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Overexpression of GPX3, a potential biomarker for diagnosis and prognosis of breast cancer, inhibits progression of breast cancer cells in vitro.

ABSTRACT: Background:Growing evidence has demonstrated that glutathione peroxidases (GPXs) family genes play critical roles in onset and progression of human cancer. However, a systematic study regarding expression, diagnostic and prognostic values, and function of GPXs family genes in breast cancer remains absent. Materials and methods:Several databases were employed to perform in silico analyses for GPXs family genes. qRT-PCR, western blot and immunohistochemistry staining were introduced to validate GPX3 expression in breast cancer. The functions of GPX3 in breast cancer cells were successively determined. Results:By combination of receiver operating characteristic (ROC) curve analysis, survival analysis and expression analysis, GPX3 was considered as a potential tumor suppressor and a promising diagnostic/prognostic biomarker in breast cancer. Next, low expression of GPX3 was confirmed in breast cancer cells and tissues when compared with corresponding normal controls. Overexpression of GPX3 markedly suppressed proliferation, colony formation, migration and invasion of breast cancer in vitro. Moreover, two potential mechanisms responsible for GPX3 downregulation in breast cancer, including hypermethylation of GPX3 promoter and release of hsa-miR-324-5p inhibition. Conclusions:Collectively, we demonstrate that GPX3 is markedly downregulated in breast cancer, possesses significant diagnostic and prognostic values and attenuated in vitro growth and metastasis of breast cancer.

SUBMITTER: Lou W

PROVIDER: S-EPMC7412804 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Overexpression of GPX3, a potential biomarker for diagnosis and prognosis of breast cancer, inhibits progression of breast cancer cells in vitro.

Lou Weiyang W Ding Bisha B Wang Shuqian S Fu Peifen P

Cancer cell international 20200806

<h4>Background</h4>Growing evidence has demonstrated that glutathione peroxidases (GPXs) family genes play critical roles in onset and progression of human cancer. However, a systematic study regarding expression, diagnostic and prognostic values, and function of GPXs family genes in breast cancer remains absent.<h4>Materials and methods</h4>Several databases were employed to perform in silico analyses for GPXs family genes. qRT-PCR, western blot and immunohistochemistry staining were introduced ...[more]

PMID: 32782436

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Project description:Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.

Project description:This study analyzes the expression and clinical significance of long non-coding RNA (lncRNA) BM466146 in breast cancer, and explores the role of BM466146 in immune regulation. The expression of BM466146 in 89 cases of breast cancer and their corresponding non-cancerous breast tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis was applied to evaluate patient survival. EDU and CCK-8 experiments on breast cancer cells were performed to verify the function of BM466146 in vitro. The target genes of BM466146 were screened by informatics analysis to predict associated miRNAs and their corresponding mRNAs, immune genes associated with lncRNAs and chemokines associated with CD8. Immunohistochemistry was used to detect the expression of CD8, Ki-67, and CXCL-13 in the 89 breast cancer tissues. It was found that the expression of lncRNA BM466146 in breast cancer tissues was significantly lower than that in normal breast tissues (P < 0.001). In breast cancer, tissues that overexpressed BM466146 exhibited a lower Ki-67 index compared with that of low BM466146 expression (P = 0.048). Kaplan-Meier survival analysis showed that breast cancer patients with overexpression of BM466146 had longer overall survival. EDU and CCK8 experiments showed that overexpression of BM466146 inhibited the proliferation of breast cancer cells. The hsa-miR-224-3p is associated with BM466146, and its target gene might be CXCL-13. The positive CD8 cells in the BM466146 overexpression group was higher than that in the low BM466146 expression group (P=0.027), and the positive CD8 cells in the CXCL-13 positive group was higher (P=0.023) than that of the negative group. Our results indicate that the lncRNA BM466146 has the function of tumor suppressor gene. Overexpression of BM466146 is associated with better prognosis. BM466146 could regulate CXCL-13 by adsorbing hsa-miR-224-3p and inducing CD8+ T cells to accumulate in the tumor area which regulate immune response. Therefore, BM466146 could be a prognostic biomarker and a molecular immune target of breast cancer.

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Overexpression of GPX3, a potential biomarker for diagnosis and prognosis of breast cancer, inhibits progression of breast cancer cells in vitro.

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Overexpression of GPX3, a potential biomarker for diagnosis and prognosis of breast cancer, inhibits progression of breast cancer cells in vitro.

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