单位：[1]Department of Surgery, Miller School of Medicine, University of Miami, RosenstielMed Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL 33136‑1015,USA[2]Department of Gastroenterology, Beijing Friendship Hospital, CapitalMedical University, Beijing, P.R.China临床科室国家中心消化分中心消化内科首都医科大学附属北京友谊医院[3]Department of Medicine, ColumbiaUniversity, New York, NY 10027, USA[4]Department of Molecular and CellularPharmacology & Sylvester Comprehensive Cancer Center, University of MiamiMiller School of Medicine, Miami, FL, USA[5]Department of Medicine and HerbertIrving Comprehensive Cancer Center, Columbia University Irving MedicalCenter, New York, NY, USA[6]Department of Oncology, University of Torinoand Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy[7]Departmentof Veterans Affairs, Miami Healthcare System, Miami, FL, USA[8]Departmentof Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136,USA[9]Sylvester Comprehensive Cancer Center, Miller School of Medicine,University of Miami, Miami, FL, USA
Background Esophageal adenocarcinoma (EAC) is characterized by poor prognosis and low survival rate. Chronic gastroesophageal reflux disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE), a preneoplastic metaplastic condition, and its progression to EAC. Yes-associated protein 1 (YAP1) activation mediates stem-like properties under cellular stress. The role of acidic bile salts (ABS) in promoting YAP1 activation under reflux conditions remains unexplored. Methods A combination of EAC cell lines, transgenic mice, and patient-derived xenografts were utilized in this study. mRNA expression and protein levels of APE1 and YAP1 were evaluated by qRT-PCR, western blot, and immunohistochemistry. YAP1 activation was confirmed by immunofluorescence staining and luciferase transcriptional activity reporter assay. The functional role and mechanism of regulation of YAP1 by APE1 was determined by sphere formation assay, siRNA mediated knockdown, redox-specific inhibition, and co-immunoprecipitation assays. Results We showed that YAP1 signaling is activated in BE and EAC cells following exposure to ABS, the mimicry of reflux conditions in patients with GERD. This induction was consistent with APE1 upregulation in response to ABS. YAP1 activation was confirmed by its nuclear accumulation with corresponding up-regulation of YAP1 target genes. APE1 silencing inhibited YAP1 protein induction and reduced its nuclear expression and transcriptional activity, following ABS treatment. Further investigation revealed that APE1-redox-specific inhibition (E3330) or APE1 redox-deficient mutant (C65A) abrogated ABS-mediated YAP1 activation, indicating an APE1 redox-dependent mechanism. APE1 silencing or E3330 treatment reduced YAP1 protein levels and diminished the number and size of EAC spheroids. Mechanistically, we demonstrated that APE1 regulated YAP1 stability through interaction with beta-TrCP ubiquitinase, whereas APE1-redox-specific inhibition induced YAP1 poly-ubiquitination promoting its degradation. Conclusion Our findings established a novel function of APE1 in EAC progression elucidating druggable molecular vulnerabilities via targeting APE1 or YAP1 for the treatment of EAC.
基金：
U.S. National Institutes of Health (NIH) [P01CA268991, R01CA206563, R01CA224366]; [P30CA240139]
第一作者单位：[1]Department of Surgery, Miller School of Medicine, University of Miami, RosenstielMed Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL 33136‑1015,USA
通讯作者：
通讯机构：[1]Department of Surgery, Miller School of Medicine, University of Miami, RosenstielMed Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL 33136‑1015,USA[7]Departmentof Veterans Affairs, Miami Healthcare System, Miami, FL, USA[9]Sylvester Comprehensive Cancer Center, Miller School of Medicine,University of Miami, Miami, FL, USA
推荐引用方式(GB/T 7714)：
Farah Ballout,Heng Lu,Lei Chen,et al.APE1 redox function is required for activation of Yes-associated protein 1 under reflux conditions in Barrett's-associated esophageal adenocarcinomas[J].JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH.2022,41(1):doi:10.1186/s13046-022-02472-5.
APA：
Farah Ballout,Heng Lu,Lei Chen,Kannappan Sriramajayam,Jianwen Que...&Wael El‑Rifai.(2022).APE1 redox function is required for activation of Yes-associated protein 1 under reflux conditions in Barrett's-associated esophageal adenocarcinomas.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,41,(1)
MLA：
Farah Ballout,et al."APE1 redox function is required for activation of Yes-associated protein 1 under reflux conditions in Barrett's-associated esophageal adenocarcinomas".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 41..1(2022)
医学