Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discr...Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.展开更多
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
Background:Microribose nucleic acids(miRNAs)are implicated in the progression of lung adenocarcinoma.MicroRNA-345-5p(miR-345-5p)is a recently identified anti-oncogene in some human cancers,but its functional role and ...Background:Microribose nucleic acids(miRNAs)are implicated in the progression of lung adenocarcinoma.MicroRNA-345-5p(miR-345-5p)is a recently identified anti-oncogene in some human cancers,but its functional role and possible molecular mechanism in lung adenocarcinoma remain unknown.This study aimed to identify the biological function and underlying mechanism of miR-345-5p in lung adenocarcinoma cells.Methods:In this study,lung adenocarcinoma tissues and adjacent tissues were collected in the First Affiliated Hospital of Anhui Medical University between April 2016 and February 2017.The expression of miR-345-5p and ras homolog family member A(RhoA)in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines(A549,H1650,PC-9,and H441)was detected by reverse transcription quantitative polymerase chain reaction analysis.Functional assays including colony formation,flow cytometry analysis,wound healing,and transwell assays were performed to assess the proliferation,apoptosis,migration,and invasion of lung adenocarcinoma cells.In addition,RNA pulldown and luciferase reporter assays were conducted to evaluate the relationship between miR-345-5p and RhoA.Difference between the two groups was analyzed with Student’st test,while that among multiple groups was analyzed with one-way analysis of variance.Results:MiR-345-5p expression displayed lower level in lung adenocarcinoma tissues(0.241±0.095vs.1.000±0.233,t=19.247,P<0.001)and cell lines(F=56.992,P<0.001)than control tissues and cells.Functional experiments demonstrated that upregulation of miR-345-5p inhibited the malignant phenotypes of lung adenocarcinoma cells via suppressing cell proliferation,migration,invasion,and facilitating cell apoptosis.Additionally,RhoA was verified to be the downstream target of miR-345-5p.Expression of RhoA was downregulated by overexpression of miR-345-5p in PC-9(0.321±0.047vs.1.000±0.127,t=8.536,P<0.001)and H1650(0.398±0.054vs.1.000±0.156,t=4.429,P=0.011)cells.Rescue assays revealed that overexpression of RhoA rescued the suppressive effects of miR-345-5p upregulation on proliferation,migration,and invasion of lung adenocarcinoma cells.Further,miR-345-5p was found to regulate the Rho/Rho-associated protein kinase(ROCK)signaling pathway by downregulation of RhoA in lung adenocarcinoma cells.Conclusions:MiR-345-5p plays a tumor suppressor role in lung adenocarcinoma cells by downregulating RhoA to inactivate the Rho/ROCK pathway.展开更多
基金This work was supported by the Natural Science Foundation of Guangdong Province(Grant No.2019A1515011354).
文摘Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
文摘Background:Microribose nucleic acids(miRNAs)are implicated in the progression of lung adenocarcinoma.MicroRNA-345-5p(miR-345-5p)is a recently identified anti-oncogene in some human cancers,but its functional role and possible molecular mechanism in lung adenocarcinoma remain unknown.This study aimed to identify the biological function and underlying mechanism of miR-345-5p in lung adenocarcinoma cells.Methods:In this study,lung adenocarcinoma tissues and adjacent tissues were collected in the First Affiliated Hospital of Anhui Medical University between April 2016 and February 2017.The expression of miR-345-5p and ras homolog family member A(RhoA)in lung adenocarcinoma tissues and human lung adenocarcinoma cell lines(A549,H1650,PC-9,and H441)was detected by reverse transcription quantitative polymerase chain reaction analysis.Functional assays including colony formation,flow cytometry analysis,wound healing,and transwell assays were performed to assess the proliferation,apoptosis,migration,and invasion of lung adenocarcinoma cells.In addition,RNA pulldown and luciferase reporter assays were conducted to evaluate the relationship between miR-345-5p and RhoA.Difference between the two groups was analyzed with Student’st test,while that among multiple groups was analyzed with one-way analysis of variance.Results:MiR-345-5p expression displayed lower level in lung adenocarcinoma tissues(0.241±0.095vs.1.000±0.233,t=19.247,P<0.001)and cell lines(F=56.992,P<0.001)than control tissues and cells.Functional experiments demonstrated that upregulation of miR-345-5p inhibited the malignant phenotypes of lung adenocarcinoma cells via suppressing cell proliferation,migration,invasion,and facilitating cell apoptosis.Additionally,RhoA was verified to be the downstream target of miR-345-5p.Expression of RhoA was downregulated by overexpression of miR-345-5p in PC-9(0.321±0.047vs.1.000±0.127,t=8.536,P<0.001)and H1650(0.398±0.054vs.1.000±0.156,t=4.429,P=0.011)cells.Rescue assays revealed that overexpression of RhoA rescued the suppressive effects of miR-345-5p upregulation on proliferation,migration,and invasion of lung adenocarcinoma cells.Further,miR-345-5p was found to regulate the Rho/Rho-associated protein kinase(ROCK)signaling pathway by downregulation of RhoA in lung adenocarcinoma cells.Conclusions:MiR-345-5p plays a tumor suppressor role in lung adenocarcinoma cells by downregulating RhoA to inactivate the Rho/ROCK pathway.
