Background:Hepatocellular carcinoma(HCC)is a prevalent liver malignancy.This study examined the roles of transforming growth factor beta(TGF-β)and cytochrome b5 domain containing 2(CYB5D2)in HCC etiology and their pr...Background:Hepatocellular carcinoma(HCC)is a prevalent liver malignancy.This study examined the roles of transforming growth factor beta(TGF-β)and cytochrome b5 domain containing 2(CYB5D2)in HCC etiology and their prognostic biomarker potential.Methods:Key modules and prognostic genes were identified by analyzing the GSE101685 dataset by weighted gene co-expression network analysis(WGCNA)and Least absolute shrinkage and selection operator(LASSO)Cox regression.The expression levels of CYB5D2 and TGF-βin HCC cell lines were quantified using Quantitative reverse transcription polymerase chain reaction(qRT-PCR)and Western blotting(WB)assays.Effects of CYB5D2 overexpression on cell proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT)marker regulation were assessed in vitro,while in vivo tumorigenicity was evaluated using a xenograft model of HCC in nude mice.Results:In this study,WGCNA identified the turquoise module as significantly associated with HCC,containing 452 DEGs.LASSO Cox regression analysis revealed 9 key prognostic genes,with CYB5D2 being underexpressed in HCC cells and tissues.TGF-βwas negatively correlated with CYB5D2 expression,resulting in poor patient prognosis.Functional assays demonstrated that CYB5D2 overexpression inhibited proliferation,migration,and invasion of HCC cell lines,and altered EMT marker expression.Furthermore,the addition of TGF-βpartially reversed the suppressive effects caused by CYB5D2 overexpression.In vivo,CYB5D2 overexpression significantly reduced tumor growth,indicating its potential as a therapeutic target for HCC.Conclusion:The tumor suppressor function of CYB5D2 in HCC and its interaction with TGF-βoffered fresh information on the molecular pathophysiology of HCC and possible treatment avenues.展开更多
OBJECTIVE It is unclear whether differentiation disturbances or deregulation of neural stem cells (NSCs) are the early key steps for gliomagenesis and tumor development. Furthermore, relevant molecular changes and gen...OBJECTIVE It is unclear whether differentiation disturbances or deregulation of neural stem cells (NSCs) are the early key steps for gliomagenesis and tumor development. Furthermore, relevant molecular changes and gene-regulation pathways are unknown. This study focused on screening and validating differentiation-associated genes from both human NSCs and glioma cells with malignant progression, for the purpose of offering an experimental basis for the cellular origin of gilomas and molecular pathology of gliomagenesis. METHODS The differential-gene expression profiles of malignant progression of gliomas were established, then the differentiation related genes were screened out with a bioinformatics analysis. Expression levels of these genes was further analyzed in cultured human fetal NSCs undergoing differentiation processes with a semi-quantitative RT-PCR assay. RESULTS Eight genes were screened out from the gene-expression profiling of which the expression levels were associated with the differentiation processes of NSCs, namely CXCR4, TN-C, GLT1, IL1-RI, EGFR-8, CDC2, Ndr3 and MAPKK4. Three of them, ie., GLT1, CDC2 and MAPKK4, were further analyzed, showing that expression levels decreased with the differentiation processes of NSCs, and increased with the malignant progression of ganglioglioma. CONCLUSION Three differentiation associated genes were found negatively associated with NSCs differentiation and positively associated with malignant progression of gliomas, suggesting that differentiation disturbances of neural stem cells may be involved in oncogenesis, and that further studies on their roles in gliomagenesis should be conducted.展开更多
Objective: To establish gene expression profiles associated with malignant progression of ganglioglioma. Methods: The primary and two recurrent glioma specimens were collected intraoperatively from the same patient wh...Objective: To establish gene expression profiles associated with malignant progression of ganglioglioma. Methods: The primary and two recurrent glioma specimens were collected intraoperatively from the same patient who experienced tumor transformation into anaplastic astrocytoma and glioblastoma multiform for the first and second recurrence respectively. Gene expression was assayed through cDNA array and bioinformatics analysis. Results: A total of 197 differentially expressed genes with differential ratio value more than 3 compared with normal brain tissue were obtained. Among 109 functionally denned genes, those associated with development ranked the first by frequency, followed by genes associated with metabolism, differentiation, signal transduction and so on. As a result of cluster analysis among 368 genes, eleven genes were up regulated with malignant progression, while six genes were down regulated. Conclusion: Gene expression profiles associated with malignant progression of glioma were successfully established, which provides a powerful tool for research on molecular mechanisms of malignant progression of gliomas.展开更多
A Japanese herbal(Kampo,汉方)medicine,十全大补汤(juzentaihoto/Shi-Quan-Da-Bu-Tang),is one of the nourishing agents, a so-called"补剂(Hozai/Bu-Ji)," that is used for improving disturbance and imbalances in th...A Japanese herbal(Kampo,汉方)medicine,十全大补汤(juzentaihoto/Shi-Quan-Da-Bu-Tang),is one of the nourishing agents, a so-called"补剂(Hozai/Bu-Ji)," that is used for improving disturbance and imbalances in the homeostatic condition of the body. This formulation is orally administered to patients in various weakened states, including postsurgery patients and patients with chronic illness, where it can alleviate general symptoms such as extreme fatigue, pale complexion, loss of appetite, dry or scaly skin, night sweating, and dryness of the mouth.Recently, juzentaihoto/Shi-Quan-Da-Bu-Tang has been shown to have a variety of biological activities, including activation of natural killer cells and macrophages, cytokine induction, antibody production, antitumor effects in combination with surgical excision or other drugs, and protection against the adverse effects of anticancer drugs and radiation, including immunosuppression and bone marrow toxicity. This article focuses on the antitumor and antimetastatic properties of some Kampo medicines and mainly describes the effects of juzentaihoto and its related formulations on tumor development, progression, and metastasis in vivo. We also discuss the inhibitory mechanism of action and the importance of the prescription and constituent crude drugs in determining the efficacy.展开更多
Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims...Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims to investigate the potential role of Transmembrane protein 33(TMEM33)in the development of lung adenocarcinoma.Methods:We leveraged The Cancer Genome Atlas(TCGA)database to analyze the connection between TMEM33 expression to the prognosis of lung adenocarcinoma(LUAD).Cell proliferation,invasiveness,and sphere formation were analyzed by various experiments.The association of miR-214-3p with TMEM33 was explored using luciferase reporter assay,immunoblotting,and real-time quantitative PCR(RT-qPCR).Additionally,TMEM33’s biological role was confirmed in the mouse xenograft model through lung cancer transplantation and metastasis studies.Results:TMEM33 showed high expression within both LUAD tissues and cells,with its expression correlating with poor patient survival outcomes.Silencing TMEM33 resulted in significant reductions in cell proliferation,invasiveness,and stem-like properties.Further investigation suggested that miR-214-3p negatively regulated TMEM33.In both cellular and animal models,we further demonstrated that TMEM33 knockdown could effectively suppress the aggressiveness of lung cancer cells,impeding tumor growth and inhibiting metastasis in the mouse model.Moreover,reducing TMEM33 expression reduced key signaling molecules within the Wnt/β-catenin pathway,providing insights into TMEM33’s mechanistic role in LUAD.Conclusion:TMEM33 functions as an oncogene,which is under the negative regulation of miR-214-3p,to promote the LUAD malignant characteristics by engaging the Wnt/β-catenin cascade.展开更多
Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities...Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities.Nevertheless,the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated.Methods:Cell proliferation and apoptosis were detected using CCK-8,real-time cell analysis(RTCA),EdU,and flow cytometric assays.Cellular mobility and invasive capacity were detected using wound-healing,Transwell,and cell motility assays.Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models.The antitumor effects of CLT-003 were evaluated using patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.Results:CLT-003 significantly inhibited cellular proliferation,enhanced cellular apoptosis,and attenuated cellular invasion and migration of pancreatic cancer cells.Mechanistically,CLT-003 suppressed the translation of HIF-1a by inhibiting the PI3K/AKT/mTOR signaling pathway.In the mouse tumor models,CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors.Moreover,the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1a expression.Conclusions:This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.展开更多
Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant...Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant progression of glioma cells,as well as the molecular mechanisms underlying these malignant behaviors.Methods:The correlation between CAMK2B expression in gliomas and patient prognosis was analyzed using immunohistochemistry,quantitative reverse transcription polymerase chain reaction(qRT-PCR),and western blot.Furthermore,the study explored the role of CAMK2B in glioma cell proliferation,invasion,and migration using cell counting kit-8(CCK-8),5-Ethynyl-2′-deoxyuridine(EdU),wound healing,transwell,and in vivo tumor xenograft assays.Result:Patients with high CAMK2B expression exhibited significantly better prognostic outcomes compared to those with low expression levels.Furthermore,CAMK2B expression was significantly lower in glioma tissues and cells compared to both normal brain tissue and human astrocyte cell lines.Notably,overexpression of CAMK2B in glioma cells led to an approximate 40%reduction in proliferative capacity and a 60–70%decrease in invasive and migratory abilities,compared to control glioma cells.These differences were statistically significant at p<0.05.Conversely,knockdown of CAMK2B using siRNA-CAMK2B significantly enhanced the proliferative,invasive,and migratory capabilities of glioma cells in both in vitro and in vivo settings,enhancing these abilities by 1.5 to 3 times.Notably,these effects were reversed through the application of the Rat Sarcoma viral oncogene homolog(Ras)pathway inhibitor,Salirasib.Western blot analysis revealed that knockdown of CAMK2B led to activation of the Ras/Rapidly Accelerated Fibrosarcoma(Raf)/Mitogen-activated protein kinase kinase(MEK)/Extracellular signal-regulated kinase(ERK)signaling pathway in glioma cell lines,whereas overexpression of CAMK2B resulted in the suppression of this pathway.Conclusion:CAMK2B inhibits glioma proliferation,invasion,andmigration through the Ras/Raf/MEK/ERK signaling pathway.展开更多
Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being con...Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted,and the results are promising for preventing cancers.However,the detailed mechanism of PRMT5 promoting colorectal cancer(CRC)malignant progression remains unclear.Here,we found that PRMT5 directly catalyzes AlkB homologue 5(ALKBH5)symmetric dimethylation at the R316 residue(meR316-ALKBH5),which enhances TRIM28-mediated ALKBH5 ubiquitination degradation.Then,an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′untranslated region,which increases CD276 messenger RNA stability and its expression in CRC cells.Furthermore,a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions.Moreover,we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo.Furthermore,we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC.Finally,we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC.Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.展开更多
基金National Natural Science Foundation of China Youth Training Project(2021GZR003)Medical-Engineering Interdisciplinary Research Youth Training Project(2022YGJC001).
文摘Background:Hepatocellular carcinoma(HCC)is a prevalent liver malignancy.This study examined the roles of transforming growth factor beta(TGF-β)and cytochrome b5 domain containing 2(CYB5D2)in HCC etiology and their prognostic biomarker potential.Methods:Key modules and prognostic genes were identified by analyzing the GSE101685 dataset by weighted gene co-expression network analysis(WGCNA)and Least absolute shrinkage and selection operator(LASSO)Cox regression.The expression levels of CYB5D2 and TGF-βin HCC cell lines were quantified using Quantitative reverse transcription polymerase chain reaction(qRT-PCR)and Western blotting(WB)assays.Effects of CYB5D2 overexpression on cell proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT)marker regulation were assessed in vitro,while in vivo tumorigenicity was evaluated using a xenograft model of HCC in nude mice.Results:In this study,WGCNA identified the turquoise module as significantly associated with HCC,containing 452 DEGs.LASSO Cox regression analysis revealed 9 key prognostic genes,with CYB5D2 being underexpressed in HCC cells and tissues.TGF-βwas negatively correlated with CYB5D2 expression,resulting in poor patient prognosis.Functional assays demonstrated that CYB5D2 overexpression inhibited proliferation,migration,and invasion of HCC cell lines,and altered EMT marker expression.Furthermore,the addition of TGF-βpartially reversed the suppressive effects caused by CYB5D2 overexpression.In vivo,CYB5D2 overexpression significantly reduced tumor growth,indicating its potential as a therapeutic target for HCC.Conclusion:The tumor suppressor function of CYB5D2 in HCC and its interaction with TGF-βoffered fresh information on the molecular pathophysiology of HCC and possible treatment avenues.
基金This work was supported by the NationalNatural Science Foundation of China(No. 30371457, 30400457).
文摘OBJECTIVE It is unclear whether differentiation disturbances or deregulation of neural stem cells (NSCs) are the early key steps for gliomagenesis and tumor development. Furthermore, relevant molecular changes and gene-regulation pathways are unknown. This study focused on screening and validating differentiation-associated genes from both human NSCs and glioma cells with malignant progression, for the purpose of offering an experimental basis for the cellular origin of gilomas and molecular pathology of gliomagenesis. METHODS The differential-gene expression profiles of malignant progression of gliomas were established, then the differentiation related genes were screened out with a bioinformatics analysis. Expression levels of these genes was further analyzed in cultured human fetal NSCs undergoing differentiation processes with a semi-quantitative RT-PCR assay. RESULTS Eight genes were screened out from the gene-expression profiling of which the expression levels were associated with the differentiation processes of NSCs, namely CXCR4, TN-C, GLT1, IL1-RI, EGFR-8, CDC2, Ndr3 and MAPKK4. Three of them, ie., GLT1, CDC2 and MAPKK4, were further analyzed, showing that expression levels decreased with the differentiation processes of NSCs, and increased with the malignant progression of ganglioglioma. CONCLUSION Three differentiation associated genes were found negatively associated with NSCs differentiation and positively associated with malignant progression of gliomas, suggesting that differentiation disturbances of neural stem cells may be involved in oncogenesis, and that further studies on their roles in gliomagenesis should be conducted.
基金This work was supported by the NationalNatural Science Foundation of China(No.30070772)
文摘Objective: To establish gene expression profiles associated with malignant progression of ganglioglioma. Methods: The primary and two recurrent glioma specimens were collected intraoperatively from the same patient who experienced tumor transformation into anaplastic astrocytoma and glioblastoma multiform for the first and second recurrence respectively. Gene expression was assayed through cDNA array and bioinformatics analysis. Results: A total of 197 differentially expressed genes with differential ratio value more than 3 compared with normal brain tissue were obtained. Among 109 functionally denned genes, those associated with development ranked the first by frequency, followed by genes associated with metabolism, differentiation, signal transduction and so on. As a result of cluster analysis among 368 genes, eleven genes were up regulated with malignant progression, while six genes were down regulated. Conclusion: Gene expression profiles associated with malignant progression of glioma were successfully established, which provides a powerful tool for research on molecular mechanisms of malignant progression of gliomas.
基金supported in part by Grant-in-Aids for Cancer Research(No.14030028)
文摘A Japanese herbal(Kampo,汉方)medicine,十全大补汤(juzentaihoto/Shi-Quan-Da-Bu-Tang),is one of the nourishing agents, a so-called"补剂(Hozai/Bu-Ji)," that is used for improving disturbance and imbalances in the homeostatic condition of the body. This formulation is orally administered to patients in various weakened states, including postsurgery patients and patients with chronic illness, where it can alleviate general symptoms such as extreme fatigue, pale complexion, loss of appetite, dry or scaly skin, night sweating, and dryness of the mouth.Recently, juzentaihoto/Shi-Quan-Da-Bu-Tang has been shown to have a variety of biological activities, including activation of natural killer cells and macrophages, cytokine induction, antibody production, antitumor effects in combination with surgical excision or other drugs, and protection against the adverse effects of anticancer drugs and radiation, including immunosuppression and bone marrow toxicity. This article focuses on the antitumor and antimetastatic properties of some Kampo medicines and mainly describes the effects of juzentaihoto and its related formulations on tumor development, progression, and metastasis in vivo. We also discuss the inhibitory mechanism of action and the importance of the prescription and constituent crude drugs in determining the efficacy.
文摘Background:Lung cancer remains a major factor causing cancer-associated mortality globally.While there have been advancements in treatment options,advanced lung cancer patients still have poor outcomes.This study aims to investigate the potential role of Transmembrane protein 33(TMEM33)in the development of lung adenocarcinoma.Methods:We leveraged The Cancer Genome Atlas(TCGA)database to analyze the connection between TMEM33 expression to the prognosis of lung adenocarcinoma(LUAD).Cell proliferation,invasiveness,and sphere formation were analyzed by various experiments.The association of miR-214-3p with TMEM33 was explored using luciferase reporter assay,immunoblotting,and real-time quantitative PCR(RT-qPCR).Additionally,TMEM33’s biological role was confirmed in the mouse xenograft model through lung cancer transplantation and metastasis studies.Results:TMEM33 showed high expression within both LUAD tissues and cells,with its expression correlating with poor patient survival outcomes.Silencing TMEM33 resulted in significant reductions in cell proliferation,invasiveness,and stem-like properties.Further investigation suggested that miR-214-3p negatively regulated TMEM33.In both cellular and animal models,we further demonstrated that TMEM33 knockdown could effectively suppress the aggressiveness of lung cancer cells,impeding tumor growth and inhibiting metastasis in the mouse model.Moreover,reducing TMEM33 expression reduced key signaling molecules within the Wnt/β-catenin pathway,providing insights into TMEM33’s mechanistic role in LUAD.Conclusion:TMEM33 functions as an oncogene,which is under the negative regulation of miR-214-3p,to promote the LUAD malignant characteristics by engaging the Wnt/β-catenin cascade.
基金supported by the National Natural Science Foundation of China(Grant Nos.82472973,82030092,82273362,82272680,and 82103006)the National Key Research and Development Program of China(Grant No.2021YFA1201100)+2 种基金the Tianjin Natural Science Foundation(Grant Nos.19JCJQJC63100 and 22JCQNJC00100)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2022KJ221)the Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-009A).
文摘Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities.Nevertheless,the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated.Methods:Cell proliferation and apoptosis were detected using CCK-8,real-time cell analysis(RTCA),EdU,and flow cytometric assays.Cellular mobility and invasive capacity were detected using wound-healing,Transwell,and cell motility assays.Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models.The antitumor effects of CLT-003 were evaluated using patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.Results:CLT-003 significantly inhibited cellular proliferation,enhanced cellular apoptosis,and attenuated cellular invasion and migration of pancreatic cancer cells.Mechanistically,CLT-003 suppressed the translation of HIF-1a by inhibiting the PI3K/AKT/mTOR signaling pathway.In the mouse tumor models,CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors.Moreover,the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1a expression.Conclusions:This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.
基金supported by the Natural Science Foundation of Hebei Province(H2021206037)the Government-funded Project on Training of Outstanding Clinical Medical Personnel of Hebei Province in the year 2021(303-16-20-06)the Medical Research Project of Hebei Provincial Health Commission(20230031).
文摘Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant progression of glioma cells,as well as the molecular mechanisms underlying these malignant behaviors.Methods:The correlation between CAMK2B expression in gliomas and patient prognosis was analyzed using immunohistochemistry,quantitative reverse transcription polymerase chain reaction(qRT-PCR),and western blot.Furthermore,the study explored the role of CAMK2B in glioma cell proliferation,invasion,and migration using cell counting kit-8(CCK-8),5-Ethynyl-2′-deoxyuridine(EdU),wound healing,transwell,and in vivo tumor xenograft assays.Result:Patients with high CAMK2B expression exhibited significantly better prognostic outcomes compared to those with low expression levels.Furthermore,CAMK2B expression was significantly lower in glioma tissues and cells compared to both normal brain tissue and human astrocyte cell lines.Notably,overexpression of CAMK2B in glioma cells led to an approximate 40%reduction in proliferative capacity and a 60–70%decrease in invasive and migratory abilities,compared to control glioma cells.These differences were statistically significant at p<0.05.Conversely,knockdown of CAMK2B using siRNA-CAMK2B significantly enhanced the proliferative,invasive,and migratory capabilities of glioma cells in both in vitro and in vivo settings,enhancing these abilities by 1.5 to 3 times.Notably,these effects were reversed through the application of the Rat Sarcoma viral oncogene homolog(Ras)pathway inhibitor,Salirasib.Western blot analysis revealed that knockdown of CAMK2B led to activation of the Ras/Rapidly Accelerated Fibrosarcoma(Raf)/Mitogen-activated protein kinase kinase(MEK)/Extracellular signal-regulated kinase(ERK)signaling pathway in glioma cell lines,whereas overexpression of CAMK2B resulted in the suppression of this pathway.Conclusion:CAMK2B inhibits glioma proliferation,invasion,andmigration through the Ras/Raf/MEK/ERK signaling pathway.
基金supported by grants from the Excellent Youth Foundation of Jiangsu Province,China(BK20220119)the Major Project of the University Natural Science Foundation of Jiangsu Province,China(22KJA310006)+3 种基金the Outstanding Youth Project of the University Natural Science Research in Anhui Province(2024AH020013)the Launch Foundation for High Level Talent Research of Wannan Medical College(WYRCQD2024011)the Key Project of the University Natural Science Research in Anhui Province(2023AH051774)Jiangsu Provincial Key Medical Discipline,the Project of Invigorating Health Care through Science,Technology,and Education(No.ZDXKA2016014).
文摘Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5(PRMT5).Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted,and the results are promising for preventing cancers.However,the detailed mechanism of PRMT5 promoting colorectal cancer(CRC)malignant progression remains unclear.Here,we found that PRMT5 directly catalyzes AlkB homologue 5(ALKBH5)symmetric dimethylation at the R316 residue(meR316-ALKBH5),which enhances TRIM28-mediated ALKBH5 ubiquitination degradation.Then,an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3′untranslated region,which increases CD276 messenger RNA stability and its expression in CRC cells.Furthermore,a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions.Moreover,we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo.Furthermore,we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC.Finally,we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC.Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5–CD276 axis-targeting treatment approach for CRC.
