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Overexpression of PDK4 is associated with cell proliferation, drug resistance and poor prognosis in ovarian cancer.

ABSTRACT: Purpose:Ovarian cancer is a major type of gynecological malignancy which characterized by the chemoresistance, heterogeneity and highly metastasis. However, the mechanism underlying the progression of ovarian cancer remains elusive. Pyruvate dehydrogenase kinase family plays critical roles in tumorigenesis, and PDK4 has been demonstrated to be an oncogene in many types of cancers. The aim of this study was to identify the role of PDK4 in ovarian cancer. Methods:We explored the PDK4 expression according to the public database containing patients with different effect of chemotherapy. Cell proliferation and invasion assays were used to determine the function of PDK4. Mice xenograft experiment was conducted to test the pro-tumorigenesis function of PDK4 in vivo. Cell apoptosis under treatment of chemo drugs was detected by flow cytometry and TUNEL analysis. Spheroid formation assay and CD133+ cell population were used to determine the PDK4-induced stem-like traits. Immunohistochemical staining was performed to test the expression of PDK4 in ovarian cancer tissues, and Kaplan- Meier curve with log-rank test was performed to determine the association between PDK4 expression and ovarian cancer patients' prognosis. Results:Overexpression of PDK4 markedly promoted cell proliferation, invasion and tumor growth in vivo. Furthermore, PDK4 confers cell resistant to chemotherapy-induced apoptosis. Mechanically, we demonstrated that PDK4 induced stem-like traits. Meanwhile, PDK4 expression was significantly evaluated in ovarian cancer tissues compared to that in adjacent non-cancer tissues, and high expression of PDK4 was associated with poor overall survival and progression-free survival of ovarian cancer patients. Conclusion:These results identify a novel role of PDK4 in regulating cell stem-like trait, which directly enhances the cell proliferation, invasion and chemoresistance in ovarian cancer, and targeting PDK4 could be a potential approach for ovarian cancer treatments.

SUBMITTER: Wang J

PROVIDER: S-EPMC6307676 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Overexpression of PDK4 is associated with cell proliferation, drug resistance and poor prognosis in ovarian cancer.

Wang Jinghao J Qian Yu Y Gao Meiyan M

Cancer management and research 20181224

<h4>Purpose</h4>Ovarian cancer is a major type of gynecological malignancy which characterized by the chemoresistance, heterogeneity and highly metastasis. However, the mechanism underlying the progression of ovarian cancer remains elusive. Pyruvate dehydrogenase kinase family plays critical roles in tumorigenesis, and PDK4 has been demonstrated to be an oncogene in many types of cancers. The aim of this study was to identify the role of PDK4 in ovarian cancer.<h4>Methods</h4>We explored the PDK ...[more]

PMID: 30636897

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Project description:BackgroundSolute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa.MethodsExpression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients' prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments.ResultsBased on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (all P < 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group.ConclusionsOur data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy.

Project description:Historically, immunotherapies have only resulted in a partial response from patients with advanced ovarian cancer, resulting in poor clinical efficacy. A full understanding of immune-related gene expression and immunocyte infiltration in ovarian cancer would be instrumental for the improved implementation of immunotherapy. The Capping Actin Protein, Gelsolin-Like (CAPG) gene encodes an actin-regulatory protein, which plays important roles in tumor progression and immune regulation. This study is aimed at identifying the potential therapeutic and prognostic roles of CAPG in ovarian cancer. CAPG expression and clinical information were investigated in the data collected from TCGA, Oncomine, GEPIA, UALCAN, and Kaplan-Meier plotter. CAPG coexpression networks were evaluated by LinkedOmics, GeneMANIA, and NetworkAnalyst. The correlation of CAPG with immune infiltrates was analyzed via TIMER, ImmuCellAI, and GEPIA. Our result showed that patients with high tumoral CAPG expression had significantly shorter 5-year overall survival. Functional enrichment analysis indicated that CAPG-related phenotypes were largely involved in inflammatory response, chemokine and cytokine signaling, cell adhesion, and Toll-like receptor signaling pathways. CAPG expression was positively correlated with infiltrating levels of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and exhausted T cells (Texs) while being negatively correlated with infiltrating levels of natural killer T cells (NKTs) and neutrophils in ovarian cancer. Moreover, the expression of FOXP3, CD25, CD127, CCR8, and TGFβ in respect to Tregs; CCL2 and CD68 in respect to TAM; CD163, VSIG4, and MS4A4A in respect to M2 macrophages; CD33 and CD11b in respect to myeloid-derived suppressor cells (MDSCs); and PD1, CTLA4, LAG3, TIM3, GZMB, 2B4, and TIGIT in respect to Texs was significantly correlated with CAPG expression in ovarian cancer. These findings suggest that CAPG may contribute to the immunosuppressive tumor microenvironment in ovarian cancer, leading to an exhausted T cell phenotype and tumor progression. Therefore, CAPG can be used as a potential biomarker for determining prognosis and immunotherapy effectiveness in ovarian cancer.

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Overexpression of PDK4 is associated with cell proliferation, drug resistance and poor prognosis in ovarian cancer.

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Overexpression of PDK4 is associated with cell proliferation, drug resistance and poor prognosis in ovarian cancer.

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