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Glutathione S-Transferase Mu-3 Predicts a Better Prognosis and Inhibits Malignant Behavior and Glycolysis in Pancreatic Cancer.

ABSTRACT: Background: Pancreatic cancer (PC) is a lethal malignancy with an extremely unfavorable 5-year survival rate and a high mortality rate. Glutathione S-transferase mu-3 (GSTM3) has been shown to exert different functions in the progression and development of various cancers, except for PC. This study aimed to explore the role of GSTM3 in the malignant behavior and metabolic aspects of PC, its clinical significance, and its possible molecular mechanism in pancreatic cancer. Methods: Tumor microarrays of pancreatic ductal adenocarcinoma (PDAC) were used to evaluate the clinicopathological variables and GSTM3 expression by immunohistochemical staining. Kaplan-Meier survival and Cox regression analyses were further performed to assess the prognosis. The effect of GSTM3 on PC aggressiveness was detected using overexpressing and silencing transfection methods. Western blot, RT-qPCR, CCK-8, and cell cycle assay were applied to evaluate the expression level and proliferation. A xenograft animal model was assessed. Reactive oxygen species (ROS) were measured using the laser confocal scanner and glycolysis was detected using an Agilent Seahorse kit. RNA sequencing was used to assess the underlying mechanism and the signaling pathway involved. Results: GSTM3 was relatively poorly expressed in PDAC tissues compared to para-tumoral tissues and a high level of GSTM3 indicated good overall survival. Functionally, overexpression of GSTM3 could significantly inhibit cell proliferation by delaying the G0/G1 transition, whereas the opposite results were found in the GSTM3 downregulation group. In addition, xenograft animal models further confirmed the effect on proliferation. Moreover, silencing of GSTM3 induced ROS accumulation and promoted glycolysis in PC, indicating its tumor suppressive effect, and vice versa when GSTM3 was upregulated. Finally, RNA sequencing results demonstrated that GSTM3 facilitates anti-tumorigenicity partly via the JAK-STAT signaling pathway in PC. Conclusion: GSTM3 inhibited tumor progression and altered the metabolic pattern in PC. This may be a potential predictive biomarker in PC and a prospective therapeutic target.

SUBMITTER: Wang S

PROVIDER: S-EPMC7485563 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Glutathione S-Transferase Mu-3 Predicts a Better Prognosis and Inhibits Malignant Behavior and Glycolysis in Pancreatic Cancer.

Wang Shunda S Yang Jinshou J Ding Cheng C Li Junjie J You Lei L Dai Menghua M Zhao Yupei Y

Frontiers in oncology 20200828

<b>Background:</b> Pancreatic cancer (PC) is a lethal malignancy with an extremely unfavorable 5-year survival rate and a high mortality rate. Glutathione S-transferase mu-3 (GSTM3) has been shown to exert different functions in the progression and development of various cancers, except for PC. This study aimed to explore the role of GSTM3 in the malignant behavior and metabolic aspects of PC, its clinical significance, and its possible molecular mechanism in pancreatic cancer. <b>Methods:</b> T ...[more]

PMID: 32984010

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Project description:Background: Transducin-like enhancer of split-1 (TLE1), a member of the Groucho/TLE family of transcriptional corepressors, has been reported to be involved in the tumorigenesis of various cancers and function as a clinical prognostic indicator. However, the mechanisms and prognostic significance of TLE1 in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. Methods: In this study, western blot analyses and real-time polymerase chain reaction (RT-PCR) were employed to evaluate the expression of TLE1 and related proteins in PDAC cell lines. Wound healing, transwell migration and invasion, and Cell Counting Kit-8 (CCK-8) assays were used to determine cell line-specific differences in metastasis and proliferation. Flow cytometry was performed for cell cycle detection. RNA sequencing and bioinformatics were undertaken to explore the molecular mechanisms and potential targeted molecules of TLE1. TLE1 expression in tumor and para-tumor tissues was evaluated by tissue microarray-based immunohistochemistry using a semiquantitative method (H-score) in 262 patients with radical PDAC resection. Correlation, Kaplan-Meier survival, univariate, and multivariate analyses were also performed. Results: Our findings showed that TLE1 expression was common in PDAC cell lines. Upregulation of TLE1 inhibited PDAC cell migration, invasion, and proliferation in vitro by delaying the G0/G1 transition. Immunohistochemistry revealed that TLE1 was specifically expressed in the nucleus and at higher levels in tumor tissues compared with para-tumor tissues. Generally, high TLE1 expression was associated with no vascular invasion. In univariate analyses, high TLE1 expression was associated with longer disease-specific survival (DSS) in all patients and in 16 patient subgroups. In multivariate analyses, TLE1 expression was independently associated with DSS in all patients and four patient subgroups. Conclusion: In conclusion, these results suggest that TLE1 has an inhibitory role in PDAC progression and is a favorable prognostic indicator for patients with resectable PDAC.

Dataset Information

Glutathione S-Transferase Mu-3 Predicts a Better Prognosis and Inhibits Malignant Behavior and Glycolysis in Pancreatic Cancer.

Publications

Glutathione S-Transferase Mu-3 Predicts a Better Prognosis and Inhibits Malignant Behavior and Glycolysis in Pancreatic Cancer.

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