BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
Branchio-oto-renal(BOR)syndrome is an uncommon disorder inherited in an autosomal dominant manner.Its main clinical manifestations include branchial cleft cysts,anterior auricular fistula,hearing impairment,and kidney...Branchio-oto-renal(BOR)syndrome is an uncommon disorder inherited in an autosomal dominant manner.Its main clinical manifestations include branchial cleft cysts,anterior auricular fistula,hearing impairment,and kidney malformations.BOR syndrome is associated with heterozygous pathogenic variants including EYA1,SIX1,and SIX5.The study focused on a 13-year-old Chinese boy who presented with hearing impairment,renal malformations,and bony atresia of the right external auditory canal with microtia.The boy's clinical manifestations met the diagnostic criteria for BOR syndrome.Two of the boy's family members underwent clinical examination.However,neither displayed a phenotype associated with BOR syndrome.The boy and his two relatives provided blood samples for genomic DNA extraction,followed by Sanger sequencing.A novel mutation in the GREB1L gene was identified in the boy,but neither of his family members exhibited the same variant.Identifying a novel mutation in GREB1L offers valuable insights into the genotype-phenotype correlation of BOR syndrome,improving the precision of early diagnosis and promoting the advancement of personalized treatment strategies.展开更多
BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitorin...BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells.However,the role of the multiple ERAD complexes in liver cancer remains unclear.AIM To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro.METHODS Huh7 cells were treated with ERAD inhibitor to identify ERAD’s role.Cell counting kit-8,5-ethynyl-2’-deoxyuridine and colony formation experiments were performed.Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay,respectively.Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats,proliferation,apoptosis,and migration were assessed through previous experiments.The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry,respectively.RESULTS The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis.SEL1L-HRD1 significantly influenced Huh7 cell growth.SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis.Mass spectrometry revealed EXT2 is a primary substrate of ERAD.SEL1L knockout significantly increased the protein expression of EXT2.Furthermore,EXT2 knockdown partially restored the effect of SEL1L knockout.CONCLUSION ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis.EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.展开更多
目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基...目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果:在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带已知变异c.151C>G/p.(Arg51Gly),患者双眼小眼畸形伴虹膜脉络膜缺损,伴骨关节屈曲。母亲携带相同杂合变异但表型正常;先证者2携带未报道的变异c.1042G>T/p.(Glu348*),左眼小眼畸形,右眼正常且无全身异常。结合文献回顾发现,在显性遗传模式下,80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52区域,导致小眼无眼或眼缺损异常(microphthalmia,anophthalmia or coloboma,MAC);携带该区域MAB21L2基因杂合突变的患者除MAC外,部分还伴骨骼关节发育异常(12/24,50%);杂合截短变异发生在MAB21L2基因可导致MAC(5/5,100%),而发生在MAB21L1则不致病。结论:在2个小眼畸形家系中发现了MAB21L2基因1个新致病变异和1个已知热点致病变异,通过文献综述比较和总结了MAB21L1和MAB21L2基因的突变频谱以及基因型-表型相互关系,为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。展开更多
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
文摘Branchio-oto-renal(BOR)syndrome is an uncommon disorder inherited in an autosomal dominant manner.Its main clinical manifestations include branchial cleft cysts,anterior auricular fistula,hearing impairment,and kidney malformations.BOR syndrome is associated with heterozygous pathogenic variants including EYA1,SIX1,and SIX5.The study focused on a 13-year-old Chinese boy who presented with hearing impairment,renal malformations,and bony atresia of the right external auditory canal with microtia.The boy's clinical manifestations met the diagnostic criteria for BOR syndrome.Two of the boy's family members underwent clinical examination.However,neither displayed a phenotype associated with BOR syndrome.The boy and his two relatives provided blood samples for genomic DNA extraction,followed by Sanger sequencing.A novel mutation in the GREB1L gene was identified in the boy,but neither of his family members exhibited the same variant.Identifying a novel mutation in GREB1L offers valuable insights into the genotype-phenotype correlation of BOR syndrome,improving the precision of early diagnosis and promoting the advancement of personalized treatment strategies.
基金Supported by the National Natural Science Foundation of China,No.82241219,No.82127808 and No.81921004The Shenzhen Science and Technology Program,No.JCYJ20210324120813037.
文摘BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells.However,the role of the multiple ERAD complexes in liver cancer remains unclear.AIM To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro.METHODS Huh7 cells were treated with ERAD inhibitor to identify ERAD’s role.Cell counting kit-8,5-ethynyl-2’-deoxyuridine and colony formation experiments were performed.Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay,respectively.Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats,proliferation,apoptosis,and migration were assessed through previous experiments.The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry,respectively.RESULTS The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis.SEL1L-HRD1 significantly influenced Huh7 cell growth.SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis.Mass spectrometry revealed EXT2 is a primary substrate of ERAD.SEL1L knockout significantly increased the protein expression of EXT2.Furthermore,EXT2 knockdown partially restored the effect of SEL1L knockout.CONCLUSION ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis.EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.
文摘目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道的MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果:在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带已知变异c.151C>G/p.(Arg51Gly),患者双眼小眼畸形伴虹膜脉络膜缺损,伴骨关节屈曲。母亲携带相同杂合变异但表型正常;先证者2携带未报道的变异c.1042G>T/p.(Glu348*),左眼小眼畸形,右眼正常且无全身异常。结合文献回顾发现,在显性遗传模式下,80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52区域,导致小眼无眼或眼缺损异常(microphthalmia,anophthalmia or coloboma,MAC);携带该区域MAB21L2基因杂合突变的患者除MAC外,部分还伴骨骼关节发育异常(12/24,50%);杂合截短变异发生在MAB21L2基因可导致MAC(5/5,100%),而发生在MAB21L1则不致病。结论:在2个小眼畸形家系中发现了MAB21L2基因1个新致病变异和1个已知热点致病变异,通过文献综述比较和总结了MAB21L1和MAB21L2基因的突变频谱以及基因型-表型相互关系,为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。
