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
Background:Patients with gastric cancer(GC)are prone to lymph node metastasis(LNM),which is an important factor for recurrence and poor prognosis of GC.Nowadays,more and more studies have confirmed that exosomes can p...Background:Patients with gastric cancer(GC)are prone to lymph node metastasis(LNM),which is an important factor for recurrence and poor prognosis of GC.Nowadays,more and more studies have confirmed that exosomes can participate in tumor lymphangiogenesis.An in-depth exploration of the pathological mechanism in the process of LNM in GC may provide effective targets and improve the diagnosis and treatment effect.Materials and Methods:We used sequencing analysis of collected serum to screen out exo-miRNA related to LNM in GC.ELISA,qRT-PCR,Western Blot,RNA pull-down assay,Transwell assay,animal experiments,and other experiments were used to verify the results.Results:In this study,we screened out miR-224-3p related to GC progression and LNM in a vascular endothelial growth Factor C(VEGFC)-independent manner.We found that exo-miR-224-3p derived from GC cells could enter human lymphatic endothelial cells(HLECs)and promote the tube formation and migration of HLECs.In addition,it was revealed that miR-224-3p could bind to the 3′UTR region of GSK3B mRNA.Then,we proved that inhibiting the expression of GSK3B could suppress the phosphorylation ofβ-catenin and promote the transcription of PROX1,thus leading to tumor lymphangiogenesis.Furthermore,it was also found that hnRNPA1 mediated the sorting of miR-224-3p into exosomes,and the high expression of PKM2 promoted the secretion of exomiR-224-3p.Conclusions:Our discovery of the exo-miR-224-3p/GSK3B/β-catenin/PROX1 axis may provide a new direction for the clinical treatment of GC.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.
基金supported by grants from the National Natural Science Foundation of China(Nos.82072664,81974374,82173125,82103677).
文摘Background:Patients with gastric cancer(GC)are prone to lymph node metastasis(LNM),which is an important factor for recurrence and poor prognosis of GC.Nowadays,more and more studies have confirmed that exosomes can participate in tumor lymphangiogenesis.An in-depth exploration of the pathological mechanism in the process of LNM in GC may provide effective targets and improve the diagnosis and treatment effect.Materials and Methods:We used sequencing analysis of collected serum to screen out exo-miRNA related to LNM in GC.ELISA,qRT-PCR,Western Blot,RNA pull-down assay,Transwell assay,animal experiments,and other experiments were used to verify the results.Results:In this study,we screened out miR-224-3p related to GC progression and LNM in a vascular endothelial growth Factor C(VEGFC)-independent manner.We found that exo-miR-224-3p derived from GC cells could enter human lymphatic endothelial cells(HLECs)and promote the tube formation and migration of HLECs.In addition,it was revealed that miR-224-3p could bind to the 3′UTR region of GSK3B mRNA.Then,we proved that inhibiting the expression of GSK3B could suppress the phosphorylation ofβ-catenin and promote the transcription of PROX1,thus leading to tumor lymphangiogenesis.Furthermore,it was also found that hnRNPA1 mediated the sorting of miR-224-3p into exosomes,and the high expression of PKM2 promoted the secretion of exomiR-224-3p.Conclusions:Our discovery of the exo-miR-224-3p/GSK3B/β-catenin/PROX1 axis may provide a new direction for the clinical treatment of GC.
