Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis

Zhang, Xi; Liu, Yang; Li, Jie; Tan, Juan; Song, Zewen

doi:10.3389/pore.2021.594649

Cited by 13 publications

(19 citation statements)

References 55 publications

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“…The gene expression data, phenotype data, and corresponding survival information (if available) of liver hepatocellular carcinoma (LIHC) of The Cancer Genome Atlas (TCGA), the liver cancer project (code: LIRI_JP) of the International Cancer Genome Consortium (ICGC), GSE64041, GSE14520/GPL3921, GSE76427, GSE104580, GSE109211, and GSE25097 were downloaded from public databases and were processed as reported in our previous publications (29)(30)(31). The single-cell analysis of FDX1 in hepatocellular carcinoma was conducted in the Tumor Immune Single-Cell Hub (TISCH) database (http:// tisch.comp-genomics.org/).…”

Section: Public Data Acquisition and Processingmentioning

confidence: 99%

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

et al. 2022

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AimsCuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear.MethodsA set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed.ResultsFDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively.SignificanceThe cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.

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Section: Public Data Acquisition and Processingmentioning

confidence: 99%

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

et al. 2022

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“…In addition, BAG2 is deubiquitinated and stabilized by USP49, and knockdown of USP49 markedly inhibits colorectal cancer proliferation, colony formation, and chemoresistance resistance in vitro 19 . BAG2 is associated with the progression and prognosis of hepatocellular carcinoma 20 . BAG2 is related to poor prognosis and promotes the proliferation, invasion, and migration of oral squamous cell carcinoma cells by activating the MAPK signaling pathway 21 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, BAG2 also interacts with PINK1, a Parkinson's disease-related protein, and directly binds and stabilizes both wild-type PINK1 and the R492X PINK1 mutant by decreasing their ubiquitination, which contributes to the pathogenesis of Parkinson's disease [16]. Notably, upregulation of BAG2 is found in many types of cancer, including gastric cancer, glioma, hepatocellular carcinoma, oral cancer, and colorectal cancer, and is associated with the malignant progression of cancer [17][18][19][20][21]. Recently, BAG2 was reported to enhance mutant p53 levels and accumulation, and promote tumorigenesis in tumors [22].…”

Section: Introductionmentioning

confidence: 99%

BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate

Huang¹,

Shi²,

Wu³

et al. 2023

Theranostics

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Rationale: Chemoresistance is a major challenge in the clinical management of patients with breast cancer. Mutant p53 proteins tend to form aggregates that promote tumorigenesis in cancers. We here aimed to explore the mechanism for the generation of mutant p53 aggregates in breast cancer and assess its role in inducing chemoresistance. Methods: Expression of BCL2-associated athanogene 2 (BAG2) was evaluated by qRT-PCR, western blotting, and immunohistochemistry in breast cancer patient specimens. The significance of BAG2 expression in prognosis was assessed by Kaplan-Meier survival analysis and the Cox regression model. The roles of BAG2 in facilitating the formation of mutant p53 aggregates were analyzed by co-immunoprecipitation, immunofluorescence, and semi-denaturing detergent-agarose gel electrophoresis assays. The effects of BAG2 on the chemoresistance of breast cancer were demonstrated by cell function assays and mice tumor models. Results:In the present study, we found that BAG2 was significantly upregulated in relapse breast cancer patient tissues and high BAG2 was associated with a worse prognosis. BAG2 localized in mutant p53 aggregates and interacted with misfolded p53 mutants. BAG2 exacerbated the formation of the aggregates and recruited HSP90 to promote the propagation and maintenance of the aggregates. Consequently, BAG2-mediated mutant p53 aggregation inhibited the mitochondrial apoptosis pathway, leading to chemoresistance in breast cancer. Importantly, silencing of BAG2 or pharmacological targeting of HSP90 substantially reduced the aggregates and increased the sensitivity of chemotherapy in breast cancer. Conclusion:These findings reveal a significant role of BAG2 in the chemoresistance of breast cancer via exacerbating mutant p53 aggregates and suggest that BAG2 may serve as a potential therapeutic target for breast cancer patients with drug resistance.

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“…The BAG family acts athánatos—the Greek term “against death” for which these proteins are named [ 95 ]. Cancer cells inherently share this behavior, and multiple cancer types have been linked to the Bag proteins ( Table 2 ) [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Given the myriad ways in which Bag1–6 and their cochaperones have been observed in oncology, the therapeutic potential of PQC manipulation at the level of the directional proteins is not limited to glioblastoma.…”

Section: Glioblastoma As a Proteinopathymentioning

confidence: 99%

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

Rocchi

Wollebo

Khalili

2022

IJMS

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Protein quality control allows eukaryotes to maintain proteostasis under the stress of constantly changing conditions. In this review, we discuss the current literature on PQC, highlighting flaws that must exist for malignancy to occur. At the nidus of PQC, the expression of BAG1-6 reflects the cell environment; each isoform directs proteins toward different, parallel branches of the quality control cascade. The sum of these branches creates a net shift toward either homeostasis or apoptosis. With an established role in ALP, Bag3 is necessary for cell survival in stress conditions including those of the cancerous niche (i.e., hypoxia, hypermutation). Evidence suggests that excessive Bag3–HSP70 activity not only sustains, but also propagates cancers. Its role is anti-apoptotic—which allows malignant cells to persist—and intercellular—with the production of infectious ‘oncosomes’ enabling cancer expansion and recurrence. While Bag3 has been identified as a key prognostic indicator in several cancer types, its investigation is limited regarding glioblastoma. The cochaperone HSP70 has been strongly linked with GBM, while ALP inhibitors have been shown to improve GBM susceptibility to chemotherapeutics. Given the highly resilient, frequently recurrent nature of GBM, the targeting of Bag3 is a necessary consideration for the successful and definitive treatment of GBM.

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Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis

Cited by 13 publications

References 55 publications

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma

BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

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