RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2

Yang, Yin Long; Zhang, Ye; Li, Dou Dou; Zhang, Fang Lin; Liu, Hong Yi; Liao, Xiao Hong; Xie, Haiyang; Lu, Qiong; Zhang, Lin; Hong, Quan; Dong, Wen; Li, Da Qiang; Shao, Zhi Min

doi:10.1038/s41418-019-0400-z

Cited by 44 publications

(56 citation statements)

References 43 publications

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“…In the case of breast cancers, conflicting results were published. Accordingly, immunohistochemistry-based studies linked a high level of HSPA2 in tumor with unfavorable clinicopathological characteristics and shorter overall as well as disease-free survival [ 27 , 47 ]. Instead, analysis of the transcriptomic data showed that a high level of HSPA2 mRNA predicts a favorable outcome [ 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells

Sojka

Gogler-Pigłowska

Klarzyńska

et al. 2020

Cancers

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Heat Shock Protein A2 (HSPA2) is a member of the HSPA (HSP70) chaperone family and has a critical role for male fertility. HSPA2 is present in a number of somatic organs. Limited evidence suggests that HSPA2 may be involved in regulating epithelial cell differentiation. HSPA2 also emerged as a cancer-related chaperone; however, no consensus on its functional significance has been reached so far. In this study, we compared the phenotypic effects of HSPA2 deficit in non-transformed human bronchial epithelial cells (HBEC), and in lung, breast, and cervical cancer cells. We used various techniques to inhibit the HSPA2 gene expression in order to examine the impact of HSPA2 deficiency on cell growth, migration, adhesion, and invasion. Our results show that HBEC but not cancer cells are sensitive to HSPA2 deficit. HSPA2 knockdown in HBEC cells impaired their clone-forming ability and adhesiveness. Thus, our results indicate that epithelial cells can rely on a specific activity of HSPA2, but such dependence can be lost in epithelial cells that have undergone malignant transformation.

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Section: Discussionmentioning

confidence: 99%

HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells

Sojka

Gogler-Pigłowska

Klarzyńska

et al. 2020

Cancers

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“…The up regulation of hnRNP-K transcriptional activity mediated by SERPINA3 promotes the survival and proliferation of HCC cells, which may be an indicator of poor prognosis in HCC patients (17). Heat shock protein family a member 2 (HSPA2), a putative oncoprotein, is often up-regulated in human cancers and promotes tumor growth and progression (18). NFKBIE aberrations are common genetic events in trans-b-cell malignancies, and NFKBIE deletion is a new marker of poor prognosis in primary mediastinal B-cell lymphoma (PMBL) (19).…”

Section: Discussionmentioning

confidence: 99%

Identification of an independent immune-genes prognostic index for breast cancer

Chen

Dong

Pan

et al. 2020

Preprint

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Objective Increasing evidence has indicated an association between immune micro-environment in breast cancer and clinical outcomes. The aim of this research is to comprehensively investigate the effect of tumor immune genes on the prognosis of breast cancer patients. Methods 2498 immune genes were downloaded from ImmPort database. Additionally, we identified and downloaded the transcriptome data of patients with breast cancer from the TCGA database through the R package, as well as relevant clinical information. Survival R package was applied in survival analyses for hub-genes. Cox regression analysis was used to analyze the effect of immune genes on the prognosis of breast cancer. Immune risk scoring model was constructed based on the statistical correlation between hub immune genes and survival. Meanwhile, multivariate cox regression analysis was utilized to investigate whether the immune genes risk score model was an independent factor for predicting the prognosis of breast cancer. Nomogram was constructed to comprehensively predict the survival rate of breast cancer. P < 0.05 was considered to be statistically significant. Results The results of the difference analysis showed that 556 immune genes exhibited differential expression between normal and breast cancer tissues (p < 0. 05). Univariate cox regression analysis revealed 66 immune genes statistically correlated with breast cancer related survival risk, of which 30 were associated with overall survival (P < 0.05). In addition, a 15-genes based immune genes risk scoring model was constructed through lasso COX regression analysis. KM curve indicated that patients in high-risk were associated with poor outcomes (p < 0.001). ROC curve indicated that the immune risk score model was reliable in predicting survival risk (5-year OS, AUC = 0.752). Our model showed satisfying AUC and survival correlation in the validation dataset (3-year over survival (OS) AUC = 0.685, 5-year OS AUC = 0.717, P = 0.00048). Furthermore, multivariate cox regression analysis confirmed that the immune risk score model was an independent factor for predicting the prognosis of breast cancer. A nomogram was established to comprehensively predict the survival of breast cancer patients with the results of multivariate cox regression analysis. Finally, we found that 15 immune genes and risk scores were significantly associated with clinical factors and prognosis, and were involved in multiple oncogenic pathways. Conclusion Collectively, tumor immune genes played an essential role in the prognosis of breast cancer. Furthermore, immune risk score was an independent predictive factor of breast cancer, indicating a poor survival.

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“…To validate the reliability of HSPA2 detection in cellular environment highly enriched in stress-inducible HSPAs, we evoked proteotoxic stress in MCF7 cells using MG132, a reversible proteasome inhibitor. We used MCF7 cells, since a massive accumulation of HSPA2 following MG132 treatment can be detected in these cells, as shown recently using the Proteintech antibody [9]. For detection of stress-inducible HSPA1 and HSPA6, and constitutive HSPA8, we used commercial antibodies (Table 3).…”

Section: Detection Of the Endogenous Hspa2 In Cells Under Proteotoxicmentioning

confidence: 99%

“…In this aspect, the usage of validated primary antibody is an absolute must to obtain reliable results. The IHC technique was used in several studies aimed at evaluating HSPA2 as potential cancer biomarker (details in Table 1) [9,12,14,16,17]. However, in only one of these studies [12] was an anti-HSPA2 antibody with previously proven specificity used [15].…”

Section: The Impact Of Anti-hspa2 Antibody Used For Ihc Detection Onmentioning

confidence: 99%

“…However, conflicting conclusions on HSPA2 prognostic value were achieved in studies employing classical immunohistochemistry (IHC) method, as compared to studies analyzing mRNA expression. For example, in breast cancer, an IHC-based study showed that a high level of HSPA2 in primary tumors is related with unfavorable clinicopathological characteristics [8], and shorter overall and disease-free survival [9]; while analysis of the transcriptomic data revealed that high levels of HSPA2 mRNA predict a favorable outcome [6,10,11]. Intriguingly, such a discrepancy was not detected in the studies on non-small cell lung carcinoma (NSCLC) and pancreatic adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

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Various Anti-HSPA2 Antibodies Yield Different Results in Studies on Cancer-Related Functions of Heat Shock Protein A2

Ścieglińska

Sojka

Gogler-Pigłowska

et al. 2020

IJMS

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Heat shock proteins (HSPs) constitute a major part of the molecular chaperone system and play a fundamental role in cell proteostasis. The HSPA (HSP70) family groups twelve highly homologous HSPA proteins. Certain HSPAs are regarded as important cancer-related proteins, prospective therapeutic targets for cancer treatment, and also as potential cancer biomarkers. Heat Shock Protein A2 (HSPA2), a testis-enriched chaperone and one of the least characterized members of the HSPA family, has recently emerged as an important cancer-relevant protein with potential biomarker significance. Nevertheless, conflicting conclusions have been recently drawn both according to HSPA2 role in cancer cells, as well as to its prognostic value. In this work we have shown that one of the serious limitations in HSPA2 protein research is cross-reactivity of antibodies marketed as specific for HSPA2 with one or more other HSPA(s). Among non-specific antibodies were also those recently used for HSPA2 detection in functional and biomarker studies. We showed how using non-specific antibodies can generate misleading conclusions on HSPA2 expression in non-stressed cancer cells and tumors, as well as in cancer cells exposed to proteotoxic stress. Our findings addressed concerns on some published studies dealing with HSPA2 as a cancer-related protein.

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RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2

Cited by 44 publications

References 43 publications

HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells

HSPA2 Chaperone Contributes to the Maintenance of Epithelial Phenotype of Human Bronchial Epithelial Cells but Has Non-Essential Role in Supporting Malignant Features of Non-Small Cell Lung Carcinoma, MCF7, and HeLa Cancer Cells

Identification of an independent immune-genes prognostic index for breast cancer

Various Anti-HSPA2 Antibodies Yield Different Results in Studies on Cancer-Related Functions of Heat Shock Protein A2

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