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Article ; Online: Gain-of-"endocytic' function in mutant p53 cancer cells.

Lakoduk, Ashley M / Lee, Cheng-Fan / Chen, Ping-Hung

The international journal of biochemistry & cell biology

2020 Volume 131, Page(s) 105905

Abstract: Beyond its well-known canonical function as a tumor suppressor, p53 is also involved in numerous cellular processes through altered transcription under both normal and pathological conditions. The functional diversity of p53 outputs is complex and ... ...

Abstract	Beyond its well-known canonical function as a tumor suppressor, p53 is also involved in numerous cellular processes through altered transcription under both normal and pathological conditions. The functional diversity of p53 outputs is complex and dependent on cell context. However, the underlying mechanisms responsible for this diversity remain largely unclear. The emerging evidence of p53 mutations involved in regulating endocytic trafficking and signaling, in tandem to promote malignancy (invasion, exosome biogenesis and immune evasion), sheds light on possible mechanisms behind the p53-driven complexity. The interrelated nature of endocytic trafficking and receptor signaling that form dynamic and adaptable feedback loops - either positive or negative - functions to modulate multiple cellular outputs. Biasing the tunable endocytic trafficking and receptor signaling network by mutant p53 expands the purview of p53, allowing its contribution to diverse and aggressive phenotypes. In this review, we explore recent studies in which the novel role of mutant p53 in altering endocytic trafficking to bias receptor signaling and drive transforming phenotypes is revealed. Understanding the complex crosstalk of mutant p53, endocytic trafficking and receptor signaling will allow the development of therapies to selectively target p53-altered endocytic processes.
MeSH term(s)	Cell Cycle/genetics ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/immunology ; Endocytosis/genetics ; Endosomes/genetics ; Endosomes/metabolism ; ErbB Receptors/genetics ; ErbB Receptors/immunology ; Gain of Function Mutation ; Gene Expression Regulation, Neoplastic ; Humans ; Integrin beta1/genetics ; Integrin beta1/immunology ; Lung Neoplasms/genetics ; Lung Neoplasms/immunology ; Lung Neoplasms/pathology ; Ribonuclease III/genetics ; Ribonuclease III/immunology ; Signal Transduction ; Tumor Escape ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/immunology
Chemical Substances	Integrin beta1 ; Itgb1 protein, human ; Tumor Suppressor Protein p53 ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; DICER1 protein, human (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2020-12-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2020.105905
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Article: Novel urinary tract obstruction marker discovery by multi-marker profiling of urinary extracellular vesicles derived from a rat UTO model.

Haney, Nora M / Kim, Chi-Ju / Kuczler, Morgan D / Lee, Cheng-Fan / Lombardo, Kara / Bivalacqua, Trinity J / Pienta, Kenneth J / Amend, Sarah R

American journal of clinical and experimental urology

2023 Volume 11, Issue 2, Page(s) 136–145

Abstract: Introduction: Congenital urinary obstruction is a common cause of end-stage renal disease in the pediatric population. However, non-invasive diagnostics to predict which patients will benefit from early intervention are lacking.: Methods: Using a rat ...

Abstract	Introduction: Congenital urinary obstruction is a common cause of end-stage renal disease in the pediatric population. However, non-invasive diagnostics to predict which patients will benefit from early intervention are lacking. Methods: Using a rat model of upper and lower urinary tract partial obstruction and the Nanostring nCounter Fibrosis V2 Panel, we evaluated the mRNA cargo of urinary small extracellular vesicles (sEVs) and mRNA expression patterns of kidney and bladder tissues from rats with lower tract urinary obstruction and upper tract urinary obstruction. Results: While mRNA hierarchical clustering of urinary sEVs was unable to differentiate upper compared to lower tract urinary obstruction, clustering was able to detect overall disease state (UUTO or LUTO) versus healthy controls. Further, urinary sEVs carried genes unique to each treatment group (UUTO: 59 genes, LUTO: 17 genes), while only one gene was uniquely carried in the control group. Notable genes of interest found in urinary sEVs were VCAM-1 and NOS1 for UUTO, Egfr for LUTO, and Pck1 for healthy controls. Conclusion: This study provides support that differential gene expression of urinary sEV mRNA has potential to act as biomarkers in the diagnosis and prognosis of UTO. Urinary sEVs demonstrated higher numbers of unique genes representative of injury to the kidney than that of injury to the bladder. Importantly, there were genes unique to UUTO sEVs, indicating the extent and reversibility of renal damage can be independent of the function, damage, and architecture of the bladder.
Language	English
Publishing date	2023-04-15
Publishing country	United States
Document type	Journal Article
ISSN	2330-1910
ISSN	2330-1910
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Article ; Online: Nuclear morphology predicts cell survival to cisplatin chemotherapy.

Kim, Chi-Ju / Gonye, Anna Lk / Truskowski, Kevin / Lee, Cheng-Fan / Cho, Yoon-Kyoung / Austin, Robert H / Pienta, Kenneth J / Amend, Sarah R

Neoplasia (New York, N.Y.)

2023 Volume 42, Page(s) 100906

Abstract: The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been ... ...

Abstract	The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been explored, less is known about the cell biological characteristics of cancer cells that survive to eventually seed the recurrence. To identify the unique phenotypic characteristics associated with survival upon chemotherapy exposure, we characterized nuclear morphology and function as prostate cancer cells recovered following cisplatin treatment. Cells that survived in the days and weeks after treatment and resisted therapy-induced cell death showed increasing cell size and nuclear size, enabled by continuous endocycling resulting in repeated whole genome doubling. We further found that cells that survive after therapy release were predominantly mononucleated and likely employ more efficient DNA damage repair. Finally, we show that surviving cancer cells exhibit a distinct nucleolar phenotype and increased rRNA levels. These data support a paradigm where soon after therapy release, the treated population mostly contains cells with a high level of widespread and catastrophic DNA damage that leads to apoptosis, while the minority of cells that have successful DDR are more likely to access a pro-survival state. These findings are consistent with accession of the polyaneuploid cancer cell (PACC) state, a recently described mechanism of therapy resistance and tumor recurrence. Our findings demonstrate the fate of cancer cells following cisplatin treatment and define key cell phenotypic characteristics of the PACC state. This work is essential for understanding and, ultimately, targeting cancer resistance and recurrence.
MeSH term(s)	Humans ; Male ; Cisplatin/pharmacology ; Cell Survival/genetics ; Neoplasm Recurrence, Local ; DNA Repair ; DNA Damage ; Apoptosis/genetics ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor
Chemical Substances	Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2023-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2023.100906
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Article: Gain-of-“endocytic’ function in mutant p53 cancer cells

Lakoduk, Ashley M / Lee, Cheng-Fan / Chen, Ping-Hung

international journal of biochemistry & cell biology. 2021 Feb., v. 131

2021

Abstract	Beyond its well-known canonical function as a tumor suppressor, p53 is also involved in numerous cellular processes through altered transcription under both normal and pathological conditions. The functional diversity of p53 outputs is complex and dependent on cell context. However, the underlying mechanisms responsible for this diversity remain largely unclear. The emerging evidence of p53 mutations involved in regulating endocytic trafficking and signaling, in tandem to promote malignancy (invasion, exosome biogenesis and immune evasion), sheds light on possible mechanisms behind the p53-driven complexity. The interrelated nature of endocytic trafficking and receptor signaling that form dynamic and adaptable feedback loops – either positive or negative – functions to modulate multiple cellular outputs. Biasing the tunable endocytic trafficking and receptor signaling network by mutant p53 expands the purview of p53, allowing its contribution to diverse and aggressive phenotypes. In this review, we explore recent studies in which the novel role of mutant p53 in altering endocytic trafficking to bias receptor signaling and drive transforming phenotypes is revealed. Understanding the complex crosstalk of mutant p53, endocytic trafficking and receptor signaling will allow the development of therapies to selectively target p53-altered endocytic processes.
Keywords	biochemistry ; biogenesis ; exosomes ; functional diversity ; immune evasion ; mutants ; neoplasms
Language	English
Dates of publication	2021-02
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2020.105905
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Split-hand index for amyotrophic lateral sclerosis diagnosis: A frequentist and Bayesian meta-analysis.

Lu, Wei-Zhen / Lin, Hui-An / Hou, Sen-Kuang / Lee, Cheng-Fan / Bai, Chyi-Huey / Lin, Sheng-Feng

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology

2022 Volume 143, Page(s) 56–66

Abstract: Objective: Preferential wasting of the thenar muscles, the split-hand sign, may be used for early diagnosis of amyotrophic lateral sclerosis (ALS).: Methods: Electronic databases were searched for studies assessing the split-hand index (SHI) and the ... ...

Abstract	Objective: Preferential wasting of the thenar muscles, the split-hand sign, may be used for early diagnosis of amyotrophic lateral sclerosis (ALS). Methods: Electronic databases were searched for studies assessing the split-hand index (SHI) and the compound muscle action potential (CMAP) amplitudes of abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM). The SHI was obtained by multiplying CMAP amplitudes of APB and FDI and dividing the product by the CMAP amplitude of ADM. The Bayesian analysis was used for validation. Results: In total, 17 studies and 1635 patients were included. Our meta-analysis revealed that ALS patients had significantly decreased SHI (standardized mean difference [SMD], -1.60, P < 0.001), CMAP of the APB (SMD, -1.67, P < 0.001), FDI (SMD, -1.12, P < 0.001), and ADM (SMD, -1.09, P < 0.001). The binormal receiver operating characteristic curve analysis showed a threshold of < 7.4 for SHI, and cutoff values of < 6.4 mV for APB and < 8.4 mV for FDI, respectively. The Bayesian analysis validated decreased SHI in ALS patients (posterior mean difference of - 5.91). Conclusions: An SHI of < 7.4 can be used facilitating earlier diagnosis of ALS. Significance: SHI can be used as a standard neurophysiological biomarker for early diagnosis.
MeSH term(s)	Amyotrophic Lateral Sclerosis/diagnosis ; Bayes Theorem ; Hand ; Humans ; Muscle, Skeletal ; ROC Curve
Language	English
Publishing date	2022-09-06
Publishing country	Netherlands
Document type	Journal Article ; Meta-Analysis
ZDB-ID	1463630-x
ISSN	1872-8952 ; 0921-884X ; 1388-2457
ISSN (online)	1872-8952
ISSN	0921-884X ; 1388-2457
DOI	10.1016/j.clinph.2022.08.020
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Article ; Online: The Role and Mechanism of Epithelial-to-Mesenchymal Transition in Prostate Cancer Progression.

Lo, U-Ging / Lee, Cheng-Fan / Lee, Ming-Shyue / Hsieh, Jer-Tsong

International journal of molecular sciences

2017 Volume 18, Issue 10

Abstract: In prostate cancer (PCa), similar to many other cancers, distant organ metastasis symbolizes the beginning of the end disease, which eventually leads to cancer death. Many mechanisms have been identified in this process that can be rationalized into ... ...

Abstract	In prostate cancer (PCa), similar to many other cancers, distant organ metastasis symbolizes the beginning of the end disease, which eventually leads to cancer death. Many mechanisms have been identified in this process that can be rationalized into targeted therapy. Among them, epithelial-to-mesenchymal transition (EMT) is originally characterized as a critical step for cell trans-differentiation during embryo development and now recognized in promoting cancer cells invasiveness because of high mobility and migratory abilities of mesenchymal cells once converted from carcinoma cells. Nevertheless, the underlying pathways leading to EMT appear to be very diverse in different cancer types, which certainly represent a challenge for developing effective intervention. In this article, we have carefully reviewed the key factors involved in EMT of PCa with clinical correlation in hope to facilitate the development of new therapeutic strategy that is expected to reduce the disease mortality.
Language	English
Publishing date	2017-09-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18102079
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Article ; Online: The central role of Sphingosine kinase 1 in the development of neuroendocrine prostate cancer (NEPC): A new targeted therapy of NEPC.

Lee, Cheng-Fan / Chen, Yu-An / Hernandez, Elizabeth / Pong, Rey-Chen / Ma, Shihong / Hofstad, Mia / Kapur, Payal / Zhau, Haiyen / Chung, Leland Wk / Lai, Chih-Ho / Lin, Ho / Lee, Ming-Shyue / Raj, Ganesh V / Hsieh, Jer-Tsong

Clinical and translational medicine

2022 Volume 12, Issue 2, Page(s) e695

Abstract: Background: Neuroendocrine prostate cancer (NEPC) is often diagnosed as a sub-type from the castration-resistant prostate cancer (CRPC) recurred from the second generation of anti-androgen treatment and is a rapidly progressive fatal disease. The ... ...

Abstract	Background: Neuroendocrine prostate cancer (NEPC) is often diagnosed as a sub-type from the castration-resistant prostate cancer (CRPC) recurred from the second generation of anti-androgen treatment and is a rapidly progressive fatal disease. The molecular mechanisms underlying the trans-differentiation from CRPC to NEPC are not fully characterized, which hampers the development of effective targeted therapy. Methods: Bioinformatic analyses were conducted to determine the clinical correlation of sphingosine kinase 1 (SphK1) in CRPC progression. To investigate the transcriptional regulation SphK1 and neuroendocrine (NE) transcription factor genes, both chromosome immunoprecipitation and luciferase reporter gene assays were performed. To demonstrate the role of SphK1 in NEPC development, neurosphere assay was carried out along with several biomarkers determined by quantitative PCR and western blot. Furthermore, in vivo NEPC xenograft models and patient-derived xenograft (PDX) model were employed to determine the effect of SphK1 inhibitors and target validation. Results: Significant prevalence of SphK1 in NEPC development is observed from clinical datasets. SphK1 is transcriptionally repressed by androgen receptor-RE1-silencing transcription factor (REST) complex. Furthermore, sphingosine 1-phosphate produced by SphK1 can modulate REST protein turnover via MAPK signaling pathway. Also, decreased REST protein levels enhance the expression of NE markers in CRPC, enabling the transition to NEPC. Finally, specific SphK1 inhibitors can effectively inhibit the growth of NEPC tumors and block the REST protein degradation in PDX. Conclusions: SphK1 plays a central role in NEPC development, which offers a new target for this lethal cancer using clinically approved SphK1 inhibitors.
MeSH term(s)	Carcinoma, Neuroendocrine/etiology ; Carcinoma, Neuroendocrine/genetics ; Humans ; Male ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/statistics & numerical data ; Neurosecretory Systems/abnormalities ; Neurosecretory Systems/physiopathology ; Phosphotransferases (Alcohol Group Acceptor)/adverse effects ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Prostatic Neoplasms/etiology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology
Chemical Substances	Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-)
Language	English
Publishing date	2022-02-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.695
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Article ; Online: Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis.

Lin, Hsin-Ying / Ko, Chun-Jung / Lo, Tzu-Yu / Wu, Shang-Ru / Lan, Shao-Wei / Huang, Chen-An / Lin, Yi-Chin / Lin, Hsin-Hsien / Tu, Hsin-Fang / Lee, Cheng-Fan / Hsiao, Pei-Wen / Huang, Hsiang-Po / Chen, Mei-Jou / Chang, Kai-Hsiung / Lee, Ming-Shyue

Oncogene

2022 Volume 41, Issue 20, Page(s) 2833–2845

Abstract: Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine protease which can suppress prostate cancer (PCa) cell ... ...

Abstract	Dysregulation of pericellular proteolysis is strongly implicated in cancer metastasis through alteration of cell invasion and the microenvironment. Matriptase-2 (MT-2) is a membrane-anchored serine protease which can suppress prostate cancer (PCa) cell invasion. In this study, we showed that MT-2 was down-regulated in PCa and could suppress PCa cell motility, tumor growth, and metastasis. Using microarray and biochemical analysis, we found that MT-2 shifted TGF-β action towards its tumor suppressor function by repressing epithelial-to-mesenchymal transition (EMT) and promoting Smad2 phosphorylation and nuclear accumulation to upregulate two TGF-β1 downstream effectors (p21 and PAI-1), culminating in hindrance of PCa cell motility and malignant growth. Mechanistically, MT-2 could dramatically up-regulate the expression of nuclear receptor NR4A3 via iron metabolism in PCa cells. MT-2-induced NR4A3 further coactivated Smad2 to activate p21 and PAI-1 expression. In addition, NR4A3 functioned as a suppressor of PCa and mediated MT-2 signaling to inhibit PCa tumorigenesis and metastasis. These results together indicate that NR4A3 sustains MT-2 signaling to suppress PCa cell invasion, tumor growth, and metastasis, and serves as a contextual factor for the TGF-β/Smad2 signaling pathway in favor of tumor suppression via promoting p21 and PAI-1 expression.
MeSH term(s)	Cell Line, Tumor ; Cell Movement ; DNA-Binding Proteins/metabolism ; Epithelial-Mesenchymal Transition ; Humans ; Male ; Membrane Proteins/metabolism ; Neoplasm Invasiveness ; Plasminogen Activator Inhibitor 1 ; Prostate/pathology ; Prostatic Neoplasms/pathology ; Receptors, Steroid/metabolism ; Receptors, Thyroid Hormone/metabolism ; Serine Endopeptidases/metabolism ; Transforming Growth Factor beta1/metabolism ; Tumor Microenvironment
Chemical Substances	DNA-Binding Proteins ; Membrane Proteins ; NR4A3 protein, human ; Plasminogen Activator Inhibitor 1 ; Receptors, Steroid ; Receptors, Thyroid Hormone ; Transforming Growth Factor beta1 ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase 2 (EC 3.4.21.-)
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-022-02303-z
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Article ; Online: Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

Huang, Hsiang-Po / Chen, Chung-Hsin / Chang, Kai-Hsiung / Lee, Ming-Shyue / Lee, Cheng-Fan / Chao, Yen-Hsiang / Lu, Shih-Yu / Wu, Tzu-Fan / Liang, Sung-Tzu / Lin, Chih-Yu / Lin, Yuan Chi / Liu, Shih-Ping / Lu, Yu-Chuan / Shun, Chia-Tung / Huang, William J / Lin, Tzu-Ping / Ku, Ming-Hsuan / Chung, Hsiao-Jen / Chang, Yen-Hwa /

Liao, Chun-Hou / Yu, Chih-Chin / Chung, Shiu-Dong / Tsai, Yao-Chou / Wu, Chia-Chang / Chen, Kuan-Chou / Ho, Chen-Hsun / Hsiao, Pei-Wen / Pu, Yeong-Shiau

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 714

Abstract: Purpose: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk.: Methods: Urine samples from ... ...

Abstract	Purpose: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. Methods: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). Results: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. Conclusion: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.
MeSH term(s)	Humans ; Male ; Biopsy ; Neoplasm Grading ; Prostate-Specific Antigen ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/urine ; Risk Factors ; Early Detection of Cancer/methods ; Urinalysis/methods ; Metabolome ; Urine/chemistry
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Journal Article ; Validation Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-023-04424-9
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Article ; Online: Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis.

Ko, Chun-Jung / Hsu, Ting-Wei / Wu, Shang-Ru / Lan, Shao-Wei / Hsiao, Ting-Feng / Lin, Hsin-Ying / Lin, Hsin-Hsien / Tu, Hsin-Fang / Lee, Cheng-Fan / Huang, Cheng-Chung / Chen, Mei-Ju May / Hsiao, Pei-Wen / Huang, Hsiang-Po / Lee, Ming-Shyue

Oncogene

2020 Volume 39, Issue 37, Page(s) 5950–5963

Abstract: TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; ... ...

Abstract	TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2's cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.
MeSH term(s)	Animals ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Heterografts ; Humans ; Male ; Membrane Glycoproteins/chemistry ; Membrane Glycoproteins/metabolism ; Neoplasm Invasiveness ; Prostatic Neoplasms/etiology ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Proteinase Inhibitory Proteins, Secretory/metabolism ; Proteolysis ; Serine Endopeptidases/metabolism
Chemical Substances	Carrier Proteins ; Membrane Glycoproteins ; Proteinase Inhibitory Proteins, Secretory ; SPINT1 protein, human ; SPINT2 protein, human ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Keywords	covid19
Language	English
Publishing date	2020-08-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-020-01413-w
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In stock of ZB MED Cologne/Königswinter

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Order via subito

Full text online

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In stock of ZB MED Cologne/Königswinter

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