer exhibits slow progression and lacks effective treatment targets, rendering it insensitive to hormone therapy. Recent reports have highlighted the significance of Mortalin, an important oncogene, in tumor migration and invasion through various signaling pathways. Experimental evidence from in-vivo and in-vitro studies indicate upregulated expression of Mortalin in prostate cancer tissues. Moreover, it has been shown to regulate the epithelial-mesenchymal transition (EMT) process via the Wnt/ß-catenin signaling pathway, thereby promoting prostate cancer proliferation and metastasis. These findings suggest that Mortalin may serve as a promising novel immunotherapeutic target for prostate cancer.
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Objective: This study aimed to explore the efficacy of transarterial chemoembolization (TACE) combined with microwave ablation (MWA) adjuvant to lenvatinib and anti-PD-1 antibodies for patients with hepatocellular carcinoma (HCC). Methods: A retrospective analysis of 67 patients with HCC treated at our hospital between October 2018 and May 2022 was conducted. All patients underwent a combination of TACE and MWA. Among them, 29 received postoperative treatment with molecular-targeted agents, like lenvatinib, along with anti-PD-1 antibodies such as sindilizumab, karelizumab, or tirilizumab. The remaining 38 patients did not receive postoperative systemic therapies, like targeted or immunotherapy. The survival and prognosis of all patients were analyzed. Results: Nine patients in the observation group and 29 patients in the control group experienced recurrence, and the median progression-free survival 1 (PFS1) was not reached 'Not Applicable'(NA) and 17.05 months (P=0.035), respectively. Failure to combine adjuvant therapy was identified as an independent risk factor for tumor recurrence, and the observation group had a 0.245 times lower risk of recurrence compared to that in the control group (P=0.005). Multivariable Cox regression analysis confirmed that the maximum tumor size, and tumor number were risk factors for tumor recurrence. Patients with a large maximum tumor size had a 1.519 times higher risk of recurrence compared to those with a small maximum tumor size (P=0.006), and patients with a large number of tumors had a 5.978 times higher risk of recurrence compared to those with a small number of tumors (P=0.02). The median PFS2 of the two groups was 11.795 and 21.257 months, respectively, though not statistically significant (P=0.955). However, there was a disparity in the percentage of BCLC stages associated with recurrence between the two groups. In the observation group approximately 22.22% of patients progressed to stage C, while in the control group, this proportion was 34.48%. The observation group exhibited a lower risk of distant metastasis compared to the control group. Conclusion: Adjuvant treatment of HCC following TACE combined with MWA improved PFS and achieved better clinical outcomes compared to that with TACE combined with MWA alone.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/terapia , Estudios Retrospectivos , Microondas/uso terapéutico , Resultado del Tratamiento , Quimioembolización Terapéutica/efectos adversosRESUMEN
Exosomes are progressively being detected as an indicator for the diagnosis and prognosis of cancer in clinical settings. Many clinical trials have confirmed the impact of exosomes on tumor growth, particularly in anti-tumor immunity and immunosuppression of exosomes. Therefore, we developed a risk score based on genes found in glioblastoma-derived exosomes. In this study, we used the TCGA dataset as the training queue and GSE13041, GSE43378, GSE4412, and CGGA datasets as the external validation queue. Based on machine algorithms and bioinformatics methods, an exosome-generalized risk score was established. We found that the risk score could independently predict the prognosis of patients with glioma, and there were significant differences in the outcomes of patients in the high- and low-risk groups. Univariate and multivariate analyses showed that risk score is a valid predictive biomarker for gliomas. Two immunotherapy datasets, IMvigor210 and GSE78220, were obtained from previous studies. A high-risk score showed a significant association with multiple immunomodulators that could act on cancer immune evasion. The exosome-related risk score could predict the effectiveness of anti-PD-1 immunotherapy. Moreover, we compared the sensitivity of patients with high- and low-risk scores to various anti-cancer drugs and found that patients with high-risk scores had better responses to a variety of anti-cancer drugs. The risk-scoring model established in this study provides a useful tool to predict the total survival time of patients with glioma and guide immunotherapy.
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Exosomas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Pronóstico , Exosomas/genética , BiomarcadoresRESUMEN
PD-L1 is closely related to the immune escape process of tumour cells, and targeted PD-L1 clinical immunotherapy has been implemented. However, whether PD-L1 is involved in TAM/M2 polarization in the TME of NSCLC and its specific mechanism remain unclear. In order to clarify the specific role of PD-L1 in NSCLC and to seek new treatments for NSCLC, we designed a series of experimental studies. After constructing the co-culture system and conditioned medium system, the proliferation, apoptosis, metastasis, angiogenesis, EMT process and stemness of NSCLC were detected by MTT, flow cytometry, Transwell, endothelial cell tube formation and western blot assays. The results showed that αPD-L1 reversed TAM/M2 polarization by suppressing STAT3 phosphorylation in TAM/M2, therapy inhibiting NSCLC cell migration, angiogenesis, EMT process and stemness. However, αPD-L1 had no effect on the proliferation and apoptosis abilities of NSCLC cells. In vivo experiments showed that αPD-L1 inhibited lung metastasis of NSCLC and reversed TAM/M2 polarization in TME. The study investigates the mechanism by which PD-L1 regulates TAMs polarization in TME and promotes malignant progression of NSCLC, providing a new theoretical basis for PD-L1 targeted therapy of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Movimiento Celular , Apoptosis , Línea Celular Tumoral , Factor de Transcripción STAT3/genéticaRESUMEN
PURPOSE: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA which has been identified to be involved in alternative non-homologous end joining (A-NHEJ) pathways by binding with PARP1 and LIG3 in myeloma cells. This study aims to explore the roles of MALAT1 in DNA repair processes in non-small cell lung cancer (NSCLC). METHODS: The interactions between MALAT1 and proteins were identified by co-immunoprecipitation and RNA pulldown. The interactions between MALAT1 and microRNAs (miRNA) were predicted by bioinformatics tools and confirmed by luciferase assay and RNA pulldown. The DNA damages were quantified by comet assay. The cell viability was examined by MTT assay and the cell apoptosis was determined by flow cytometry. RESULTS: MALAT1 is identified to be involved in A-NHEJ pathway in NSCLC cells. However, in LIG3-null cells where A-NHEJ pathway is inactivated, targeting MALAT1 still increases DNA damages, suggesting that MALAT1 participates in other DNA repair pathways. Subsequently, MALAT1 is identified to bind with miR-146a and miR-216b, which directly target the 3'UTR of BRCA1. MALAT1 is confirmed to functions as a competing endogenous RNA (ceRNA) absorbing miR-146a and miR-216b, upregulating BRCA1 expression and protecting Homologous Recombination (HR) pathway in NSCLC cells. Finally, overexpression MALAT1 protects NSCLC cells from the cytotoxic effect of cisplatin. While, targeting MALAT1 in NSCLC cells induces DNA damages by repressing HR pathway and sensitizes NSCLC cells to cisplatin which had the potential for NSCLC treatment. CONCLUSION: MALAT1 is involved in HR pathway by protecting BRCA1 and targeting MALAT1 induces DNA damages in NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína BRCA1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , ARN Largo no Codificante/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Biología Computacional , Daño del ADN/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , ARN Largo no Codificante/agonistas , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/genética , ARN Interferente Pequeño/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
HOX (homeobox) genes encode a family of transcriptional regulators, which have an important role in morphogenesis and differentiation during embryonic development. Their deregulated expression is involved in the carcinogenesis of many human solid tumours. In the present study, we show that HOXB5 mRNA was significantly overexpressed in gastric cancer tissues compared with adjacent normal tissues. HOXB5-up-regulated cancer cells showed increased invasion and migration activity, but no change in proliferation activity, whereas HOXB5-down-regulated cells showed decreased invasion and migration activity. Up-regulation of HOXB5 resulted in up-regulation of ß-catenin, whereas inhibition of HOXB5 expression by siRNA led to the down-regulation of ß-catenin. Moreover, a significant correlation between HOXB5 and CTNNB1 (ß-catenin) mRNA expression was detected in gastric cancer tissues. Furthermore, we found that HOXB5 binds directly to the CTNNB1 promoter region and activates the transcriptional expression of ß-catenin, as well as its downstream target genes, encoding cyclin D1 and c-Myc, leading to an increase in the invasion and migration activity of human gastric cancer cells. Thus HOXB5 may be an important regulator of the Wnt/ß-catenin signalling pathway, thereby contributing to gastric cancer progression and metastasis.
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Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/biosíntesis , Neoplasias Gástricas/metabolismo , Transcripción Genética , Regulación hacia Arriba , Línea Celular Tumoral , Proliferación Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas de Homeodominio/genética , Humanos , Invasividad Neoplásica , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Vía de Señalización Wnt/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Thymosin ß4 (Tß4) is a 43-amino-acid peptide involved in many biological processes. However, the precise molecular signaling mechanism(s) of Tß4 in cell invasion and migration remain unclear. In this study, we show that Tß4 was significantly overexpressed in colorectal cancer tissues compared to adjacent normal tissues and high levels of Tß4 were correlated with stage of colorectal cancer, and that Tß4 expression was associated with morphogenesis and EMT. Tß4-upregulated cancer cells showed increased adhesion, invasion and migration activity, whereas Tß4-downregulated cells showed decreased activities. We also demonstrated that Tß4 interacts with ILK, which promoted the phosphorylation and activation of AKT, the phosphorylation and inactivation of GSK3ß, the expression and nuclear localization of ß-catenin, and integrin receptor activation. These results suggest that Tß4 is an important regulator of the ILK/AKT/ß-catenin/Integrin signaling cascade to induce cell invasion and migration in colorectal cancer cells, and is a potential target for cancer treatment.
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Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Timosina/genética , beta Catenina/genética , Anciano , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Femenino , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Integrinas/genética , Integrinas/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Timosina/metabolismo , Microambiente Tumoral , beta Catenina/metabolismoRESUMEN
BACKGROUND: Laparoscopic total gastrectomy (LTG) is a challenging surgical procedure that has substantial technical difficulties and complications. In this study, we investigated risk factors for morbidity and mortality after LTG, and the learning curve associated with postoperative morbidity. METHODS: Prospectively constructed data of 203 patients undergoing LTG between 2004 and 2013 were retrospectively reviewed. The multivariate logistic regression model was used to analyze risk factors for postoperative morbidity. The Cumulative Sum (CUSUM) technique was used to assess the learning curve. RESULTS: Postoperative morbidity and mortality after LTG was 18.7 and 1.5 %, respectively. Of 38 patients with postoperative morbidity, 7 (3.4 %) were managed with reoperation, 8 (4.0 %) with radiologic or endoscopic intervention, and 23 (11.3 %) with a conservative treatment. Of local complications, gastrointestinal bleeding was the most common (12 patients), followed by anastomosis leakage (9 patients) and intra-abdominal abscess (9 patients). Respiratory complication was the most common of the systemic complications. There were 17 cases (8.4 %) of complications exceeding grade III severity, of which anastomosis leakage was the most common. CUSUM analysis showed that postoperative morbidity reached a plateau after around 45 cases. Univariate and multivariate analyses revealed that old age (over 65 years of age) and surgical experience (<45 cases) were independent factors for postoperative morbidity after LTG. CONCLUSION: LTG is a feasible technique with acceptable morbidity and mortality. However, substantial surgical experience is of most importance to reduce postoperative morbidity and mortality.