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Aspartoacylase suppresses Prostate cancer progression by blocking LYN activation

Military Medical Research 2024年第2期11卷 180-205页

作者： Hong Weng Kang-Ping Xiong Wang Wang Kai-Yu Qian Shuai Yuan Gang Wang Fang Yu Jun Luo Meng‑Xin Lu Zhong‑Hua Yang Tao Liu Xing Huang Hang Zheng Xing-Huan Wang Department of Urology Zhongnan Hospital of Wuhan UniversityWuhan 430071China Center for Evidence‑Based and Translational Medicine Zhongnan Hospital of Wuhan UniversityWuhan 430071China Department of Biological Repositories Zhongnan Hospital of Wuhan UniversityWuhan 430071China Hubei Key Laboratory of Tumor Biological Behaviors Wuhan 430071China Department of Pathology Zhongnan Hospital of Wuhan UniversityWuhan 430071China Center for Pathology and Molecular Diagnostics Wuhan UniversityWuhan 430071China Wuhan Research Center for Infectious Diseases and cancer Chinese Academy of Medical SciencesWuhan 430071China

Background:Globally,despite Prostate cancer(PCa)representing second most prevalent malignancy in male,the precise molecular mechanisms implicated in its pathogenesis remain unclear.Consequently,elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies,ultimately advancing the management of PCa.Methods:A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University.The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa.The expression of aspartoacylase(ASPA)in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques.To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis,a comprehensive set of in vitro and in vivo assays were conducted,including orthotopic and tumor-bearing mouse models(n=8 for each group).A combination of experimental approaches,such as Western blotting,luciferase assays,immunoprecipitation assays,mass spectrometry,glutathione S-transferase pulldown experiments,and rescue studies,were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa.The Student‘s t-test was employed to assess the statistical significance between two distinct groups,while one-way analysis of variance was utilized for comparisons involving more than two groups.A two-sided P<0.05 was deemed to indicate statistical significance.Results:ASPA was identified as a novel inhibitor of PCa progression.The expression of ASPA was found to be significantly down-regulated in PCa tissue samples,and its decreased expression was independently associated with patients’prognosis(HR=0.60,95%CI 0.40–0.92,P=0.018).Our experiments demonstrated that modulation of ASPA activity,either through gain-or loss-of-function,led to the suppression or enhancement of PCa cell proliferation,migration,and invasion,respectively.The inhibitory

关键词： Prostate cancer Aspartoacylase LYN JNK AP-1 C-Jun Phosphorylation

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Membrane dual-targeting probes:A promising strategy for fluorescence-guided Prostate cancer surgery and lymph node metastases detection

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1204-1215页

作者： Ling-Ling Wu Qinxin Zhao Qinghua Wang Qingyang Zhang Feiya Yang Bo Zheng Hai-Yu Hu Nianzeng Xing State Key Laboratory of Bioactive Substances and Function of Natural Medicine Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China Department of Urology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Urology Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuan 030013China Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of Prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.

关键词： Activated probe Small molecule nanoparticle Self-assembly Dual-targeting Near-infrared Prostate cancer Fluorescence-guided surgery Metastases

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cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of Prostate cancer

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Asian Journal of Andrology 2023年第2期25卷 171-178页

作者： Yini Zhu Loan Duong Xuemin Lu Xin Lu Department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameIN 46556USA Integrated Biomedical Sciences Graduate Program University of Notre DameNotre DameIN 46556USA Tumor Microenvironment and Metastasis Program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisIN 46202USA

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced Prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of Prostate cancer.Therefore,it is paramount to understand how Prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in Prostate cancer.

关键词： immune checkpoint blockade immunosuppression immunotherapy neuroendocrine Prostate cancer Prostate cancer

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MRI-derived radiomics models for diagnosis,aggressiveness,and prognosis evaluation in Prostate cancer

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第8期24卷 663-681页

作者： Xuehua ZHU Lizhi SHAO Zhenyu LIU Zenan LIU Jide HE Jiangang LIU Hao PING Jian LU Department of Urology Peking University Third HospitalBeijing 100191China CAS Key Laboratory of Molecular Imaging Institute of AutomationChinese Academy of SciencesBeijing 100190China School of Artificial Intelligence University of Chinese Academy of SciencesBeijing 100080China Beijing Advanced Innovation Center for Big Data-Based Precision Medicine School of Engineering MedicineBeihang UniversityBeijing 100191China Key Laboratory of Big Data-Based Precision Medicine(Beihang University) Ministry of Industry and Information Technology of the People’s Republic of ChinaBeijing 100191China Department of Urology Beijing Tongren HospitalCapital Medical UniversityBeijing 100730China

Prostate cancer(PCa)is a pernicious tumor with high heterogeneity,which creates a conundrum for making a precise diagnosis and choosing an optimal treatment approach.Multiparametric magnetic resonance imaging(mp-MRI)with anatomical and functional sequences has evolved as a routine and significant paradigm for the detection and characterization of PCa.Moreover,using radiomics to extract quantitative data has emerged as a promising field due to the rapid growth of artificial intelligence(AI)and image data processing.Radiomics acquires novel imaging biomarkers by extracting imaging signatures and establishes models for precise evaluation.Radiomics models provide a reliable and noninvasive alternative to aid in precision medicine,demonstrating advantages over traditional models based on clinicopathological parameters.The purpose of this review is to provide an overview of related studies of radiomics in PCa,specifically around the development and validation of radiomics models using MRI-derived image features.The current landscape of the literature,focusing mainly on PCa detection,aggressiveness,and prognosis evaluation,is reviewed and summarized.Rather than studies that exclusively focus on image biomarker identification and method optimization,models with high potential for universal clinical implementation are identified.Furthermore,we delve deeper into the critical concerns that can be addressed by different models and the obstacles that may arise in a clinical scenario.This review will encourage researchers to design models based on actual clinical needs,as well as assist urologists in gaining a better understanding of the promising results yielded by radiomics.

关键词： Magnetic resonance imaging(MRI) Radiomics Prostate cancer Predictive model

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Scaffold protein MAPK8IP2 expression is a robust prognostic factor in Prostate cancer associated with AR signaling activity

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Asian Journal of Andrology 2023年第2期25卷 198-207页

作者： Jian Huang Wang Liu Bi-Yun Lin Jean C Li Jane Lu Ben-Yi Li Center for Pathological Diagnosis and Research The Affiliated Hospital of Guangdong Medical UniversityZhanjiang 524001China Department of Urology The University of Kansas Medical CenterKansas CityKS 66160USA

Mitogen-activated protein kinase-8-interacting protein 2(MAPK8IP2)is a scaffold protein that modulates MAPK signal cascades.Although MAPK pathways were heavily implicated in Prostate cancer progression,the regulation of MAPK8IP2 expression in Prostate cancer is not yet reported.We assessed MAPK8IP2 gene expression in Prostate cancer related to disease progression and patient survival outcomes.MAPK8IP2 expression was analyzed using multiple genome-wide gene expression datasets derived from The cancer Genome Atlas(TCGA)RNA-sequence project and complementary DNA(cDNA)microarrays.Multivariable Cox regressions and log-rank tests were used to analyze the overall survival outcome and progression-free interval.MAPK8IP2 protein expression was evaluated using the immunohistochemistry approach.The quantitative PCR and Western blot methods analyzed androgen-stimulated MAPK8IP2 expression in LNCaP cells.In primary Prostate cancer tissues,MAPK8IP2 mRNA expression levels were significantly higher than those in the case-matched benign prostatic tissues.Increased MAPK8IP2 expression was strongly correlated with late tumor stages,lymph node invasion,residual tumors after surgery,higher Gleason scores,and preoperational serum prostate-specific antigen(PSA)levels.MAPK8IP2 upregulation was significantly associated with worse overall survival outcomes and progression-free intervals.In castration-resistant Prostate cancers,MAPK8IP2 expression strongly correlated with androgen receptor(AR)signaling activity.In cell culture-based experiments,MAPK8IP2 expression was stimulated by androgens in AR-positive Prostate cancer cells.However,MAPK8IP2 expression was blocked by AR antagonists only in androgen-sensitive LNCaP but not castration-resistant C4-2B and 22RV1 cells.These results indicate that MAPK8IP2 is a robust prognostic factor and therapeutic biomarker for Prostate cancer.The potential role of MAPK8IP2 in the castration-resistant progression is under further investigation.

关键词： cell cycle regulation disease progression mitogen-activated protein kinase-8-interacting protein 2 patient survival Prostate cancer

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Therapeutic implications of cancer stem cells in Prostate cancer

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cancer Biology & Medicine 2023年第6期20卷 401-420页

作者： Pinaki Banerjee Prachi Kapse Shehnaz Siddique Moumita Kundu Jasoda Choudhari Varshasnata Mohanty Diksha Malhotra Suresh W.Gosavi Rajesh N.Gacche Gopal C.Kundu National Centre for Cell Science Savitribai Phule Pune University CampusPune 411007India School of Basic Medical Science Savitribai Phule Pune UniversityPune 411007India School of Biotechnology KIIT Deemed to be UniversityBhubaneswar 751024India Department of Biotechnology Savitribai Phule Pune UniversityPune 411007IndiaSchool of BiotechnologyKIIT Deemed to be UniversityBhubaneswar 751024India Kalinga Institute of Medical Sciences(KIMS) KIIT Deemed to be UniversityBhubaneswar 751024India

Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed Prostate cancer stem cells(PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs;methods for isolation and enrichment of PCSCs;and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.

关键词： Epithelial-mesenchymal transition metastasis Prostate cancer cancer stem cells tumor growth tumor microenvironment signaling

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FOXA1 in Prostate cancer

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Asian Journal of Andrology 2023年第3期25卷 287-295页

作者： Hui-Yu Dong Lei Ding Tian-Ren Zhou Tao Yan Jie Li Chao Liang Department of Urology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China Department of Clinical Medicine Suzhou Vocational Health CollegeSuzhou 215009China

Most Prostate cancers initially respond to androgen deprivation therapy(ADT).With the long-term application of ADT,localized Prostate cancer will progress to castration-resistant Prostate cancer(CRPC),metastatic CRPC(mCRPC),and neuroendocrine Prostate cancer(NEPC),and the transcriptional network shifted.Forkhead box protein A1(FOXA1)may play a key role in this process through multiple mechanisms.To better understand the role of FOXA1 in Prostate cancer,we review the interplay among FOXA1-targeted genes,modulators of FOXA1,and FOXA1 with a particular emphasis on androgen receptor(AR)function.Furthermore,we discuss the distinct role of FOXA1 mutations in Prostate cancer and clinical significance of FOXA1.We summarize possible regulation pathways of FOXA1 in different stages of Prostate cancer.We focus on links between FOXA1 and AR,which may play different roles in various types of Prostate cancer.Finally,we discuss FOXA1 mutation and its clinical significance in Prostate cancer.FOXA1 regulates the development of Prostate cancer through various pathways,and it could be a biomarker for mCRPC and NEPC.Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced Prostate cancer.We believe that FOXA1 would be a prognostic marker and therapeutic target in Prostate cancer.

关键词： androgen receptor forkhead box protein A1 mutation Prostate cancer

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Radiomics based on biparametric MRI for the detection of significant residual Prostate cancer after androgen deprivation therapy:using whole-mount histopathology as reference standard

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Asian Journal of Andrology 2023年第1期25卷 86-92页

作者： Zhang-Zhe Chen Wei-Jie Gu Bing-Ni Zhou Wei Liu Hua-Lei Gan Yong Zhang Liang-Ping Zhou Xiao-Hang Liu Department of Radiology Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical College of Fudan UniversityShanghai 200032China Department of Urology Fudan University Shanghai Cancer CenterShanghai 200032China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China MR Research GE HealthcareShanghai 200032China

We aimed to study radiomics approach based on biparametric magnetic resonance imaging(MRI)for determining significant residual cancer after androgen deprivation therapy(ADT).Ninety-two post-ADT Prostate cancer patients underwent MRI before prostatectomy(62 with significant residual disease and 30 with complete response or minimum residual disease[CR/MRD]).Totally,100 significant residual,52 CR/MRD lesions,and 70 benign tissues were selected according to pathology.First,381 radiomics features were extracted from T2-weighted imaging,diffusion-weighted imaging,and apparent diffusion coefficient(ADC)maps.Optimal features were selected using a support vector machine with a recursive feature elimination algorithm(SVM-RFE).Then,ADC values of significant residual,CR/MRD lesions,and benign tissues were compared by one-way analysis of variance.Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues.Third,the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve(AUC).The ADC value(mean±standard deviation[s.d.])of significant residual lesions([1.10±0.02]×10^(-3)mm^(2)s^(−1))was significantly lower than that of CR/MRD([1.17±0.02]×10^(-3)mm^(2)s^(−1)),which was significantly lower than that of benign tissues([1.30±0.02]×10^(-3)mm^(2)s^(−1);both P0.05),but superior to ADC value in differentiating significant residual from CR/MRD(AUC:0.748 vs 0.558;P=0.041).Radiomics approach with biparametric MRI could promote the detection of significant residual Prostate cancer after ADT.

关键词： androgen deprivation therapy diffusion-weighted imaging Prostate cancer radiomics

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Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal Prostate cancer

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Asian Journal of Andrology 2023年第3期25卷 296-308页

作者： Sean Seltzer Paresa N Giannopoulos Tarek A Bismar Mark Trifiro Miltiadis Paliouras Lady Davis Institute for Medical Research Segal Cancer Centre-Jewish General HospitalMontrealQC H3T 1E2Canada Cumming School of Medicine Department of Pathology and Laboratory MedicineUniversity of CalgaryCalgaryAB T2N 1N4Canada Department of Medicine Division of Experimental MedicineMcGill UniversityMontrealQC H4A 3J1Canada Department of Oncology McGill UniversityMontrealQC H4A 3T2Canada

A complete proteomics study characterizing active androgen receptor(AR)complexes in Prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing factors.Thus,we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression.We selected two AR-interacting RNA splicing factors,Src associated in mitosis of 68 kDa(SAM68)and DEAD(Asp-Glu-Ala-Asp)box helicase 5(DDX5)to examine their associative roles in AR-dependent alternative RNA splicing.To assess the true physiological role of AR in alternative RNA splicing,we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets.As a result,we were able to highlight alternative splicing events of clinical significance.Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression.The physiological significance in PCa was investigated through the application of clinical exon array analysis,where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria.Using a clinical dataset with patients categorized as Prostate cancer-specific death(PCSD),these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes.Overall,these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa.Moreover,AR-mediated alternative spicing contributes to aggressive PCa progression,where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

关键词： alternative RNA splicing androgen receptor exon-gene sets lethal Prostate cancer subtype Prostate cancer

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Identification of senescence-related molecular subtypes and key genes for Prostate cancer

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Asian Journal of Andrology 2023年第2期25卷 223-229页

作者： De-Chao Feng Wei-Zhen Zhu Xu Shi Qiao Xiong Jia You Qiang Wei Lu Yang Department of Urology Institute of UrologyWest China HospitalSichuan UniversityChengdu 610041China

We identified distinct senescence-related molecular subtypes and critical genes among Prostate cancer(PCa)patients undergoing radical prostatectomy(RP)or radical radiotherapy(RT).We conducted all analyses using R software and its suitable packages.Twelve genes,namely,secreted frizzled-related protein 4(SFRP4),DNA topoisomerase II alpha(TOP2A),pleiotrophin(PTN),family with sequence similarity 107 member A(FAM107A),C-X-C motif chemokine ligand 14(CXCL14),prostate androgen-regulated mucin-like protein 1(PARM1),leucine zipper protein 2(LUZP2),cluster of differentiation 38(CD38),cartilage oligomeric matrix protein(COMP),vestigial-like family member 3(VGLL3),apolipoprotein E(APOE),and aldehyde dehydrogenase 2 family member(ALDH2),were eventually used to subtype PCa patients from The cancer Genome Atlas(TCGA)database and GSE116918,and the molecular subtypes showed good correlations with clinical features.In terms of the tumor immune environment(TME)analysis,compared with cluster 1,cancer-associated fibroblasts(CAFs)scored significantly higher,while endothelial cells scored lower in cluster 2 in TCGA database.There was a statistically significant correlation between both CAFs and endothelial cells with biochemical recurrence(BCR)-free survival for PCa patients undergoing RP.For the GSE116918 database,cluster 2 had significantly lower levels of CAFs and tumor purity and higher levels of stromal,immune,and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data(ESTIMATE)scores than cluster 1;in addition,patients with high levels of CAFs,stromal scores,immune scores,and ESTIMATE scores and low levels of tumor purity tended to suffer from BCR.Based on the median of differentially expressed checkpoints,high expression of CD96,hepatitis A virus cellular receptor 2(HAVCR2),and neuropilin 1(NRP1)in GSE116918 and high expression of CD160 and tumor necrosis factor(ligand)superfamily member 18(TNFSF18)in TCGA database were associated with a significantly higher risk of BCR than their counterparts.In

关键词： cellular senescence immune checkpoints molecular subtypes Prostate cancer tumor immune environment

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