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
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
lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激...lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激(ER stress)及其引起的未折叠蛋白反应(unfolded protein response,UPR)密切相关。在肿瘤微环境中,ERAD不仅参与调控肿瘤细胞的生物学行为,对肿瘤进展发挥重要作用;其还参与对免疫细胞增殖分化、功能以及代谢途径的调节,影响免疫细胞发挥抗肿瘤免疫作用。因此,深入了解探索肿瘤微环境中SEL1L分子及ERAD的潜在机制,可为肿瘤发生、发展及免疫治疗提供新理论和新靶点。本文就SEL1L分子及其参与的内质网相关降解途径在肿瘤进展与免疫调节中的作用进行简要综述。展开更多
AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 m...AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy.Targeted sequence capture array technique was used to screen potential pathologic variants.Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.RESULTS:Fundus examination showed round macular lesions appeared in both eyes.Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye,but it was uneven and slightly elevated in the right eye.Fundus autofluorescence showed patchy hyper-autofluorescence in the macula.Visual field examination indicates central defects in both eyes.Electroretinogram(ERG)and multifocal ERG showed no obvious abnormalities.Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye.We found that the proband carried a missense variant(c.1972C>T)and a deletion variant(c.4717_4718del)of RP1L1,which were originated from the parents and formed compound heterozygous variants.Both variants are likely pathogenic according to the ACMG criteria.Multimodal imaging,ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.CONCLUSION:A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family,which expands the understanding of phenotype and genotype in RP1L1 maculopathy.展开更多
Objective: The study aimed to explore the protective mechanism of Ganoderic acid A (GAA) in renal fibrosisand to verify that GAA can ameliorate renal fibrosis by regulating the Niemann-pick C1-like 1 (NPC1L1) gene. Meth...Objective: The study aimed to explore the protective mechanism of Ganoderic acid A (GAA) in renal fibrosisand to verify that GAA can ameliorate renal fibrosis by regulating the Niemann-pick C1-like 1 (NPC1L1) gene. Methods:Transforming growth factor beta1 (TGF-β1) was used to treat Human Kidney-2 (HK-2) cells to establish a renal fibrosismodel. The differentially expressed genes in the control (CTRL) group, TGF-β1 group, and TGF-β1 + GAA group werescreened via transcriptome sequencing technology and verified by qPCR and Western blot experiments. The NPC1L1gene overexpression plasmid was constructed. The expression levels of N-cad, E-cad, and Slug-related proteins inCTRL, TGF-β1, TGF-β1+GAA (25 μg/mL), and TGF-β1+GAA (25 μg/mL) + NPC1L1 Overexpression (OE) groupswere detected by qPCR and Western blot analysis. Western blot analysis was used to identify the extracellular matrixassociated proteins Tenascin-C, α-SMA, and fibrosis-related protein Collagen I. Fibrosis marker protein Fibronectinwas detected and quantified by immunofluorescence. Results: Transcriptomic sequencing revealed that TGF-β1stimulation led to 267 differentially regulated genes, with 118 up-regulated and 149 down-regulated, while furthermodulation of 213 genes, comprising 112 up-regulated and 101 down-regulated genes, was observed in the GAAintervention group. The target gene in these processes was found to be NPC1L1 by investigations using GeneOntology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). qPCR and Western blot resultsconfirmed that TGF-β1 increased NPC1L1 expression, which was attenuated by GAA. Additionally, TGF-β1upregulated N-cad and Slug. However, GAA reversed this effect and NPC1L1 overexpression partially rescued theGAA effect. TGF-β1 also decreased E-cad expression, reversed by GAA, and NPC1L1 overexpression antagonized thisreversal. Furthermore, TGF-β1 promoted Collagen I, α-SMA, and Tenascin-C expression, and GAA reduced theselevels, effects that were reversed by NPC1L1 overexpression. Immunofluorescence results showed that TGF-β1increased fibronectin expression, which was decreased by GAA, and increased by NPC1L1 overexpression.Conclusion: GAA ameliorates renal fibrosis by antagonizing NPC1L1 gene expression inhibiting epithelialmesenchymal transition and reducing extracellular matrix formation.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。
文摘lin-12-like抑制/增强子(suppressor/enhancer of lin-12-like,SEL1L)分子可以参与调控多种肿瘤进展;同时,其作为内质网相关降解途径(endoplasmic reticulum-associated degradation,ERAD)的重要组成,还参与调控蛋白质合成,与内质网应激(ER stress)及其引起的未折叠蛋白反应(unfolded protein response,UPR)密切相关。在肿瘤微环境中,ERAD不仅参与调控肿瘤细胞的生物学行为,对肿瘤进展发挥重要作用;其还参与对免疫细胞增殖分化、功能以及代谢途径的调节,影响免疫细胞发挥抗肿瘤免疫作用。因此,深入了解探索肿瘤微环境中SEL1L分子及ERAD的潜在机制,可为肿瘤发生、发展及免疫治疗提供新理论和新靶点。本文就SEL1L分子及其参与的内质网相关降解途径在肿瘤进展与免疫调节中的作用进行简要综述。
基金Supported by Shenzhen Science and Technology Program,Shenzhen,China(No.JCYJ20200109145001814,No.SGDX20211123120001001)the National Natural Science Foundation of China(No.81970790)Sanming Project of Medicine in Shenzhen(No.SZSM202011015).
文摘AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy.Targeted sequence capture array technique was used to screen potential pathologic variants.Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.RESULTS:Fundus examination showed round macular lesions appeared in both eyes.Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye,but it was uneven and slightly elevated in the right eye.Fundus autofluorescence showed patchy hyper-autofluorescence in the macula.Visual field examination indicates central defects in both eyes.Electroretinogram(ERG)and multifocal ERG showed no obvious abnormalities.Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye.We found that the proband carried a missense variant(c.1972C>T)and a deletion variant(c.4717_4718del)of RP1L1,which were originated from the parents and formed compound heterozygous variants.Both variants are likely pathogenic according to the ACMG criteria.Multimodal imaging,ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.CONCLUSION:A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family,which expands the understanding of phenotype and genotype in RP1L1 maculopathy.
基金sponsored by KeyResearch and Development Project of Science andTechnology Department of Tibet (No. XZ202201ZY0033G).
文摘Objective: The study aimed to explore the protective mechanism of Ganoderic acid A (GAA) in renal fibrosisand to verify that GAA can ameliorate renal fibrosis by regulating the Niemann-pick C1-like 1 (NPC1L1) gene. Methods:Transforming growth factor beta1 (TGF-β1) was used to treat Human Kidney-2 (HK-2) cells to establish a renal fibrosismodel. The differentially expressed genes in the control (CTRL) group, TGF-β1 group, and TGF-β1 + GAA group werescreened via transcriptome sequencing technology and verified by qPCR and Western blot experiments. The NPC1L1gene overexpression plasmid was constructed. The expression levels of N-cad, E-cad, and Slug-related proteins inCTRL, TGF-β1, TGF-β1+GAA (25 μg/mL), and TGF-β1+GAA (25 μg/mL) + NPC1L1 Overexpression (OE) groupswere detected by qPCR and Western blot analysis. Western blot analysis was used to identify the extracellular matrixassociated proteins Tenascin-C, α-SMA, and fibrosis-related protein Collagen I. Fibrosis marker protein Fibronectinwas detected and quantified by immunofluorescence. Results: Transcriptomic sequencing revealed that TGF-β1stimulation led to 267 differentially regulated genes, with 118 up-regulated and 149 down-regulated, while furthermodulation of 213 genes, comprising 112 up-regulated and 101 down-regulated genes, was observed in the GAAintervention group. The target gene in these processes was found to be NPC1L1 by investigations using GeneOntology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). qPCR and Western blot resultsconfirmed that TGF-β1 increased NPC1L1 expression, which was attenuated by GAA. Additionally, TGF-β1upregulated N-cad and Slug. However, GAA reversed this effect and NPC1L1 overexpression partially rescued theGAA effect. TGF-β1 also decreased E-cad expression, reversed by GAA, and NPC1L1 overexpression antagonized thisreversal. Furthermore, TGF-β1 promoted Collagen I, α-SMA, and Tenascin-C expression, and GAA reduced theselevels, effects that were reversed by NPC1L1 overexpression. Immunofluorescence results showed that TGF-β1increased fibronectin expression, which was decreased by GAA, and increased by NPC1L1 overexpression.Conclusion: GAA ameliorates renal fibrosis by antagonizing NPC1L1 gene expression inhibiting epithelialmesenchymal transition and reducing extracellular matrix formation.
