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Background: Currently, the prognosis of advanced intrahepatic cholangiocarcinoma (ICC) is poor, and the current treatment methods are not effective. Objective: The aim of this study was to evaluate the anticancer efficacy of chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors (TKIs) in patients with ICC. Methods: We retrospectively screened patients with advanced intrahepatic cholangiocarcinoma (ICC) who received chemotherapy combined with lenvatinib and PD-1. We evaluated overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), the disease control rate (DCR), the tumor shrinkage rate, and safety. Results: We enrolled 95 patients with ICC and divided them into three groups with a median follow-up duration of 15.1 months. The chemotherapy group (chemo-regimen group), chemotherapy combined with immune checkpoint inhibitors (dual-regimen group), and chemotherapy combined with lenvatinib (triple-regimen group) had median OS times of 13.1 months, 20.8 months, and 39.6 months, respectively. Notably, the triple-regimen group had a significantly longer OS than did the chemo-regimen and dual-regimen groups. The chemo-regimen group, dual-regimen group, and triple-regimen group reported median PFS durations of 4.8 months, 11.9 months, and 23.4 months, respectively. Both combination groups exhibited significantly longer PFS than the chemotherapy-only group (P<0.05). The ORRs of the chemo-regimen, dual-regimen, and triple-regimen groups were 18.2%, 55.5%, and 54.7%, respectively. The DCRs were 72.7%, 90%, and 96.2%, respectively, indicating significantly better outcomes in the combination therapy groups. Conclusion: The combination of chemotherapy with PD-1 inhibitors and lenvatinib demonstrates considerable efficacy and tolerability as a treatment strategy for patients with advanced ICC.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Compuestos de Fenilurea , Receptor de Muerte Celular Programada 1 , Quinolinas , Humanos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/mortalidad , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/mortalidad , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos

RESUMEN

Background: Hepatocellular carcinoma (HCC) is the most prevalent liver cancer. Despite of the improvement of therapies, the durable response rate and survival benefit are still limited for HCC patients. It's urgent to clarify the molecular mechanisms and find therapeutic strategies to improve the clinical outcome. TNFα-stimulated gene-6 (TNFAIP6) plays a critical role in the prognosis of various tumors, but its roles in HCC are still unclear. Methods: Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of TNFAIP6 expressions in HCC patients. Cell counting kit-8 (CCK-8), Edu assay, and transwell assay were performed to evaluate the malignancy of HCC cells. Glucose uptake, lactate production, ATP production, extracellular acidification rate (ECAR) by Seahorse XF analyzer were employed to evaluate the role of TNFAIP6 in the regulation of aerobic glycolysis. The expressions of key proteins involved in glycolysis were examined by Western blot. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) were used for protein-protein interactions or protein-RNA interactions respectively. Knockdown and overexpression of TNFAIP6 in HCC cells were employed for analyzing the functions of TNFAIP6 in HCC. Results: TNFAIP6 was significantly upregulated in HCC and predicted a poor clinical prognosis. Knockdown of TNFAIP6 inhibited in vitro cell proliferation, invasion, migration, as well as glycolysis in HCC cells. Mechanistically, we clarified that TNFAIP6 interacted with heterogeneous nuclear ribonucleoprotein C (HNRNPC), stabilized c-Myc mRNA and upregulated pyruvate kinase M2 (PKM2) to promote glycolysis. Conclusions: Our study reveals a molecular mechanism by which TNFAIP6 promotes aerobic glycolysis, which is beneficial for malignance of HCC and provides a potential clinical therapy for disease management.

RESUMEN

OBJECTIVE: To investigate the role of long non-coding RNA growth arrest-specific transcript 5 (lncRNA-GAS5) in breast cancer progression and epithelial-mesenchymal transition (EMT) of the cancer cells. METHODS: Real-time quantitative PCR (qRT-PCR) was used to detect the expression of lncRNA-GAS5 in 37 pairs of breast cancer and adjacent non-tumor tissues and in parental MCF-7 cells and paclitaxel-resistant MCF-7 (MCF-7/PR) cells, and the correlation of lncRNA-GAS5 expression with the clinical stage and lymph node metastasis of breast cancer was investigated. The expressions of the genes related with cell cycle and EMT at both the mRNA and protein levels were detected using qRT-PCR, Western blotting and immunohistochemistry. The changes in the biological behaviors and morphology of breast cancer cells with either lncRNA-GAS5 knockdown or overexpression were observed. Nude mouse models were established bearing breast cancer xenografts derived from MCF-7/PR cells or MCF-7/PR cells over-expressing lncRNA-GAS5, and the inhibitory effect of paclitaxel on tumor growth was evaluated. RESULTS: The transcriptional levels of lncRNA-GAS5 were significantly lower in breast cancer tissues than in the adjacent non-tumor tissues (P<0.05), and decreased lncRNA-GAS5 expression was significantly correlated with TNM stage and lymph node metastasis of breast cancer (P<0.05). lncRNA-GAS5 expression was also significantly lowered in paclitaxel-resistant breast cancer cells and showed a positive correlation with P21 expression and a negative correlation with CDK6. MCF-7 cells during EMT presented with a lowered expression of lncRNA-GAS5, whereas lncRNA-GAS5 over-expression strongly suppressed MCF-7/PR cell migration and invasion, and increased the susceptibility of the cells to paclitaxel. In the tumor-bearing nude mouse models, lncRNA-GAS5 overexpression in the tumor cells obviously enhanced the inhibitory effect of paclitaxel on tumor growth and lung metastasis by reversing the EMT marker proteins. CONCLUSION: A decreased expression of lncRNA-GAS5 promotes lung metastasis of breast cancer by inducing EMT, suggesting the potential of lncRNA-GAS5 as a therapeutic target in breast cancer.

Asunto(s)

Neoplasias de la Mama/genética , Transición Epitelial-Mesenquimal , ARN Largo no Codificante/genética , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Ratones Desnudos

RESUMEN

MicroRNAs (miRNAs) have been identified as major post-transcriptional regulators of the initiation and progression of human cancers, including breast cancer. However, the detail role of miR-451 has not been fully elucidated in breast cancer. In this study, we aimed to investigate the biological role and molecular mechanisms of miR-451 in drug resistance in breast cancer cell lines and in xenograft model. We show that miR-451 is decreased in human breast cancer specimens and in paclitaxel-resistant (PR) cells. Ectopic expression of miR-451 could inhibit the cell migration and invasion, promoted apoptosis, induced cell-cycle arrest Furthermore, tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ) was identified as a direct target of miR-451. Remarkably, the expression of YWHAZ is inversely correlated with the level of miR-451 in human breast cancer samples. Co-treatment with miR-451 mimics and YWHAZ-siRNA significantly enhanced YWHAZ knockdown in both SKBR3/PR and MCF-7/PR cells Moreover, miR-451 markedly inhibited expression of ß-catenin via YWHAZ and subsequently inhibited downstream gene cyclin D1, c-Myc expression. The results of xenograft model in vivo showed that intratumor injection of miR-451 agomir induced a tumor-suppressive effect in SKBR3/PR drug-resistant xenograft model. Taken together, our findings suggested that miR-451 might be considered as important and potential target in paclitaxel-resistant breast cancer treatment.

Asunto(s)

Proteínas 14-3-3/genética , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Animales , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Acquisition of resistance to paclitaxel is one of the most important problems in treatment of breast cancer patients, but the molecular mechanisms underlying sensitivity to paclitaxel remains elusive. Emerging evidence has demonstrated that microRNAs (miRNAs) play important roles in regulation of cell growth, migration and invasion through inhibiting the expression of its target genes. In our previous studies, we have shown that microRNA-335 (miR­335) decreased obviously between paclitaxel-resistant (PR) and parental breast cancer cells through miRNA microarray. However, the roles of miR­335 in breast cancer progression and metastasis are still largely unknown. NT21MP was designed and synthesized as an antagonist with CXCR4 to inhibit cellular proliferation and induce apoptosis. Therefore, the aim of this study was to explore the underlying mechanism of miR­335 and NT21MP in reverse PR in breast cancer cells. In this study, we found that miR­335 expression is significantly lower in PR MCF­7 and SKBR-3 cells (MCF­7/PR and SKBR-3/PR) compared with their parental MCF­7 and SKBR-3 cells. Functional experiments showed that overexpression of miR­335 and NT21MP increased the number of apoptosis cells, arrested cells in G0/G1 phase transition, and suppressed cell migration and invasion in vitro. Dual luciferase assays revealed that SETD8 is a direct target gene of miR­335. Furthermore, miR­335 markedly inhibited expression of SETD8 via Wnt/ß­catenin signaling and subsequently inhibited the expression of its downstream genes cyclin D1, and c­Myc. Additionally, ectopic expression of miR­335 or depletion of its target gene SETD8 could enhance the sensitivity of PR cells to paclitaxel. Taken together, these date elucidated that NT21MP and miR­335 mediated PR of breast cancer cells partly through regulation of Wnt/ß­catenin signaling pathway. Activation of miR­335 or inactivation of SETD8 could be a novel approach for the treatment of breast cancer.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Quimiocinas/genética , N-Metiltransferasa de Histona-Lisina/genética , MicroARNs/genética , Péptidos/genética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocinas/uso terapéutico , Ciclina D1/genética , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Péptidos/uso terapéutico , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética