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Bioinformatics analysis of the prognostic value of CCT6A and associated signalling pathways in breast cancer.

ABSTRACT: Breast cancer (BC) is the most frequently diagnosed type of cancer and the leading cause of cancer?associated mortality among women worldwide. However, the molecular basis for the pathogenesis of BC requires further exploration. Recent studies have demonstrated that chaperonin?containing TCP1 subunit 6A (CCT6A) efficiently suppresses transforming growth factor???mediated metastasis by inhibiting the function of SMAD family member 2 in lung cancer. However, the functional significance of CCT6A in other types of cancer, including BC, remains to be investigated. Therefore, this study evaluated CCT6A expression in BC samples, and further analysed its association with survival, clinicopathological parameters and related signalling pathways using online datasets. The present study indicated that CCT6A expression was significantly higher in BC tissues compared with in surrounding noncancerous tissues at both mRNA and protein levels. Furthermore, increased CCT6A expression was significantly associated with poor survival, including overall survival, relapse?free survival, distant metastasis?free survival and post progression survival, in patients with BC. Pathway finder analysis indicated that CCT6A was significantly associated with the cell cycle, and its expression was significantly positively correlated with cyclin (CCN)B2 and CCNA2 expression. Taken together, to the best of our knowledge, the present study is the first to indicate that CCT6A may serve a significant role in BC tumour progression.

SUBMITTER: Huang K

PROVIDER: S-EPMC6472137 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Bioinformatics analysis of the prognostic value of CCT6A and associated signalling pathways in breast cancer.

Huang Kai K Zeng Yi Y Xie Yunqing Y Huang Liying L Wu Yu Y

Molecular medicine reports 20190328 5

Breast cancer (BC) is the most frequently diagnosed type of cancer and the leading cause of cancer‑associated mortality among women worldwide. However, the molecular basis for the pathogenesis of BC requires further exploration. Recent studies have demonstrated that chaperonin‑containing TCP1 subunit 6A (CCT6A) efficiently suppresses transforming growth factor‑β‑mediated metastasis by inhibiting the function of SMAD family member 2 in lung cancer. However, the functional significance of CCT6A in ...[more]

PMID: 30942452

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Project description:Background and Purpose: Breast cancer is one of the leading causes of death among women. RNA binding proteins (RBPs) play a vital role in the progression of many cancers. Functional investigation of RBPs may contribute to elucidating the mechanisms underlying tumor initiation, progression, and invasion, therefore providing novel insights into future diagnosis, treatment, and prognosis. Methods: We downloaded RNA sequencing data from the cancer genome atlas (TCGA) by UCSC Xena and identified relevant RBPs through an integrated bioinformatics analysis. We then analyzed biological processes of differentially expressed genes (DEGs) by DAVID, and established their interaction networks and performed pathway analysis through the STRING database to uncover potential biological effects of these RBPs. We also explored the relationship between these RBPs and the prognosis of breast cancer patients. Results: In the present study, we obtained 1092 breast tumor samples and 113 normal controls. After data analysis, we identified 90 upregulated and 115 downregulated RBPs in breast cancer. GO and KEGG pathway analysis indicated that these significantly changed genes were mainly involved in RNA processing, splicing, localization and RNA silencing, DNA transposition regulation and methylation, alkylation, mitochondrial gene expression, and transcription regulation. In addition, some RBPs were related to histone H3K27 methylation, estrogen response, inflammatory mediators, and translation regulation. Our study also identified five RBPs associated with breast cancer prognosis. Survival analysis found that overexpression of DCAF13, EZR, and MRPL13 showed worse survival, but overexpression of APOBEC3C and EIF4E3 showed better survival. Conclusion: In conclusion, we identified key RBPs of breast cancer through comprehensive bioinformatics analysis. These RBPs were involved in a variety of biological and molecular pathways in breast cancer. Furthermore, we identified five RBPs as a potential prognostic biomarker of breast cancer. Our study provided novel insights to understand breast cancer at a molecular level.

Project description:BRIP1 (Breast Cancer 1 Interacting Helicase 1) is a tumor suppressor gene that has vital function in preserving the genetic stability by repairing DNA damage though have significant associations with the onset of breast cancer (BC) if mutated or overexpressed. In this study, the prognostic value of BRIP1 gene was evaluated and validated through bioinformatics approaches utilizing transcriptomic (mRNA expression) data from several BC databases. To determine the prognostic value, the expression level of mRNA transcript was analyzed in context of comparison between breast tumor and normal tissues regarding clinical features, breast tumor subtypes, promoter methylation status, correlation level, mutation frequency, and survival of BC patients. BRIP1 expression was found to be significantly overexpressed in various BC molecular subtypes (e.g. PAM50, Sorlie's) and clinical status (estrogen and progesterone receptor) than associated normal tissues which correlated with prognosis. Also, in promoter methylation level, its expression was observed as upregulated-hypomethylated regarding various clinicopathological features. Multiple data mining exhibited positive correlation between BRIP1 and INTS2 (Integrator Complex Subunit 2) expressions in BC. Further, mutation analysis revealed that BRIP1 gene was altered by acquiring both somatic and germline mutations. In addition, a total of 42 mutations; 24 missense, 8 fusion, 7 truncating, and 3 inframe mutations in BC patients was detected in BRIP1 protein. Moreover, higher BRIP1 expression was found to be correlated with poor disease-specific, disease metastasis-free, relapse-free, and overall survivals of BC patients. Since, overexpression of BRIP1 was identified to be associated with different clinical features, breast tumor subtypes, promoter methylation status, and survival of BC patients that may provide a risk of ensuing malignant transformation. Thus, lower expression of BRIP1 might hinder BC prognosis. We consider that this analysis will present a proof for BRIP1 gene to be a noteworthy molecular biomarker for BC prognosis.

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Project description:BACKGROUND:Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions. METHODS:Bioinformatics functional enrichment analysis revealed a subgroup of 24 genes, potentially overexpressed in CTCs. Among these genes, the chemokine receptor CXCR4 plays a central role. After prioritization according to the CXCR4 corresponding pathways, five molecules (JUNB, YWHAB, TYROBP, NFYA, and PRDX1) were selected for further analysis in biological samples. The SKBR3, MDA-MB231, and MCF7 cell lines, as well as PBMCs from normal (n?=?10) blood donors, were used as controls to define the expression pattern of all the examined molecules. Consequently, 100 previously untreated metastatic breast cancer (mBC) patients (n?=?100) were analyzed using the following combinations of antibodies: CK (cytokeratin)/CXCR4/JUNB, CK/NFYA/?WH?? (14-3-3), and CK/TYROBP/PRDX1. A threshold value for every molecule was considered the mean expression in normal PBMCs. RESULTS:Quantification of CXCR4 revealed overexpression of the receptor in SKBR3 and in CTCs, following the subsequent scale (SKBR3>CTCs>Hela>MCF7>MDA-MB231). JUNB was also overexpressed in CTCs (SKBR3>CTCs>MCF7>MDA-MB231>Hela). According to the defined threshold for each molecule, CXCR4-positive CTCs were identified in 90% of the patients with detectable tumor cells in their blood. In addition, 65%, 75%, 14.3%, and 12.5% of the patients harbored JUNB-, TYROBP-, NFYA-, and PRDX-positive CTCs, respectively. Conversely, none of the patients revealed YWHAB-positive CTCs. Interestingly, JUNB expression in CTCs was phenotypically and statistically enhanced compared to patients' blood cells (p?=?0.002) providing a possible new biomarker for CTCs. Furthermore, the detection of JUNB-positive CTCs in patients was associated with poorer PFS (p?=?0.015) and OS (p?=?0.002). Moreover, JUNB staining of 11 primary and 4 metastatic tumors from the same cohort of patients revealed a dramatic increase of JUNB expression in metastasis. CONCLUSIONS:CXCR4, JUNB, and TYROBP were overexpressed in CTCs, but only the expression of JUNB was associated with poor prognosis, providing a new biomarker and a potential therapeutic target for the elimination of CTCs.

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Bioinformatics analysis of the prognostic value of CCT6A and associated signalling pathways in breast cancer.

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Bioinformatics analysis of the prognostic value of CCT6A and associated signalling pathways in breast cancer.

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