RESUMEN
BACKGROUND: Cirrhosis is a recognized risk factor for developing hepatocellular carcinoma (HCC). Few studies have reported the expression profile of circRNAs in HCC samples compared to paratumour dysplastic nodule (DN) samples. METHODS: The Arraystar Human circRNA Array combined with laser capture microdissection (LCM) was used to analyse the expression profile of circRNAs in HCC samples compared to paratumour DN samples. Then, both in vitro and in vivo HCC models were used to determine the role and mechanism of key circRNA in HCC progression and treatment sensitivity. RESULTS: We found that circMEMO1 was significantly downregulated in HCC samples and that the level of circMEMO1 was closely related to the OS and disease-free survival (DFS) of HCC patients. Mechanistic analysis revealed that circMEMO1 can modulate the promoter methylation and gene expression of TCF21 to regulate HCC progression by acting as a sponge for miR-106b-5p, which targets the TET family of genes and increases the 5hmC level. More importantly, circMEMO1 can increase the sensitivity of HCC cells to sorafenib treatment. CONCLUSION: Our study determined that circMEMO1 can promote the demethylation and expression of TCF21 and can be considered a crucial epigenetic modifier in HCC progression.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Carcinoma Hepatocelular/patología , Metilación de ADN , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/patología , ARN Circular/metabolismo , Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Metilación de ADN/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , MicroARNs/metabolismo , Regiones Promotoras Genéticas/genética , ARN Circular/genética , Sorafenib/uso terapéuticoRESUMEN
BACKGROUND: Amplification of chromosome 7q21-7q31 is associated with tumor recurrence and multidrug resistance, and several genes in this region are powerful drivers of hepatocellular carcinoma (HCC). We aimed to investigate the key circular RNAs (circRNAs) in this region that regulate the initiation and development of HCC. METHODS: We used qRT-PCR to assess the expression of 43 putative circRNAs in this chromosomal region in human HCC and matched nontumor tissues. In addition, we used cultured HCC cells to modify circRNA expression and assessed the effects in several cell-based assays as well as gene expression analyses via RNA-seq. Modified cells were implanted into immunocompetent mice to assess the effects on tumor development. We performed additional experiments to determine the mechanism of action of these effects. RESULTS: circMET (hsa_circ_0082002) was overexpressed in HCC tumors, and circMET expression was associated with survival and recurrence in HCC patients. By modifying the expression of circMET in HCC cells in vitro, we found that circMET overexpression promoted HCC development by inducing an epithelial to mesenchymal transition and enhancing the immunosuppressive tumor microenvironment. Mechanistically, circMET induced this microenvironment through the miR-30-5p/Snail/ dipeptidyl peptidase 4(DPP4)/CXCL10 axis. In addition, the combination of the DPP4 inhibitor sitagliptin and anti-PD1 antibody improved antitumor immunity in immunocompetent mice. Clinically, HCC tissues from diabetic patients receiving sitagliptin showed higher CD8+ T cell infiltration than those from HCC patients with diabetes without sitagliptin treatment. CONCLUSIONS: circMET is an onco-circRNA that induces HCC development and immune tolerance via the Snail/DPP4/CXCL10 axis. Furthermore, sitagliptin may enhance the efficacy of anti-PD1 therapy in a subgroup of patients with HCC.
Asunto(s)
Carcinoma Hepatocelular/patología , Dipeptidil Peptidasa 4/metabolismo , Resistencia a Antineoplásicos , MicroARNs/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , ARN Circular/genética , Factores de Transcripción de la Familia Snail/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Movimiento Celular , Proliferación Celular , Dipeptidil Peptidasa 4/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Factores de Transcripción de la Familia Snail/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Rationale: PD1/PD-L1 immune checkpoint inhibitors have shown promising results for several malignancies. However, PD1/PD-L1 signaling and its therapeutic significance remains largely unknown in intrahepatic cholangiocarcinoma (ICC) cases with complex etiology. Methods: We investigated the expression and clinical significance of CD3 and PD1/PD-L1 in 320 ICC patients with different risk factors. In addition, we retrospectively analyzed 7 advanced ICC patients who were treated with PD1 inhibitor. Results: The cohort comprised 233 patients with HBV infection, 18 patients with hepatolithiasis, and 76 patients with undetermined risk factors. PD-L1 was mainly expressed in tumor cells, while CD3 and PD1 were expressed in infiltrating lymphocytes of tumor tissues. PD1/PD-L1 signals were activated in tumor tissues, and expression was positively correlated with HBV infection and lymph node invasion. More PD1+ T cells and higher PD-L1 expression were observed in tumor tissues of ICC patients with HBV infection compared to patients with hepatolithiasis or undetermined risk factors. More PD1+ T cells and/or high PD-L1 expression negatively impacted the prognosis of patients with HBV infection but not those with hepatolithiasis. Multivariate analysis showed PD1/PD-L1 expression was an independent indicator of ICC patient prognosis. Advanced ICC patients with HBV infection and less PD1+ T cells tended to have good response to anti-PD1 therapy. Conclusion: Hyperactivated PD1/PD-L1 signals in tumor tissues are a negative prognostic marker for ICCs after resection. HBV infection- and hepatolithiasis-related ICCs have distinct PD1/PD-L1 profiles. Further, PD1+ T cells could be used as a biomarker to predict prognosis and assay the efficiency of anti-PD1 immunotherapy in ICC patients with HBV infection.
