Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative status.However,the replicative capacity ...Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative status.However,the replicative capacity of HBV with PC/BCP mutations remains ambiguous.Herein,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation.Both PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse models.In human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein accumulation.Mechanistically,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status.Additionally,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice.This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.展开更多
Gliomas are the most commonly occurring tumors of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant and aggressive brain cancer in adults. Further understanding of the mechanisms underlyi...Gliomas are the most commonly occurring tumors of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant and aggressive brain cancer in adults. Further understanding of the mechanisms underlying the aggressive nature of GBM is urgently needed. Here we identified homeobox B8(HOXB8), a member of the homeobox family, as a crucial contributor to the aggressiveness of GBM. Data mining of publicly accessible RNA sequence datasets and our patient cohorts confirmed a higher expression of HOXB8 in the tumor tissue of GBM patients, and a strong positive correlation between the expression level and pathological grading of tumors and a negative correlation between the expression level and the overall survival rate. We next showed that HOXB8 promotes the proliferation and migration of glioblastoma cells and is crucial for the activation of the PI3K/AKT pathway and expression of epithelial–mesenchymal transition-related genes, possibly through direct binding to the promoter of SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) and activating its transcription. Collectively, we identified HOXB8 as a critical contributor to the aggressiveness of GBM, which provides insights into a potential therapeutic target for GBM and opens new avenues for improving its treatment outcome.展开更多
基金supported by National Key R&D Program of China(2023YFC2306800)National Natural Science Foundation of China(No.82072280 and No.82272315)Beijing Municipal Natural Science Foundation(No.7212063 and No.7222108).
文摘Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative status.However,the replicative capacity of HBV with PC/BCP mutations remains ambiguous.Herein,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation.Both PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse models.In human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein accumulation.Mechanistically,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status.Additionally,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice.This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.
基金the National Natural Science Foundation of China(31571298).
文摘Gliomas are the most commonly occurring tumors of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant and aggressive brain cancer in adults. Further understanding of the mechanisms underlying the aggressive nature of GBM is urgently needed. Here we identified homeobox B8(HOXB8), a member of the homeobox family, as a crucial contributor to the aggressiveness of GBM. Data mining of publicly accessible RNA sequence datasets and our patient cohorts confirmed a higher expression of HOXB8 in the tumor tissue of GBM patients, and a strong positive correlation between the expression level and pathological grading of tumors and a negative correlation between the expression level and the overall survival rate. We next showed that HOXB8 promotes the proliferation and migration of glioblastoma cells and is crucial for the activation of the PI3K/AKT pathway and expression of epithelial–mesenchymal transition-related genes, possibly through direct binding to the promoter of SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) and activating its transcription. Collectively, we identified HOXB8 as a critical contributor to the aggressiveness of GBM, which provides insights into a potential therapeutic target for GBM and opens new avenues for improving its treatment outcome.
