Dear Editor,MicroRNAs(miRNAs)are small non-coding RNAs crucial for post-transcriptional gene regulation,processed from primary miRNA transcripts by Drosha and Dicer.1 Latest advancements in Next Generation Sequencing ...Dear Editor,MicroRNAs(miRNAs)are small non-coding RNAs crucial for post-transcriptional gene regulation,processed from primary miRNA transcripts by Drosha and Dicer.1 Latest advancements in Next Generation Sequencing highlighted the existence of miRNA isoforms(isomiRs)resulting from alternative processing,RNA editing,or post-transcriptional modifications.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies.PDAC aggressiveness largely relies on its extraord...Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies.PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment.Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC.Here,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation.We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients.Mechanistically,we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting.In miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient deprivation.In a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction.Consistently,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner.Overall,our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.展开更多
Non-small cell lung cancer(NSCLC)is the leading cause of cancer-related mortality worldwide.Platinum-based chemotherapy represents the main treatment,despite about the 70%of tumors are intrinsically resistant.Decipher...Non-small cell lung cancer(NSCLC)is the leading cause of cancer-related mortality worldwide.Platinum-based chemotherapy represents the main treatment,despite about the 70%of tumors are intrinsically resistant.Deciphering the mechanisms of platinum-resistance is urgently needed.展开更多
Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Ac...Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Acquirement of these various hallmarks rely on different cellular pathways,including TGF-βand Wnt signaling.Recently,we reported that WW domain-containing oxidoreductase(WWOX)acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs(miRNAs)in triple-negative breast cancer(TNBC).Here,we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles;further,WWOX interacts with various proteins to exert its tumor suppressor function.Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion,invasion and motility.We further demonstrate that WWOX,through regulation of miR-146a levels,regulates SMAD3,which is a member of the TGF-βsignaling pathway.Moreover,proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled.Altogether,these findings underscore a significant role for WWOX in antagonizing metastasis,further highlighting its role and therapeutic potential in suppressing tumor progression.展开更多
基金The authors thank the Genomics Shared Resource at The Ohio State University Comprehensive Cancer Center(OSU CCC),Columbus,OH.This work was supported by the NCI(NIH)grant R35CA197706 to C.M.Croce.
文摘Dear Editor,MicroRNAs(miRNAs)are small non-coding RNAs crucial for post-transcriptional gene regulation,processed from primary miRNA transcripts by Drosha and Dicer.1 Latest advancements in Next Generation Sequencing highlighted the existence of miRNA isoforms(isomiRs)resulting from alternative processing,RNA editing,or post-transcriptional modifications.
基金We thank the Genomic Shared Resource at The Ohio State University Comprehensive cancer Center(OSU CCC),supported by the Cancer Center Support Grant P30CA016058,for conducting the Affymetrix microarray assays,in particular Dr.Paolo FaddaWe acknowledge resources from the Campus Microscopy and Imaging Facility(CMIF)at The Ohio State University,in particular Dr.Jeffrey R.Tonniges for his valuable support+2 种基金This facility is supported in part by grant P30 CA016058,National Cancer Institute,Bethesda,MDHistology and immunohistochemistry services were provided by the Comparative Pathology&Digital Imaging Shared Resource,Department of Veterinary Biosciences and the Comprehensive Cancer Center,The Ohio State University,Columbus,OH.Figs.4a,6g and Supplementary Fig.10a of this manuscript were realized by using the software BioRender.comsupported by NIH/NCI grant R35 CA197706 to C.M.C.G.B.was funded by Ricerca Corrente of Ministero della Salute.
文摘Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies.PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment.Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC.Here,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation.We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients.Mechanistically,we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting.In miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient deprivation.In a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction.Consistently,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner.Overall,our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.
文摘Non-small cell lung cancer(NSCLC)is the leading cause of cancer-related mortality worldwide.Platinum-based chemotherapy represents the main treatment,despite about the 70%of tumors are intrinsically resistant.Deciphering the mechanisms of platinum-resistance is urgently needed.
基金supported by the Israel science foundation grant(ISF grant agreement No.15/1574)ICRF-City of Hope-Harvey L.Miller Family Foundation and European Research Council(ERC)-Consolidator Grant under the European Union’s Horizon 2020 research and innovation program(grant agreement No.682118).
文摘Tumor progression and metastasis are the major causes of death among cancer associated mortality.Metastatic cells acquire features of migration and invasion and usually undergo epithelia-mesenchymal transition(EMT).Acquirement of these various hallmarks rely on different cellular pathways,including TGF-βand Wnt signaling.Recently,we reported that WW domain-containing oxidoreductase(WWOX)acts as a tumor suppressor and has anti-metastatic activities involving regulation of several key microRNAs(miRNAs)in triple-negative breast cancer(TNBC).Here,we report that WWOX restoration in highly metastatic MDA-MB435S cancer cells alters mRNA expression profiles;further,WWOX interacts with various proteins to exert its tumor suppressor function.Careful alignment and analysis of gene and miRNA expression in these cells revealed profound changes in cellular pathways mediating adhesion,invasion and motility.We further demonstrate that WWOX,through regulation of miR-146a levels,regulates SMAD3,which is a member of the TGF-βsignaling pathway.Moreover,proteomic analysis of WWOX partners revealed regulation of the Wnt-signaling activation through physical interaction with Disheveled.Altogether,these findings underscore a significant role for WWOX in antagonizing metastasis,further highlighting its role and therapeutic potential in suppressing tumor progression.
