RESUMEN
We explored the biological role of long non-coding RNA (lncRNA) MAPKAPK5_AS1 (MAAS) and the mechanism of its differential expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Differentially expressed lncRNAs in HBV-related HCC were determined using bioinformatics analysis. Gain-of-function experiments were conducted to evaluate the effect of MAAS on cell proliferation. A xenograft model was established for in vivo experiments. Dual-luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and methylated RNA immunoprecipitation were performed to elucidate the underlying molecular mechanisms. MAAS was upregulated in HBV-related HCC cancerous tissues and its high expression was closely related to the poor survival probability of patients. Functional assays revealed that MAAS overexpression facilitated the proliferation of HBV+HCC cells in vitro and in vivo. Mechanistically, MAAS promoted the MYC proto-oncogene (c-Myc)-induced transcriptional activation of cyclin-dependent kinase 4 (CDK4), CDK6, and S-phase kinase associated protein 2 via stabilizing c-Myc protein, thereby facilitating G1/S transition. The latter contributed to the paradoxical proliferation of HBV+HCC cells. Although MAAS was upregulated in HBV-related HCC cancerous tissues, it was highly expressed in M2 macrophages, a major phenotype of tumor-associated macrophages in HBV-related HCC, instead of in HBV+HCC cells. HBeAg, an HBV-associated antigen, further elevated the MAAS level in M2 macrophages by enhancing the methyltransferase-like 3-mediated N6-methyladenosine modification of MAAS. The increased MAAS in the M2 macrophages was then transferred to HBV+HCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBV+HCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its m6A modification. The upregulated MAAS is then transferred to HBV+HCC cells via exosomes, facilitating the proliferation of HBV+HCC cells by targeting c-Myc.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Antígenos e de la Hepatitis B , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Proteínas Serina-Treonina Quinasas , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
BACKGROUND: This study investigates the characteristics of a special type of cancer of unknown primary site (CUP, type 2), which is a metastasis of a definite pathological diagnosis without a detectable primary site. PATIENTS AND METHODS: Patients diagnosed between 2004 and 2014 were identified from the Surveillance Epidemiology and End Results (SEER) database. The characteristics of type 2 CUP from different sources were analyzed. For each source of type 2 CUP, tumors of the corresponding Tn N0-X M1 stage were used as controls. RESULTS: A total of 8505 patients with type 2 CUP were included in this analysis. Type 2 CUP shows an increasing trend, while type 1 shows the opposite. Type 2 CUPs have significant differences with stage IV of the same pathological primary lesion. Many characteristics influenced the prognosis of type 2 CUP patients, including marital status, age, race, sex, registration time, lymph node metastasis, surgery, chemotherapy, and radiation. CONCLUSION: Our study suggests that identifying the source of metastasis is the key to the selection of treatment and the determination of the prognosis for CUP.