|Table of Contents|

Changes of KU protein expression in tumor tissue before and after gemcitabine combined with cisplatin neoadjuvant chemotherapy for muscular invasive bladder cancer and its relationship with curative effect

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 21
Page:
4143-4148
Research Field:
Publishing date:

Info

Title:
Changes of KU protein expression in tumor tissue before and after gemcitabine combined with cisplatin neoadjuvant chemotherapy for muscular invasive bladder cancer and its relationship with curative effect
Author(s):
ZHANG Linlin1; XU Zhao2; DONG Longxin1; LI Zhen3; ZHANG Weitao1
1.Department of Urology,the Second Affiliated Hospital of Shandong First Medical University,Shandong Tai’an 271000,China;2.Department of Urology,Tai’an Central Hospital,Tai’an Central Hospital Affiliated to Qingdao University,Taishan Medical Care Center，Shandong Tai’an 271000,China;3.Department of Oncology,the Second Affiliated Hospital of Shandong First Medical University,Shandong Tai’an 271000,China.
Keywords:
muscle invasive bladder cancer; neoadjuvant chemotherapy; immunohistochemistry; gemcitabine plus cisplatin; KU proteins; markers
PACS:
R737.14
DOI:
10.3969/j.issn.1672-4992.2024.21.023
Abstract:
Objective:To investigate the expression of KU protein before and after neoadjuvant chemotherapy in patients with muscular invasive bladder cancer,and explore its correlation with the efficacy of neoadjuvant chemotherapy.Methods:A retrospective study was conducted on clinical data from 54 patients with stage T2N0M0-T4aN0M0 muscular invasive bladder cancer who underwent preoperative neoadjuvant chemotherapy at the Second Affiliated Hospital of Shandong First Medical University,Tai’an Central Hospital,and Taishan Medical Center Affiliated to Qingdao University between July 2012 and July 2023.All patients received gemcitabine combined with cisplatin for 2 to 4 cycles every 21 days.Based on treatment response,patients were categorized into complete remission group,partial remission group,stable disease group or disease progression group.Immunohistochemistry was used to detect KU protein expression in tumor tissues before and after neoadjuvant chemotherapy,and its relationship with treatment efficacy was analyzed.Results:All 54 patients completed neoadjuvant chemotherapy,with an average duration of 3 courses.Among them,50.0%(27/54) were in the partial remission group.Following neoadjuvant chemotherapy,a significant decrease in KU protein expression was observed in cancer tissues of this group(P＜0.01).In the stable disease group(16/54,29.6%),there was also a statistically significant reduction in KU protein expression after neoadjuvant chemotherapy(P＜0.05).However,no statistical significance was found for the increase in KU protein expression observed following neoadjuvant chemotherapy among patients in the progressive group(7/54,13.0%).Conclusion:The KU protein is implicated in the neoadjuvant chemotherapy response process for muscular invasive bladder cancer,and its expression in tumor tissues decreases following treatment,indicating the effectiveness of neoadjuvant chemotherapy.Immunohistochemical detection of KU protein expression can serve as a predictive method for assessing neoadjuvant chemotherapy efficacy in myoinvasive bladder cancer.

References:

［1］BRAY F,LAVERSANNE M,SUNG H,et al.Global cancer statistics 2022:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］.CA Cancer J Clin,2024,74(3):229-263.
［2］XIA C,DONG X,LI H,et al.Cancer statistics in China and United States,2022:Profiles,trends,and determinants［J］.Chin Med J(Engl),2022,135(5):584-590.
［3］HAUTMANN RE,DE PETRICONI RC,PFEIFFER C,et al.Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy:Long-term results in 1100 patients［J］.Eur Urol,2012,61(5):1039-1047.
［4］VESKIMAE E,ESPINOS EL,BRUINS HM,et al.What is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer?A European association of urology muscle invasive and metastatic bladder cancer guidelines panel systematic review［J］.Eur Urolol,2019,2(6):625-642.
［5］MA C,LU B,DIAO C,et al.Preoperative neutrophil-lymphocyte ratio and fibrinogen level in patients distinguish between muscle-invasive bladder cancer and non-muscle-invasive bladder cancer［J］.Onco Targets Ther,2016,8(9):4917-4922.
［6］ADELMANT G，CALKINS AS，GARG BK，et al.DNA ends alter the molecular composition and localization of Ku multicomponent complexes［J］.Mol Cell Proteomics,2012,11(8):411-421．
［7］STRONATI L,GENSABELLA G,LAMBERTI C,et al.Expression and DNA binding activity of the Ku heterodimer in bladder carcinoma［J］.Cancer,2001,92(9):2484-2492.
［8］JENSEN R,GLAZER PM.Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions［J］．Proc Natl Acad Sci USA,2004,101(16):6134-6139.
［9］ALFRED WJ,LEBRET T,COMPERAT EM,et al.Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer［J］.Eur Urol,2017,71(3):462-475.
［10］EISENHAUER EA,THERASSE P,BOGAERTS J,et al.New response evaluation criteria in solid tumours:Revised RECIST guideline(version1.1)［J］.Eur J Cancer,2009,45(2):228-247.
［11］HU S,QU Y,XU X,et al.Nuclear survivin and its relationship to DNA damage repair genes in non-small cell lung cancer investigated using tissue array［J］.PLoS One,2013,8(9):e74161．
［12］BELLMUNT J,PETRYLAK DP.New therapeutic challenges in advanced bladder cancer［J］.Semin Oncol,2012,39(5):598-607.
［13］斯热努尔?艾合买提，张瑞丽，魏媛，等.肌层浸润性膀胱癌患者根治术后预后相关因素分析［J］.现代肿瘤医学，2020,28（17）:2995-2999.Sirenuer?Aihemaiti,ZHANG RL,WEI Y,et al.Prognostic factors of patients with muscle-invasive bladder cancer treated by the radical cystectomy［J］.Modern Oncology，2020,28（17）:2995-2999.
［14］XIE W,BI J,WEI Q,et al.Survival after radical cystectomy for bladder cancer:Multicenter comparison between minimally invasive and open approaches［J］.Asian J Urol,2020,7(3):291-300.
［15］YAGODA A,WATSON RC,GONZALEZ-VITALE JC,et al.Cis-dichlorodiammineplatinum(Ⅱ) in advanced bladder cancer［J］.Cancer Treat Rep,1976,60(7):917-923.
［16］YAGODA A.Phase-Ⅱ trials in patients with urothelial tract tumors［J］.Cancer Chemother Pharmaeol,1983,11(Suppl):S9-S12.
［17］WITJES JA，BRUINS HM，CATHOMAS R，et al.European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer:Summary of the 2020 Guidelines［J］.Eur Urol，2021,79(1):82-104.
［18］PETRELLI F,COINU A,CABIDDU M,et al.Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy:A meta-analysis［J］.Eur Urol,2014,65(2):350-357.
［19］YIN M,JOSHI M,MEIJER RP,et al.Neoadjuvant chemotherapy for muscle-invasive bladder cancer:A systematic review and two-step meta-analysis［J］.Oncologist,2016,21(6):708-715.
［20］MMEJE CO,BENSON CR,NOGUERAS-GONZALEZ GM,et al.Determing the optimal time for radical cystectomy after neoadjuvant chemotherapy［J］.Bju International,2018,12(1):89-98.
［21］FLAIG TW,SPIESS PE,AGARWAL N,et al.Bladder cancer,Version 3.2020,NCCN clinical practice guidelines in oncology［J］.J Natl Compr Canc Netw,2020,18(3):329-354.
［22］WITJES JA,BRUINS HM,CATHOMAS R,et al.European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer:Summary of the 2020 guidelines［J］.Eur Urol,2021,79(1):82-104.
［23］GALSKY MD,PAL SK,CHOWDHURY S,et al.Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate,vinblastine,doxorubicin,plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer［J］.Cancer,2015,121(15):2586-2593.
［24］VONDERMAASE HV,SENGELOV L,ROBERTS JT,et al.Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin,with methotrexate,vinblastine,doxorubicin,plus cisplatin in patients with bladder cancer［J］.J Clin Oncol,2005,23(21):4602-4608.
［25］曹明,赵宏,穆鑫,等.吉西他滨联合顺铂方案新辅助化疗联合全膀胱切除术治疗肌层浸润性膀胱癌的９年回顾性分析［J］.中华泌尿外科杂志,2014,35(1):49-53.CAO M,ZHAO H,MU X,et al.A 9-year retrospective analysis of neoadjuvant chemotherapy with gemcitabine combined with cisplatin regimen combined with total cystectomy for muscle invasive bladder cancer［J］.Chinese Journal of Urology,2014,35(1):49-53.
［26］ZERNIAK B,DINNEY C,MCCONKEY D,et al.Origins of bladder cancer［J］.Annu Rev Pathol,2016,11:149-174.
［27］CULP SH,DICKSTEIN RJ,GROSSMAN HB,et al.Refining patient selection for neoadjuvant chemotherapy before radical cystectomy［J］.J Urol,2014,191(1):40-47.
［28］VANALLEN EM,MOUW KW,KIM P,et al.Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma［J］.Cancer Discov,2014,4(10):1140-1153.
［29］LIU D,PLIMACK ER,HOFFMAN-CENSITS J,et al.Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma［J］.JAMA Oncol,2016,2(8):1094-1096.
［30］LOTAN Y,WOLDU SL,SANLI O,et al.Modelling cost-effectiveness of a biomarker-based approach to neoadjuvant chemotherapy for muscle-invasive bladder cancer［J］.BJU Int,2018,122(3):434-440.
［31］YANG Z,ZHANG R,GE Y,et al.Somatic FGFR3 mutations distinguish a subgroup of muscle-invasive bladder cancers with response to neoadjuvant chemotherapy［J］.EBio Medicine,2018,35:198-203.
［32］KAMOUN A,DE REYNIES A,ALLORY Y,et al.A consensus molecular classification of muscle invasive bladder cancer［J］.Eur Urol,2020,77(4):420-433.
［33］SJODAHL G,ABRAHAMSSON J,HOLMSTEN K,et al.Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes［J］.Eur Urol，2022，8l(5):523-532.
［34］SEILE R,ASHAB H,ERHO N,et al.Impact of molecular subtypes in muscle invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy［J］.Eur Urol,2017,72(4):544-554．
［35］MO Q,NIKPLOS F,CHEN F,et al.Prognostic power of a tumor differentiation gene signature for bladder urothelial carcinomas［J］.J Natl Cancer Inst,2018,110(5):448-459．
［36］KIM J,KWLATKOWKI D,MCCONKEY DJ,et al.The cancer genome atlas expression subtypes stratify response to checkpoint inhibition in advanced urothelial cancer and identify a subset of patients with high survival probability［J］.Eur Urol,2019,75(6):961-964．
［37］NECCHI A,RAGGI D,GALLINA A,et al.Impact of molecular subtyping and immune infiltration on pathological response and outcome following neoadjuvant pembrolizumab in muscle-invasive bladder cancer［J］.Eur Urol,2020,77(6):701-710.
［38］SZABADOS B,KOCKX M,ASSAF ZJ,et al.Final results of neoadjuvant atezolizumab in cisplatin-ineligible patients with muscle-inwtsive urothelial cancer of the bladder［J］.Eur Urol,2022,82(2):212-222.
［39］范亚莉，王娟红，魏威，等.Ku80在甲状腺乳头状癌组织中的表达及其临床意义［J］.现代肿瘤医学，2019，27（03）:393-396.FAN YL，WANG JH，WEI W，et al.Expression of Ku80 in thyroid papillary carcinoma and its clinical significance［J］.Modern Oncology，2019，27（03）:393-396.
［40］孟瑾，刘新利，车玲，等.Ku70乙酰化修饰介导曲古霉素A（TSA）促结肠癌细胞凋亡的作用机制研究［J］.现代肿瘤医学，2020，28（03）:355-360.MENG J，LIU XL，CHE L，et al.The mechanism of Ku70 acetylation modification mediating apoptosis of colon cancer cells induced by trichostatin A(TSA)［J］.Modern Oncology，2020，28（03）:355-360.
［41］GULLO C,AU M,FENG G,et al.The biology of Ku and its potential oncogenic role in cancer［J］.Biochim Biophys Acta,2006,1765(2):223-234.
［42］RIGAS B,BORGO S,ELHOSSEINY A,et al.Decreased expression of DNA-dependent protein kinase,a DNA repair protein,during human colon carcinogenesis［J］.Cancer Res,2001,61(23):8381-8384.
［43］LIM JW,KIM H,KIM KH,et al.Expression of Ku70 and Ku80 mediated by NF-kappa B and cyclooxygenase-2 is related to proliferation of human gastric cancer cells［J］.J Biol Chem,2002,277(48):46093-46100．
［44］WILSON CR,DAVIDSON SE,MARGISON GP,et al.Expression of Ku70 correlates with survival in carcinoma of the cervix［J］.Br J Cancer,2000,83(12):1702-1706.
［45］HE F,LI L,KIM D,et al.Adenovirus-mediated expression of a dominant negative Ku70 fragment radiosensitizes human tumor cells under aerobic and hypoxic conditions［J］.Cancer Res,2007,67(2):634-642．
［46］RICHTER C,MARQUARDT S,LI F,et al.Rewiring E2F1 with classical NHEJ via APLF suppression promotes bladder cancer invasiveness［J］.J Exp Clin Cancer Res,2019,38(1):292.
［47］QIABO B,KERR M,GROSELJ B,et al.Imatinib radiosensitizes bladder cancer by targeting homologous recombination［J］.Cancer Re,2013,73(5):1611-1620.

Memo

Memo:
山东省泰安市科技创新发展项目（政策引导类）（编号：2022NS202）
Last Update: 2024-09-30