Buchananogle2219

Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients' survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. PRGL493 Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT-DNA-PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN-ATM-CHK2 signal and ATR-CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β family, is associated with tumor progression, metastasis, and cell apoptosis. However, controversy persists regarding the role of GDF15 in different tumor types, and its function in glioma stem cells (GSCs) remains unknown. Here, we report that GDF15 promotes the GSC-like phenotype in GSC-like cells (GSCLCs) through the activation of leukemia inhibitor factor (LIF)-STAT3 signaling. Mechanistically, GDF15 was found to upregulate expression of the transcription factor c-Fos, which binds to the LIF promoter, leading to enhanced transcription of LIF in GSCLCs. Furthermore, GDF15 may activate the ERK1/2 signaling pathway in GSCLCs, and the upregulation of LIF expression and the GSC-like phenotype was dependent on ERK1/2 signaling. In addition, the small immunomodulator imiquimod induced GDF15 expression, which in turn activated the LIF-STAT3 pathway and subsequently promoted the GSC-like phenotype in GSCLCs. Thus, our results demonstrate that GDF15 can act as a proliferative and pro-stemness factor for GSCs, and therefore, it may represent a potential therapeutic target in glioma treatment.Although identified as the key environmental driver of common cutaneous melanoma, the role of ultraviolet radiation (UVR)-induced DNA damage in mucosal melanoma is poorly defined. We analyze 10 mucosal melanomas of conjunctival origin by whole genome sequencing and our data shows a predominance of UVR-associated single base substitution signature 7 (SBS7) in the majority of the samples. Our data shows mucosal melanomas with SBS7 dominance have similar genomic patterns to cutaneous melanomas and therefore this subset should not be excluded from treatments currently used for common cutaneous melanoma.The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.Currently, the controversy regarding the expression profile and function of BUB1B in different malignancies still exist. In this project, we aimed to explore the role and molecular mechanism of BUB1B in the progression of extrahepatic cholangiocarcinoma (ECC). The expression levels of BUB1B in human ECC were evaluated by immunohistochemistry, western blot, and real-time PCR. The role and mechanism of BUB1B in CCA cell proliferation and invasion were investigated in both in vitro and in vivo functional studies. To indicate the clinical significance, a tissue microarray was performed on 113 ECC patients, followed by univariate and multivariate analyses. The expression of BUB1B was increased in both human CCA tissues and CCA cells. Results from loss-of-function and gain-of-function experiments suggested that the inhibition of BUB1B decreased the proliferation and invasiveness of CCA cells in vitro and in vivo, while overexpression of BUB1B achieved the opposite effect. Furthermore, the activation of c-Jun N-terminal kinase-c-Jun (JNK)-c-Jun pathway was regulated by BUB1B. BUB1B regulated the proliferation and invasiveness of CAA cells in a JNK-c-Jun-dependent manner. Clinically, ECC patients with BUB1B high expression had worse overall survival and recurrence-free survival than those with BUB1B low expression. Multivariate analysis identified that BUB1B was an independent predictor for postoperative recurrence and overall survival of ECC patients. In conclusion, BUB1B promoted ECC progression via JNK/c-Jun pathways. These findings suggested that BUB1B could be a potential therapeutic target and a biomarker for predicting prognosis for ECC patients.