Tankyrase (TNKS) is a crucial mediator of Wnt signal transduction and has been recognized as a novel molecular target for Wnt-pathway dependent cancer. TNKS is stabilized by the ubiquitin-specific protease 25 (USP25). The effect of disruption of the interaction between TNKS and USP25 by small molecules on prostate cancer proliferation is unknown. In this study we conducted a hierarchical virtual screening with more than 200,000 compounds on the characterized structures of the USP25/TNKS-ARC5 protein complex. In silico analysis and in vitro validation revealed that a small molecule, called C44, binds to the protein-protein interaction (PPI) interface of TNKS and USP25. We show that C44 disrupts the interaction between TNKS and USP25 leading to a higher half-life of AXIN and the breakdown of -catenin protein. We also show that the selective inhibition of the TNKS-USP25 interaction by C44 significantly reduces proliferation of prostate cancer cells in vitro and in vivo. Our study reveals a new PPI inhibitor that lowers the stability of TNKS protein and inhibits Wnt pathway signaling. C44 is a promising new drug for the treatment of Wnt-pathway dependent prostate cancer.

目的 总结和分析输尿管癌的典型临床表现及影像学特点,提高输尿管癌的诊疗水平.方法 回顾性总结2008年7月至2017年3月该院术后病理证实为输尿管癌28例,分析其典型临床表现、影像学特点及治疗方案.结果 28例中8例仅表现为无痛性全程肉眼血尿,4例仅表现为腰痛,12例表现为全程肉眼血尿伴腰痛,血尿皆出现于腰痛之前,4例无任何临床表现均于体检时发现.泌尿系B超的检出率为66.7％;CT尿路造影(CTU)的检出率为85.7％;静脉尿路造影(IVU)+尿路平片(KUB)的检出率为71.4％;逆行肾盂造影检出率为75.0％;输尿管镜检的检出率为92.9％,所取组织病理活检检出率为57.7％;荧光原位杂交技术(FISH)检出率为64.3％.28例皆行腹腔镜联合下腹部切口输尿管癌根治性切除术,术后病理检查皆证实为输尿管癌,其中浸润性高级别尿路上皮癌20例,浸润性低级别尿路上皮癌8例.结论 肉眼血尿是输尿管癌的主要临床表现,可伴或不伴有腰痛.影像学检查常提示患侧肾积水、梗阻部位以上输尿管扩张积水等表现.输尿管镜检对输尿管癌的检出率最高,但由此方法所取的组织病理活检阳性率并不理想;CTU、逆行肾盂造影的检出率也较高,但均稍低于输尿管镜检+病理活检,泌尿系B超、FISH、IVU+K UB可作为输尿管癌的术后复查及初筛手段.联合运用CT U和输尿管镜检+病理活检可有效提高输尿管癌的正确诊断率.目前输尿管癌以手术治疗为主,标准术式为腹腔镜联合下腹部切口输尿管癌根治性切除术,切除范围包括患侧肾脏、全长输尿管及膀胱袖状切除.

Objective To analyze the typical clinical manifestations and imaging characteristics of renal pelvic carcinoma.Methods The clinical data in 69 cases of renal pelvic carcinoma verified by postoperative pathology in this department of the hospital from July 2013 to November 2016 were retrospectively summarized to analyze its typical clinical manifestations,imaging features and treatment regimens.Results All the cases were hospitalized due to hematuria and presented gross hematuria.The detectable rate of B-ultrasonic examination was 71.43 ％,which of computed tomography urography(CTU) was 84.21％ and which of intravenous urography(IVU) + kidney ureter bladder(KUB) was 70.27 ％,which of retrograde pyelography(RP) was 90.32 ％,which of flexible ureteroscope(FU) was 91.67 ％,the pathological detection rate of biopsy tissue by this method was 58.33 ％ and detection rate of fluorescence in situ hybridization was 79.07 ％.Sixty-nine cases all were performed the retroperitoneal laparoscopy combined with hypogastric incision renal pelvic carcinoma radical operation,postoperative pathological examination verified renal pelvis carcinoma.Conclusion Flexible ureteroscope examination has the highest definite diagnosis rate of renal pelvic carcinoma,but the pathological positive rate of biopsy tissue by this method is not ideal;the definite diagnosis rate of RP and CTU were secondary,urinary system B-ultrasonic examination,FISH and KUB+IVP can serve as the preliminary screening and postoperative re-examination means of renal pelvic carcinoma.