Objective:To screen clinically significant potential drug targets in liver cancer and to study the function and potential molecular mechanisms of this target protein in the development of liver cancer.Methods:By using...Objective:To screen clinically significant potential drug targets in liver cancer and to study the function and potential molecular mechanisms of this target protein in the development of liver cancer.Methods:By using the clinical database GEPIAto find genes that are differentially expressed in liver cancer compared to normal tissues,we further screened the genes that are highly expressed in hepatocellular carcinoma and have clinical prognostic relevance.Heat maps were used to sort these genes according to their clinical prognostic relevance,so as to screen for the target gene of interest.The characteristics of target gene expression and clinical prognosis in hepatocellular carcinoma were studied.The target gene was knocked down through siRNA,and cell proliferation experiments and apoptosis experiments were used to verify the importance of the target gene in the occurrence and development of liver cancer.Finally,we elucidated the potential molecular mechanism of the target gene's function in liver cancer based on the mutual regulatory relationship between the target gene and key apoptosis genes.Results:1482 genes were significantly underexpressed in liver cancer,and 725 genes were significantly overexpressed in liver cancer,of which RNaseH2A was significantly overexpressed in liver cancer and had a significant clinical prognosis.Knockdown of RNaseH2A inhibited the proliferation of hepatocellular carcinoma cells and induced apoptosis.Knockdown of RNaseH2A induced the high expression of Fas,a key gene for apoptosis,and liver cancer usually features low expression of Fas.After hepatocellular carcinoma cells that were knocked down of RNaseH2A continued were subject to Fas knockdown,hepatocellular carcinoma cell proliferation and apoptosis returned to normal levels.Conclusion:The high expression of RNaseH2A regulates the low expression of Fas,a key gene for apoptosis,thereby inhibiting apoptosis,promoting cell proliferation,and participating in the development of liver cancer.展开更多
Aicardi-Goutières syndrome (AGS) is a rare inflammatory encephalopathy mimicking in utero acquired viral infection. Cardinal findings comprise leukodystrophy, basal ganglia calcifications and cerebral atrophy alo...Aicardi-Goutières syndrome (AGS) is a rare inflammatory encephalopathy mimicking in utero acquired viral infection. Cardinal findings comprise leukodystrophy, basal ganglia calcifications and cerebral atrophy along with cerebrospinal fluid lymphocytosis and elevated interferon-α. In the majority of cases AGS is inherited as an autosomal recessive trait and caused by mutations in six genes including RNASEH2A, RNASEH2B, RNASEH2C, TREX1, SAMHD1 and ADAR1, all of which encode enzymes acting on nucleic acid species. Most patients present with first neurological signs in early infancy and experience severe global developmental delay. Here, we report on the unusual divergent phenotype of two siblings who both carry the most frequent AGS causing p.A177T (c.529G > A) RNASEH2B mutation in the homozygous state. While one sibling showed a typical AGS presentation with early onset and severe statomotor and mental impairment, the older sibling was intellectually completely normal. She was only diagnosed because of mild spasticity of the legs and serological signs of autoimmunity. These findings highlight the phenotypic variability of AGS and suggest that AGS may be underdiagnosed among children with mild cerebral palsy.展开更多
Natural antisense transcripts （NAT） and alternative polyadenylation （APA） of messenger RNA （mRNA） are important contributors of transcriptome complexity, each playing a critical role in multiple biological proce...Natural antisense transcripts （NAT） and alternative polyadenylation （APA） of messenger RNA （mRNA） are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense （S-AS） gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over-expression of the antisense KAT5 gene promoted the usage of distal polyA （pA） site in sense gene RNASEH2C, which generated longer 3＇ untranslated region （3＇UTR） and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol II occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene＇s protein level in RNASEH2C.KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype.展开更多
基金General Special Scientific Research Project of Shaanxi Provincial Department of Education“Molecular Mechanism of MiR-122 Competing Endogenous IncRNA in the Development of Liver Cancer”(Project Number:20JK0887)。
文摘Objective:To screen clinically significant potential drug targets in liver cancer and to study the function and potential molecular mechanisms of this target protein in the development of liver cancer.Methods:By using the clinical database GEPIAto find genes that are differentially expressed in liver cancer compared to normal tissues,we further screened the genes that are highly expressed in hepatocellular carcinoma and have clinical prognostic relevance.Heat maps were used to sort these genes according to their clinical prognostic relevance,so as to screen for the target gene of interest.The characteristics of target gene expression and clinical prognosis in hepatocellular carcinoma were studied.The target gene was knocked down through siRNA,and cell proliferation experiments and apoptosis experiments were used to verify the importance of the target gene in the occurrence and development of liver cancer.Finally,we elucidated the potential molecular mechanism of the target gene's function in liver cancer based on the mutual regulatory relationship between the target gene and key apoptosis genes.Results:1482 genes were significantly underexpressed in liver cancer,and 725 genes were significantly overexpressed in liver cancer,of which RNaseH2A was significantly overexpressed in liver cancer and had a significant clinical prognosis.Knockdown of RNaseH2A inhibited the proliferation of hepatocellular carcinoma cells and induced apoptosis.Knockdown of RNaseH2A induced the high expression of Fas,a key gene for apoptosis,and liver cancer usually features low expression of Fas.After hepatocellular carcinoma cells that were knocked down of RNaseH2A continued were subject to Fas knockdown,hepatocellular carcinoma cell proliferation and apoptosis returned to normal levels.Conclusion:The high expression of RNaseH2A regulates the low expression of Fas,a key gene for apoptosis,thereby inhibiting apoptosis,promoting cell proliferation,and participating in the development of liver cancer.
基金supported by the Deutsche Forschungsgemeinschaft(VT 421/2-1 to V.T.,LE 1074/4-1 to M.L.-K.)a MeDDrive grant of the Medical Faculty,TU Dresdensupport by the Deutsche Forschungsgemeinschaft and the Open Access Publication Funds of the TU Dresden
文摘Aicardi-Goutières syndrome (AGS) is a rare inflammatory encephalopathy mimicking in utero acquired viral infection. Cardinal findings comprise leukodystrophy, basal ganglia calcifications and cerebral atrophy along with cerebrospinal fluid lymphocytosis and elevated interferon-α. In the majority of cases AGS is inherited as an autosomal recessive trait and caused by mutations in six genes including RNASEH2A, RNASEH2B, RNASEH2C, TREX1, SAMHD1 and ADAR1, all of which encode enzymes acting on nucleic acid species. Most patients present with first neurological signs in early infancy and experience severe global developmental delay. Here, we report on the unusual divergent phenotype of two siblings who both carry the most frequent AGS causing p.A177T (c.529G > A) RNASEH2B mutation in the homozygous state. While one sibling showed a typical AGS presentation with early onset and severe statomotor and mental impairment, the older sibling was intellectually completely normal. She was only diagnosed because of mild spasticity of the legs and serological signs of autoimmunity. These findings highlight the phenotypic variability of AGS and suggest that AGS may be underdiagnosed among children with mild cerebral palsy.
基金We thank Drs. Li Jin, Feng Qian, Jun Zhu and Hongjie Yao for constructive suggestions of this manuscript. The vectors of CRISPR/ Cas9 are the generous gifts from Drs. Yangming Wang and Yong- ming Wang. This work was supported by the National Basic Research Program （973 Program） （Nos. 2013CB530700 and 2015CB943000 to T. N.） and National Natural Science Foundation of China （Grant Nos. 31471192 and 31521003 to T. N.）.
文摘Natural antisense transcripts （NAT） and alternative polyadenylation （APA） of messenger RNA （mRNA） are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense （S-AS） gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over-expression of the antisense KAT5 gene promoted the usage of distal polyA （pA） site in sense gene RNASEH2C, which generated longer 3＇ untranslated region （3＇UTR） and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol II occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene＇s protein level in RNASEH2C.KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype.
