BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses si...BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.展开更多
Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its correspondin...Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its corresponding mechanism is limited.Here,we found that morin significantly potentiated the inhibitory effects of the natural compound celastrol on the proliferation of lung cancer cells.Morin and celastrol synergistically exhibit marked apoptosis induction in lung cancer cells,accompanied by changes in the abundance of apoptosis-related proteins.Transcriptome analyses revealed that the combination of morin and celastrol had a significant impact on the number of differentially expressed genes in lung cancer cells.Among these genes,BIRC3 was one of the most significantly different ones,which plays a crucial role in the process of tumor resistance to apoptosis.In addition,several genes identified are primarily associated with intracellular signal transduction pathways,specifically the NF-κB signaling pathway.Importantly,the treatment combining morin and celastrol in tumor-bearing mice results in a synergistic effect that significantly suppressed tumor growth.These findings indicate that morin could be a promising functional adjuvant,and the combination of morin and celastrol has potential for the treating lung cancer.展开更多
Background:Colorectal cancer(CRC)is one of the most aggressive malignancies of the digestive tract,characterized by aberrant post-transcriptional RNA modifications,including pseudouridine(Ψ).TruB pseudouridine syntha...Background:Colorectal cancer(CRC)is one of the most aggressive malignancies of the digestive tract,characterized by aberrant post-transcriptional RNA modifications,including pseudouridine(Ψ).TruB pseudouridine synthase family member 1(TRUB1)is a key pseudouridine synthase but its role in CRC progression remains unclear.Methods:Public databases and CRC cell lines were analysed to assess TRUB1 expression in CRC.Receiver-operating characteristic(ROC)curve analysis and survival analysis were performed to evaluate the diagnostic and prognostic significance of TRUB1.The impact of TRUB1 on tumor proliferation andΨmodification was examined in TRUB1-knock-down HCT116 cell lines.Mechanistically,RNA sequencing of control and TRUB1-knock-down HCT116 cells was conducted to identify potential pathways,which were validated by using real-time polymerase chain reaction(PCR),Western blot,and immunofluorescence assays.Results:TRUB1 was significantly upregulated in CRC tumor tissues and cell lines.ROC analysis showed that TRUB1 had strong diagnostic potential and its overexpression was associated with poorer overall survival in CRC patients.In TRUB1-knock-down HCT116 cells,apoptosis increased and tumor growth slowed in nude mice,with a corresponding increase in apoptosis-related proteins and decreasedΨmodification.Mechanistically,RNA sequencing indicated that tumor necrosis factorαsignaling via the nuclear factor kappa B(NFκB)pathway was activated in TRUB1-knock-down HCT116 cells.Further analysis identified Baculoviral inhibitor of apoptosis proteins repeat-containing 3(BIRC3)as a potential downstream target gene that was regulated by TRUB1 in the NFκB pathway.Conclusions:TRUB1 serves as a potential biomarker for CRC diagnosis and prognosis,and it can inhibit apoptosis in CRC cells via BIRC3-mediated NFκB signaling.展开更多
基金the Tianjin Municipal Education Commission Scientific Research Project,No.2018KJ055.
文摘BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.
基金supported by the National Nature Science Foundation Project(32202067)the Young Talent Fund of Association for Science and Technology in Shaanxi,China(20230203)。
文摘Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its corresponding mechanism is limited.Here,we found that morin significantly potentiated the inhibitory effects of the natural compound celastrol on the proliferation of lung cancer cells.Morin and celastrol synergistically exhibit marked apoptosis induction in lung cancer cells,accompanied by changes in the abundance of apoptosis-related proteins.Transcriptome analyses revealed that the combination of morin and celastrol had a significant impact on the number of differentially expressed genes in lung cancer cells.Among these genes,BIRC3 was one of the most significantly different ones,which plays a crucial role in the process of tumor resistance to apoptosis.In addition,several genes identified are primarily associated with intracellular signal transduction pathways,specifically the NF-κB signaling pathway.Importantly,the treatment combining morin and celastrol in tumor-bearing mice results in a synergistic effect that significantly suppressed tumor growth.These findings indicate that morin could be a promising functional adjuvant,and the combination of morin and celastrol has potential for the treating lung cancer.
基金supported by the Guangzhou Science and Technology Plan Project[202002020048]Guangzhou Nansha District Science and Technology Plan Project[2023MS003].
文摘Background:Colorectal cancer(CRC)is one of the most aggressive malignancies of the digestive tract,characterized by aberrant post-transcriptional RNA modifications,including pseudouridine(Ψ).TruB pseudouridine synthase family member 1(TRUB1)is a key pseudouridine synthase but its role in CRC progression remains unclear.Methods:Public databases and CRC cell lines were analysed to assess TRUB1 expression in CRC.Receiver-operating characteristic(ROC)curve analysis and survival analysis were performed to evaluate the diagnostic and prognostic significance of TRUB1.The impact of TRUB1 on tumor proliferation andΨmodification was examined in TRUB1-knock-down HCT116 cell lines.Mechanistically,RNA sequencing of control and TRUB1-knock-down HCT116 cells was conducted to identify potential pathways,which were validated by using real-time polymerase chain reaction(PCR),Western blot,and immunofluorescence assays.Results:TRUB1 was significantly upregulated in CRC tumor tissues and cell lines.ROC analysis showed that TRUB1 had strong diagnostic potential and its overexpression was associated with poorer overall survival in CRC patients.In TRUB1-knock-down HCT116 cells,apoptosis increased and tumor growth slowed in nude mice,with a corresponding increase in apoptosis-related proteins and decreasedΨmodification.Mechanistically,RNA sequencing indicated that tumor necrosis factorαsignaling via the nuclear factor kappa B(NFκB)pathway was activated in TRUB1-knock-down HCT116 cells.Further analysis identified Baculoviral inhibitor of apoptosis proteins repeat-containing 3(BIRC3)as a potential downstream target gene that was regulated by TRUB1 in the NFκB pathway.Conclusions:TRUB1 serves as a potential biomarker for CRC diagnosis and prognosis,and it can inhibit apoptosis in CRC cells via BIRC3-mediated NFκB signaling.
