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Loss of cyclin-dependent kinase-like 2 predicts poor prognosis in gastric cancer, and its overexpression suppresses cells growth and invasion.

ABSTRACT: Cyclin-dependent kinase-like 2 (CDKL2), a new member of the cyclin-dependent kinase family, may be involved in gastric cancer (GC) progression. Thus, we conducted this study to explore the clinical effect of CDKL2 in GC. Immunohistochemistry was used to measure CDKL2 levels in gastric tissues. The association of a high CDKL2 level with clinical and pathological characteristics, and the correlation between the CDKL2 level and disease-free and overall survival were analyzed. Transfection was employed to overexpress CDKL2 in GC cells and to investigate the effect of CDKL2 overexpression on cell proliferation and invasion. Loss of CDKL2 was positively correlated with several clinical and pathological characteristics, and patients with a low CDKL2 level had significantly poorer disease-free and overall survival than those with a high level (P = .005 and .001, respectively). Univariate analysis using the Cox proportional hazards model indicated that a low CDKL2 level was a prognosticator for inferior disease-free survival (P = .007). Based on immmunoblotting data, AGS and HGC-27 GC cells were chosen for CDKL2 overexpression. Cellular studies revealed that CDKL2 overexpression impaired cell proliferation and invasion. Loss of CDKL2 may serve as a biomarker for predicting GC patient outcomes and a potential therapeutic target for GC treatment.

SUBMITTER: Fang CL

PROVIDER: S-EPMC6051174 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Loss of cyclin-dependent kinase-like 2 predicts poor prognosis in gastric cancer, and its overexpression suppresses cells growth and invasion.

Fang Chia-Lang CL Uen Yih-Huei YH Chen Han-Kun HK Hseu You-Cheng YC Lin Chih-Chan CC Hung Shih-Ting ST Sun Ding-Ping DP Lin Kai-Yuan KY

Cancer medicine 20180523 7

Cyclin-dependent kinase-like 2 (CDKL2), a new member of the cyclin-dependent kinase family, may be involved in gastric cancer (GC) progression. Thus, we conducted this study to explore the clinical effect of CDKL2 in GC. Immunohistochemistry was used to measure CDKL2 levels in gastric tissues. The association of a high CDKL2 level with clinical and pathological characteristics, and the correlation between the CDKL2 level and disease-free and overall survival were analyzed. Transfection was emplo ...[more]

PMID: 29790675

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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.

Project description:BackgroundPlenty of studies have showed matrix metalloproteinase 14 (MMP14) expression might be associated with the prognosis of gastric cancer (GC). However, no definite conclusion has been obtained for the contradictory results.MethodsWe searched PubMed, Web of science, Embase, and Cochrane library for eligible studies. The association between MMP14 expression and prognostic outcomes of GC was evaluated. Hazard ratio (HR) and 95% confidence interval (CI) were integrated to show the effect of MMP14 expression on the overall survival (OS) or recurrence-free survival (RFS). Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was used to validate the association of MMP14 expression with OS or RFS in GC. A brief bioinformatics analysis was also performed to determine the prognostic role of MMP14 expression in GC.ResultsHigh MMP14 expression was associated with shorter OS compared to low MMP14 expression in GC (HR = 1.95, P < .01). Patients with high MMP14 expression tended to have worse differentiation (P = .03), deeper tumor invasion (P < .01), earlier lymph node metastasis (P < .01), earlier distant metastasis (P < .01) and more advanced clinical stage (P < .01) compared to those with low MMP14 expression. The data from TCGA and GEO showed MMP14 was overexpressed in tumor tissues compared to normal tissues (P < .05), and high MMP14 expression was significantly related to shorter OS (HR = 1.70, 95% CI = 1.32-2.20, P < .01) and RFS (HR = 1.45, 95% CI = 1.15-1.83, P < .01) compared to low MMP14 expression in GC. Expression of MMP14 was linked to functional networks involving the biological process, metabolic process, response to stimulus, cell communication and so on. Functional network analysis suggested that MMP14 regulated the protein digestion and absorption, extracellular matrix receptor interaction, focal adhesion, ribosome, spliceosome, and so on.ConclusionHigh MMP14 expression was associated with worse prognosis of GC compared to low MMP14 expression. MMP14 expression could serve as a prognostic factor and potential therapeutic target of GC.

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Loss of cyclin-dependent kinase-like 2 predicts poor prognosis in gastric cancer, and its overexpression suppresses cells growth and invasion.

Publications

Loss of cyclin-dependent kinase-like 2 predicts poor prognosis in gastric cancer, and its overexpression suppresses cells growth and invasion.

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