Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancre...Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancreatic ductal adenocarcinoma(PDAC).Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients.Because RNF43 loss-of-function mutations and KRAS gain-of-function mutations concur in a subset of IPMN and PDAC,their biological significance and therapeutic potential should be elucidated.Methods:Pancreatic Rnf43 knockout and Kras activated mice(Rnf43^(−/−);Kras^(G12D))were generated to evaluate their clinical significance in pancreatic pre-neoplastic initiation and malignant transformation.Results:Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice.The Wnt/β-catenin signaling pathway was activated in pan-creatic Kras^(G12D)and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly.Conclusions:Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation.This genetically reconstituted autochthonous pancreatic Rnf43^(−/−);Kras^(G12D)preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β-catenin signaling.Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs,patients with these genetic anomalies warrant surveillance,surgery,and/or targeted therapeutics such as Wnt/β-catenin inhibitors.展开更多
Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clin...Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.展开更多
环指蛋白43(ring finger protein 43,RNF43)是Wnt信号通路中重要的负向调控因子之一。RNF43的异常表达、突变等改变与肿瘤的发生、发展密切相关,在临床上具有较为重要的意义。该文对RNF43的结构、功能及各项研究进展作一概述,描述其在...环指蛋白43(ring finger protein 43,RNF43)是Wnt信号通路中重要的负向调控因子之一。RNF43的异常表达、突变等改变与肿瘤的发生、发展密切相关,在临床上具有较为重要的意义。该文对RNF43的结构、功能及各项研究进展作一概述,描述其在肿瘤发生、发展进程中的作用。展开更多
As evolutionarily conserved signals,roof plate-specific spondins(R-spondins;RSPOs)are a family with four members(RSPO1e4)exerting distinctly different functions.RSPOs have five receptors and correlate with different s...As evolutionarily conserved signals,roof plate-specific spondins(R-spondins;RSPOs)are a family with four members(RSPO1e4)exerting distinctly different functions.RSPOs have five receptors and correlate with different signaling pathways through these receptors and then perform various functions.Moreover,their best-known molecular function is the capacity to enhance WNT signaling pathways,which play critical roles in several processes.A recent study shows that RSPOs not only potentiate the WNT/beta(b)-catenin signaling pathway but are also involved in the WNT/planar cell polarity signaling pathway.RSPOs influence liver homeostasis and the development of multiple liver diseases.RSPO1 increases cell proliferation,protects hepatocytes from injury,improves liver regenerative potential,and affects liver metabolic zonation.RSPO2 not only regulates proliferation-associated genes and promotes differentiation in the liver but also participates in liver fibrosis through the WNT/b-catenin signaling pathway.RSPO3 is a key determinant of proper liver function,such as promoting hepatocyte regeneration and maintaining liver zonation.RSPO3 is upregulated in liver fibrosis and livers of patients with nonalcoholic steatohepatitis.Besides,RSPO2 and RSPO3 are confirmed as oncogenes and involved in the occurrence of liver cancer.The role of RSPO4 in the liver remains unclear.In this review,the structural and biochemical properties of RSPOs and their receptors and their roles in liver homeostasis and disease are summarized.展开更多
Intraductal papillary mucinous neoplasm(IPMN)is a pre-malignant,mucin-producing epithelial lesion arising from pancreatic ducts.Observational reports define IPMN behavior as ranging from indolent,asymptomatic lesions ...Intraductal papillary mucinous neoplasm(IPMN)is a pre-malignant,mucin-producing epithelial lesion arising from pancreatic ducts.Observational reports define IPMN behavior as ranging from indolent,asymptomatic lesions to dysplasia that sometimes degenerate into pancreatic adenocarcinoma.The goal of IPMN management is risk-reducing surgery for high-risk cysts and observation of the remainder.Discriminating high-from low-risk IPMN disease still relies on imaging and clinical cyst characteristics.Here,we review the accepted classification of IPMN including the most common histological subtypes,their clinical features,and currently-accepted high-risk phenotypes.We then deeply examine the known molecular landscape of IPMN,which has largely been derived from post-resection analysis.This includes those gene variants unique to IPMN,chiefly GNAS and RNF43,but also examines the overlap between IPMN and conventional pancreatic adenocarcinoma.Utilizing molecular markers in the clinical setting relies on endoscopically-obtained cyst fluid and presumes that it accurately represents the molecular characteristics of the cystic epithelium.We synthesize existing data on mutational analysis from IPMN cyst fluid and consider the benefits and proper role of current commercially-available cyst fluid molecular analysis kits.We conclude that carefully interpreted molecular analysis of resected IPMN tissue reveals insights into its biology and natural history while cyst fluid analysis offers prognostication and data to guide treatment decisions.However,knowledge gaps remain,especially in characterizing IPMN molecular heterogeneity,time to progression,and correlating cyst fluid genotype data with surveillance strategies.As such,substantial additional research is required before the promise of true molecular guidance of IPMN management can be realized.展开更多
基金The National Natural Science Foundation of China(81872287,81730078)the Chinese Academy of Medical Sciences Initiative for Innovative Medicine(2021-1-I2M-018).
文摘Background:Largely due to incidental detection,asymptomatic pancreatic cystic le-sions(PCLs)have become prevalent in recent years.Among them,intraductal papillary mucinous neoplasm(IPMN)infrequently advances to pancreatic ductal adenocarcinoma(PDAC).Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients.Because RNF43 loss-of-function mutations and KRAS gain-of-function mutations concur in a subset of IPMN and PDAC,their biological significance and therapeutic potential should be elucidated.Methods:Pancreatic Rnf43 knockout and Kras activated mice(Rnf43^(−/−);Kras^(G12D))were generated to evaluate their clinical significance in pancreatic pre-neoplastic initiation and malignant transformation.Results:Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice.The Wnt/β-catenin signaling pathway was activated in pan-creatic Kras^(G12D)and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly.Conclusions:Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation.This genetically reconstituted autochthonous pancreatic Rnf43^(−/−);Kras^(G12D)preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β-catenin signaling.Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs,patients with these genetic anomalies warrant surveillance,surgery,and/or targeted therapeutics such as Wnt/β-catenin inhibitors.
基金supported by the Top-Level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03)National Natural Science Foundation of China (Nos.81773154,81902565,81772747,81974391)+4 种基金Shanghai Natural Science Foundation (No.20ZR1449600)Pudong New Area Science and Technology Development Fund Special Fund for People’s Livelihood Research (Medical and Health) (PKJ2019-Y19)Young Scientists Foundation of Changzhou No.2 People’s Hospital (2019K008)Changzhou Sci&Tech Program (CJ20190100)the Program of Shanghai Academic/Technology Research Leader (No.19XD1405100).
文摘Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.
基金This work was supported by grants from the Scientific Research Common Program of Beijing Municipal Commission of Education(No.KM202010025029)the National Natural Science Foundation of China(No.82070623 and 81970532)the Beijing Natural Science Foundation(No.7202007).
文摘As evolutionarily conserved signals,roof plate-specific spondins(R-spondins;RSPOs)are a family with four members(RSPO1e4)exerting distinctly different functions.RSPOs have five receptors and correlate with different signaling pathways through these receptors and then perform various functions.Moreover,their best-known molecular function is the capacity to enhance WNT signaling pathways,which play critical roles in several processes.A recent study shows that RSPOs not only potentiate the WNT/beta(b)-catenin signaling pathway but are also involved in the WNT/planar cell polarity signaling pathway.RSPOs influence liver homeostasis and the development of multiple liver diseases.RSPO1 increases cell proliferation,protects hepatocytes from injury,improves liver regenerative potential,and affects liver metabolic zonation.RSPO2 not only regulates proliferation-associated genes and promotes differentiation in the liver but also participates in liver fibrosis through the WNT/b-catenin signaling pathway.RSPO3 is a key determinant of proper liver function,such as promoting hepatocyte regeneration and maintaining liver zonation.RSPO3 is upregulated in liver fibrosis and livers of patients with nonalcoholic steatohepatitis.Besides,RSPO2 and RSPO3 are confirmed as oncogenes and involved in the occurrence of liver cancer.The role of RSPO4 in the liver remains unclear.In this review,the structural and biochemical properties of RSPOs and their receptors and their roles in liver homeostasis and disease are summarized.
文摘Intraductal papillary mucinous neoplasm(IPMN)is a pre-malignant,mucin-producing epithelial lesion arising from pancreatic ducts.Observational reports define IPMN behavior as ranging from indolent,asymptomatic lesions to dysplasia that sometimes degenerate into pancreatic adenocarcinoma.The goal of IPMN management is risk-reducing surgery for high-risk cysts and observation of the remainder.Discriminating high-from low-risk IPMN disease still relies on imaging and clinical cyst characteristics.Here,we review the accepted classification of IPMN including the most common histological subtypes,their clinical features,and currently-accepted high-risk phenotypes.We then deeply examine the known molecular landscape of IPMN,which has largely been derived from post-resection analysis.This includes those gene variants unique to IPMN,chiefly GNAS and RNF43,but also examines the overlap between IPMN and conventional pancreatic adenocarcinoma.Utilizing molecular markers in the clinical setting relies on endoscopically-obtained cyst fluid and presumes that it accurately represents the molecular characteristics of the cystic epithelium.We synthesize existing data on mutational analysis from IPMN cyst fluid and consider the benefits and proper role of current commercially-available cyst fluid molecular analysis kits.We conclude that carefully interpreted molecular analysis of resected IPMN tissue reveals insights into its biology and natural history while cyst fluid analysis offers prognostication and data to guide treatment decisions.However,knowledge gaps remain,especially in characterizing IPMN molecular heterogeneity,time to progression,and correlating cyst fluid genotype data with surveillance strategies.As such,substantial additional research is required before the promise of true molecular guidance of IPMN management can be realized.
