Pancreatic ductal adenocarcinoma(PDAC)has poor prognosis due to limited therapeutic options.This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets.We hav...Pancreatic ductal adenocarcinoma(PDAC)has poor prognosis due to limited therapeutic options.This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets.We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness.HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4.Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC(log-rank P=0.036;HR=1.60,95%CI=1.03–2.47).We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency.Furthermore,Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC(log-rank P=0.022;HR=0.31,95%CI=0.14–0.68)but not in patients with SMAD4-normal PDAC.Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway.These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.展开更多
Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to ...Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.展开更多
基金We gratefully appreciate Y.L.,Q.C.and L.P.for their assistances in data analysis and T.L.,Y.C.and W.F.for their assistances in preparation of figures.We also thank G.Y.and Y.D.for their assistances in cell lines and animal experiments.This work was supported by National Science Fund for Distinguished Young Scholars(Grant No.81725015 to C.W.)Beijing Outstanding Young Scientist Program(Grant No.BJJWZYJH01201910023027 to C.W.)CAMS Innovation Fund for Medical Sciences(CIFMS)(Grant No.2016-I2M-3-019 to D.L.,Grant No.2016-I2M-4-002 to C.W.and Grant No.2016-I2M-1-001 to W.T.).
文摘Pancreatic ductal adenocarcinoma(PDAC)has poor prognosis due to limited therapeutic options.This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets.We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness.HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4.Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC(log-rank P=0.036;HR=1.60,95%CI=1.03–2.47).We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency.Furthermore,Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC(log-rank P=0.022;HR=0.31,95%CI=0.14–0.68)but not in patients with SMAD4-normal PDAC.Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway.These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.
基金supported by the National Natural Science Foundation of China(32372247)the National Key Research and Development Program of China(2023YFF1104501)to Huiyuan Guo.
文摘Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.
