Role of Microtubule-Associated Protein 1b in Urothelial Carcinoma: Overexpression Predicts Poor Prognosis.
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ABSTRACT:
SUBMITTER: Chien TM
PROVIDER: S-EPMC7139768 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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Role of Microtubule-Associated Protein 1b in Urothelial Carcinoma: Overexpression Predicts Poor Prognosis.
Chien Tsu-Ming TM Chan Ti-Chun TC Huang Steven Kuan-Hua SK Yeh Bi-Wen BW Li Wei-Ming WM Huang Chun-Nung CN Li Ching-Chia CC Wu Wen-Jeng WJ Li Chien-Feng CF
Cancers 20200309 3
We sought to examine the relationship between microtubule-associated proteins (MAPs) and the prognosis of urothelial carcinoma by assessing the microtubule bundle formation genes using a reappraisal transcriptome dataset of urothelial carcinoma (GSE31684). The result revealed that microtubule-associated protein 1b (<i>MAP1B</i>) is the most significant upregulated gene related to cancer progression. Real-time reverse-transcription polymerase chain reaction was used to measure <i>MAP1B</i> transc ...[more]
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Project description:BackgroundThe mitochondrial pyruvate dehydrogenase complex (PDC) link glycolysis to the tricarboxylic acid cycle by decarboxylating pyruvate to acetyl coenzyme A irreversibly. Cancer cells are characterized by a shift in cellular metabolism from mitochondrial respiration to glycolysis. PDC activity inhibition mediated by phosphorylation via pyruvate dehydrogenase kinase (PDK) has been linked to cancer. However, the clinical significance of PDKs in urothelial cancer prognosis is not clear. We investigated the role and prognostic value of PDK3 expression in patients with upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC).Patients and methodsWe retrospectively analyzed clinical data and pathological features. Formalin-fixed urothelial carcinoma (UC) tissues were collected and embedded in paraffin. The correlation of PDK3 expression with clinical characteristics, pathological findings and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS) were analyzed by Pearson's chi-square test, Kaplan-Meier analysis, and the multivariate Cox proportional hazards model.ResultsData from 295 patients with UBUC and 340 patients with UTUC were evaluated. High PDK3 expression significantly correlated with several pathologic variables such as high T stage, lymph node metastases, high tumor grade, vascular invasion, and high mitotic rate (all P < 0.001). High PDK3 expression was associated with poor disease-specific survival (DSS) (P < 0.0001) and metastatic free survival (MFS) (P < 0.0001) in a Kaplan-Meier analysis. Additionally, multivariate analysis demonstrated increased PDK3 expression is a significant predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.79, P = 0.009; in UTUC, 2.561, P = 0.03] and MFS (HR in UBUC, 1.907, P = 0.024; in UTUC, 1.793, P = 0.044). The gene co-expression analysis showed abundant PDK3 co-upregulated genes were involved in the processes of DNA replication and repair through the Gene Ontology classification system.ConclusionHigh PDK3 expression has been linked to negative pathologic characteristics and poor oncological outcomes, suggesting that it could be used as a predictive biomarker for UC. PDK3 mRNA levels and its co-upregulated genes were strongly associated with DNA replication and repair. These results suggest that PDK3 may play a key role in tumor proliferation and development.
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Project description:PurposeThe majority deaths of cancer patients are related to metastasis, thus genes associated with cell motility interest us. SPOCK1 was elected by data mining and serial evaluation. In addition, SPOCK1 has been reported to be highly expressed in different human cancers and been related to adverse outcomes. Therefore, we validate its prognostic significance in urothelial carcinoma (UC).Materials and methodsReal-time RT-PCR assay was used to detect SPOCK1 transcript level in 27 urinary tract urothelial carcinoma (UTUC) and 27 urinary bladder urothelial carcinoma (UBUC) samples. Immunohistochemistry evaluated by H-score determined SPOCK1 expressions in 340 UTUCs and 295 UBUCs. The transcript and protein expression were correlated with clinicopathological features. Further evaluations of the prognostic significance of SPOCK1 for disease-specific survival (DSS) and metastasis-free survival (MeFS) were analyzed.ResultsThe expressions of SPOCK1 in UC were higher than those in normal urothelium by immunohistochemistry. The statistical analysis of clinicopathologic characteristics and immunohistochemistry showed that the higher expression of SPOCK1 was correlated to pT status (P<0.001), lymph node metastasis (UTUC, P=0.006; UBUC, P=0.033), higher histological grade (UTUC, P<0.001; UBUC, P<0.001), vascular invasion (UTUC, P<0.001; UBUC, P<0.001), perineurial invasion (UTUC, P<0.001; UBUC, P=0.001) and frequent mitosis (UTUC, P<0.001; UBUC, P=0.001). The prognosis of SPOCK1 of UC showed high SPOCK1 expression had significantly worse DSS and MeFS.ConclusionsThe investigation demonstrated that the higher expression of SPOCK1 correlates with a poor prognosis in UC.
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Project description:BackgroundUrothelial carcinoma (UC) commonly occurs in the urinary bladder (UB) and rarely in upper the upper urinary tract (UT). Its molecular pathogenesis, however, remains obscure. Though the constitutive phosphorylation of Signal Transducer and Activator of Transcription 5 (STAT5) is an important part of carcinogenesis generally, researchers have not systematically investigated this process specifically in relation to UC. The present study addresses this gap. Through data mining a published transcriptomic database of UBUCs (GSE32894), it identified Colony Stimulating Factor 2 (CSF2) as the stepwise upregulated gene of much significance among those related to the positive regulation of tyrosine phosphorylation of STAT5 (GO:0042523). Since the phosphorylation of STAT5, a key process in the development of UC, is closely associated with CSF2, we then examine CSF2 transcript and protein expression, justifying their association with clinicopathological features and survival in our well-established cohort of patients with UC.DesignLaser capture microdissection in conjunction with real-time qRT-PCR are used to detect CSF2 transcript levels in 24 UBUCs and 6 non-tumor urothelium samples. We then used the H-score method to evaluate the immunohistochemistry in order to determine CSF2 protein expression in 296 UBUCs and 340 UTUCs, respectively. After correlating protein expression status with key clinicopathological features, the prognostic significance of CSF2 protein expression was determined for disease-specific survival (DSS) and metastasis-free survival (MeFS).ResultsWe exclusively detected the CSF2 transcript, which was stepwise upregulated in tumor lesions (p=0.010). In both groups of UC we found overexpression of CSF2 significantly related to incremental pT status (UTUC, p=0.011; UBUC, p<0.001), as well as with perineural invasion (UTUC, p=0.002; UBUC, p=0.001). Univariate analysis found a close correlation between CSF2 overexpression and unfavorable prognosis for both DSS (UTUC, p=0.0001; UBUC, p<0.0001) and MeFS (UTUC, p=0.0001; UBUC, p=0.0002). High expression of CSF2 still remained prognostically for DSS (UTUC, p=0.015; UBUC, p=0.004) and MeFS (UTUC, p=0.008; UBUC, p=0.027) in multivariate comparison.ConclusionOur data showed that overexpression of CSF2 was inferred in advanced disease status and poor clinical outcomes for both UTUC and UBUC patients, suggesting that CSF2 may serve as an important prognosticator and a potential therapeutic target of UC.
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Project description:PurposeCartilage oligomeric matrix protein (COMP) is known as a large pentameric glycoprotein, which interacts with various extracellular matrix proteins in tissues. COMP has been reported to play a role in multiple connective tissue disorders. Recently, elevated COMP levels have been found to be associated with increased tumor size, metastases, faster recurrence of cancer, and overall poorer survival in several cancers. However, the clinical importance of COMP in urothelial carcinoma remains unclear. We investigated the association between COMP expression and clinical outcomes in urothelial carcinoma.Patients and methodsIn this retrospective study, we collected urothelial carcinoma (UC) tissue from 340 upper urinary tract UC (UTUC) patients and 295 urinary bladder UC (UBUC) patients. Pearson's chi-square test, Kaplan-Meier analysis, and the multivariate Cox proportional hazards model was used to examine the relationship between COMP expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MFS) and disease-specific survival (DSS).ResultsA total of 295 UBUC patients and 340 UTUC patients were recruited. The COMP mRNA level was significantly higher among invasive tumors (pT2-pT4) than in noninvasive tumors (pTa-T1) in UBUC groups (P < 0.01). COMP overexpression was associated with advanced T stage, nodal metastases, vascular invasion, perineural invasion, high histological grade, and high mitotic rate in both UBUC and UTUC cohorts. COMP overexpression was predictive of shorter DSS (hazard ratio [HR] in UBUC, 3.986, P < 0.001; in UTUC, 2.283, P = 0.027] and MFS (HR in UBUC, 6.813, P < 0.001; in UTUC, 4.070, P < 0.001). Kaplan-Meier analysis demonstrated high COMP expression associated with poor DSS and MFS in UTUC and UBUC groups (all P < 0.0001).ConclusionCOMP overexpression was linked to poor clinical prognosis and poor pathological features in UC. These results suggest COMP as a biomarker for UC.
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Project description:BackgroundDihydropyrimidinase-like 3 (DPYSL3) is a cytosolic phosphoprotein expressed in the nervous system and is crucial for neurogenesis. A previous study showed that increased DPYSL3 expression promotes tumour aggressiveness in pancreatic ductal adenocarcinoma, gastric cancer, and colon cancer. However, the role of DPYSL3 in affecting the biological behaviour of urothelial carcinoma (UC) is not yet understood.MethodsA UC transcriptomic dataset from the Gene Expression Omnibus and the Urothelial Bladder Cancer (BLCA) dataset from The Cancer Genome Atlas were used for the in silico study. We collected 340 upper urinary tract urothelial carcinoma (UTUC) and 295 urinary bladder urothelial carcinoma (UBUC) samples for the immunohistochemical study. Fresh tumour tissue from 50 patients was used to examine the DPYSL3 mRNA level. In addition, urothelial cell lines with and without DPYSL3 knockdown were used for the functional study.ResultsThe in silico study revealed that DPYSL3 correlated with advanced tumour stage and metastasis development while functioning primarily in the nucleobase-containing compound metabolic process (GO:0006139). DPYSL3 mRNA expression is significantly upregulated in advanced UC. Furthermore, overexpression of the DPYSL3 protein is significantly associated with the aggressive behaviour of UTUC and UBUC. DPYSL3 expression independently predicts disease-specific survival (DSS) and metastatic-free survival (MFS) in patients with UC. In non-muscle-invasive UBUC, DPYSL3 expression predicts local recurrence-free survival. UC cell lines with DPYSL3 knockdown exhibited decreased proliferation, migration, invasion, and human umbilical vein endothelial cells (HUVECs) tube formation but increased apoptosis and G1 arrest. Gene ontology enrichment analysis revealed that the enriched processes related to DPYSL3 overexpression in UC were tissue morphogenesis, cell mesenchyme migration, smooth muscle regulation, metabolic processes, and RNA processing. In vivo study revealed DPYSL3 knockdown in UC tumours significantly suppressed the growth of tumours and decreased MYC and GLUT1 protein expression.ConclusionsDPYSL3 promotes the aggressiveness of UC cells by changing their biological behaviours and is likely associated with cytoskeletal and metabolic process modifications. Furthermore, DPYSL3 protein overexpression in UC was associated with aggressive clinicopathological characteristics and independently predicted poor clinical outcomes. Therefore, DPYSL3 can be used as a novel therapeutic target for UC.
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