结直肠癌是全世界最常见的恶性肿瘤之一,也是我国大中城市发病率排名高居第二、三位的恶性肿瘤,且其近年来发病率呈上升趋势,严重地威胁了人们的健康和生命,现已采取了手术及放化疗等一系列综合治疗,但其治疗效果仍有待提高[1]。从分子...结直肠癌是全世界最常见的恶性肿瘤之一,也是我国大中城市发病率排名高居第二、三位的恶性肿瘤,且其近年来发病率呈上升趋势,严重地威胁了人们的健康和生命,现已采取了手术及放化疗等一系列综合治疗,但其治疗效果仍有待提高[1]。从分子水平上研究结直肠癌的发生、发展和转移,已成为目前结直肠癌研究的热点。信号传导及转录激活因子3（signal transducers and activators of tran-scription,STAT3）是STATs家族中的一员.展开更多
Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historicall...Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historically been challenging,and currently,there are no approved p53-based therapeutics for clinical use worldwide.In this study,we discovered that ubiquitin carboxyl terminal hydrolase L3(UCHL3)plays a crucial role in high-level glycolysis,enhanced stem-like properties,and 5-fluorouracil(5-FU)chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilizeα-enolase(ENO1)protein.Notably,we identified a newly Food and Drug Administration(FDA)-approved drug,pacritinib,that potently suppresses UCHL3 expression by blocking the janus kinase 2(JAK2)–signal transducer and activator of transcription 3(STAT3)pathway in TP53-mutant CRC.Furthermore,Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC.Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC.Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.展开更多
文摘结直肠癌是全世界最常见的恶性肿瘤之一,也是我国大中城市发病率排名高居第二、三位的恶性肿瘤,且其近年来发病率呈上升趋势,严重地威胁了人们的健康和生命,现已采取了手术及放化疗等一系列综合治疗,但其治疗效果仍有待提高[1]。从分子水平上研究结直肠癌的发生、发展和转移,已成为目前结直肠癌研究的热点。信号传导及转录激活因子3（signal transducers and activators of tran-scription,STAT3）是STATs家族中的一员.
基金supported by the National Key Research and Development Program of China(No.2022YFC3401000 to Zitong Zhao)the National Natural Science Foundation of China(No.82173332 to Yongmei Song,No.82272909 to Guiying Wang)+2 种基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2023-I2M-2-004 to Yongmei Song,China)the Hebei Province Natural Innovation Group Program(No.H2022206355 to Guiying Wang,China)the Hebei Province Central Guide Local Science and Technology Special Project(No.236Z7757G to Guiying Wang,China).
文摘Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historically been challenging,and currently,there are no approved p53-based therapeutics for clinical use worldwide.In this study,we discovered that ubiquitin carboxyl terminal hydrolase L3(UCHL3)plays a crucial role in high-level glycolysis,enhanced stem-like properties,and 5-fluorouracil(5-FU)chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilizeα-enolase(ENO1)protein.Notably,we identified a newly Food and Drug Administration(FDA)-approved drug,pacritinib,that potently suppresses UCHL3 expression by blocking the janus kinase 2(JAK2)–signal transducer and activator of transcription 3(STAT3)pathway in TP53-mutant CRC.Furthermore,Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC.Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC.Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.
