Downregulation of <scp>AGR</scp>2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma

Alves, Mariana Rezende; Melo, Natália Cruz e; Barros-Filho, Mateus Camargo; Amaral, Nayra Soares do; Silva, Felipe Ilelis de Barros; Baiocchi, Glauco; Soares, Fernando Augusto; Brot, Louise De

doi:10.1002/cam4.1530

Cited by 18 publications

(16 citation statements)

References 48 publications

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“…Through the interaction with the proliferating cell nuclear antigen (PCNA),/p21 was able to inhibit DNA replication (Rossig et al, 2001). Our current study showed that p21 was highly expressed in normal tissues but reduced in ovarian cancer tissues, which was associated with better survival of patients, consistent with a previous study (Alves et al, 2018). Indeed, a previous study demonstrated that pyridine derivative-induced ovarian cancer cell senescence occurred through p21 activation (Shang et al, 2018).…”

Section: Discussionsupporting

confidence: 92%

Prognostic values of GMPS, PR, CD40, and p21 in ovarian cancer

Wang

Zhang

et al. 2019

PeerJ

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Early detection and prediction of prognosis and treatment responses are all the keys in improving survival of ovarian cancer patients. This study profiled an ovarian cancer progression model to identify prognostic biomarkers for ovarian cancer patients. Mouse ovarian surface epithelial cells (MOSECs) can undergo spontaneous malignant transformation in vitro cell culture. These were used as a model of ovarian cancer progression for alterations in gene expression and signaling detected using the Illumina HiSeq2000 Next-Generation Sequencing platform and bioinformatical analyses. The differential expression of four selected genes was identified using the gene expression profiling interaction analysis (http://gepia.cancer-pku.cn/) and then associated with survival in ovarian cancer patients using the Cancer Genome Atlas dataset and the online Kaplan–Meier Plotter (http://www.kmplot.com) data. The data showed 263 aberrantly expressed genes, including 182 up-regulated and 81 down-regulated genes between the early and late stages of tumor progression in MOSECs. The bioinformatic data revealed four genes (i.e., guanosine 5′-monophosphate synthase (GMPS), progesterone receptor (PR), CD40, and p21 (cyclin-dependent kinase inhibitor 1A)) to play an important role in ovarian cancer progression. Furthermore, the Cancer Genome Atlas dataset validated the differential expression of these four genes, which were associated with prognosis in ovarian cancer patients. In conclusion, this study profiled differentially expressed genes using the ovarian cancer progression model and identified four (i.e., GMPS, PR, CD40, and p21) as prognostic markers for ovarian cancer patients. Future studies of prospective patients could further verify the clinical usefulness of this four-gene signature.

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Section: Discussionsupporting

confidence: 92%

Prognostic values of GMPS, PR, CD40, and p21 in ovarian cancer

Wang

Zhang

et al. 2019

PeerJ

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“…The prognostic value of AGR2 remains largely inconclusive. A study demonstrated that higher level of AGR2 was related to less aggressive tumors and better prognosis in epithelial ovarian carcinoma 27 , which is in line with Ames and colleagues who found absence of AGR2 was associated with increased malignancy and tumor progression, and relapse in endometrioid and muinous subtypes 28 . AGR2 overexpression was found to contributed to the poor OS in lung cancer 29 , whereas another study showed that AGR2 overexpression did not show any prongnostic value in non-small-cell lung cancer 30 .…”

Section: Dicussionsupporting

confidence: 75%

Integrative analysis of AGR2 based on data mining reveals new insights in breast cancer

Zhou¹,

Zhang²,

Liu³

et al. 2020

Preprint

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Background: Belonging to the protein disulfide isomerase (PDI) family, anterior gradient 2 (AGR2) is overexpressed in mucus-secreting cells and endocrine organs such as breast, lung, and ovarian, but its exact function and regulation remain unclear. We aimed to perform integrative analysis of AGR2 in breast cancer.Methods: In our study, a serious of bioinformatic online databases were used to analyze the expression, regulation, prognostic value, and function of AGR2 in breast cancer.Results: The results suggested that AGR2 mRNA was overexpressed in non-basal-like or non-triple-negative breast cancer, but underexpressed in basal-like/ triple-negative breast cancer. AGR2 mRNA expression was correlated with its protein expression. Moreover, the expression of AGR2 was lower in more malignant breast cancer. Furthermore, we also found that DNA methylation, rather than copy number variation, led to AGR2 mRNA overexpression. Prognosis analysis showed no significant correlation between AGR2 level and survival, but in subtype investigation, patients with higher AGR2 level had a significantly better outcome in patients with basal-like / triple-negative breast cancer. Enrichment analysis for co-expression genes of AGR2 revealed that gene sets enriched for chromosome segregation, DNA conformation change, chromosomal region, and GABA receptor activity may play important roles in breast cancer, and that the most significant pathway was “ribosome biogenesis in eukaryotes”, in which negative co-expression genes of AGR2 were enriched.Conclusions: Overexpression of AGR2 was found in less malignant breast cancer, for the first time, our results propose that DNA methylation rather than copy number variation leads to AGR2 overexpression, which can predict favorable prognosis in basal-like/ triple-negative breast cancer, and AGR2 could be a possible regulator of ribosome biogenesis in patients with breast cancer.

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“…Therefore, various studies have attempted to elucidate the mechanisms of resistance to overcome or delay the resistance of NSCLC cells (22,23,25,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). In addition, recent comprehensive proteomic technologies display a great opportunity to investigate novel clinically relevant oncogenic pathways that may have been over-looked by cancer gene screens (46,47). AGR2, one of these recently discovered oncogenes related to p53, is directly involved in malignant transformation and is able to act as a survival factor through drug resistance (48).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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Background/Aim: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. Materials and Methods: Using datasets from a pair of NSCLCsensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. Results: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. Conclusion: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide, and comprises 85% of all lung cancer cases (1). Acquired drug resistance in tumor cells is a major obstacle in the field of anti-cancer chemotherapies. Likewise, NSCLC patients who initially show a good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib (Gef), acquire resistance to treatment (2). However, studies on the mechanisms through which overexpression of specific genes is involved in EGFR-TKI resistanse of NSCLC cells are scarce and its role remains to be elucidated. Therefore, novel approaches are required to elucidate their role in drug resistanse of cancer cells. The anterior gradient-2 (AGR2) has been identified in Xenopus laevis and plays a critical role in cemet gland differentiation (3). Recent studies have suggested that elevated expression of AGR2 is correlated with cell proliferation, metastasis, and drug resistance in various human cancer cell lines, such as prostate (4), breast (5), and pancreatic cancer (6). Moreover, overexpression of AGR2 has been notably correlated with a poor outcome of estrogen receptor-negative breast cancer patients (7). AGR2 is also a pro-oncogenic protein that has been shown to stimulate the epidermal growth factor receptor (EGFR) ligand amphiregulin, regulate p53 signaling, and interact with the AAA+ protein Reptin (8), suggesting its modulatory roles in gene expression. High expression of AGR2 has also been shown to be predictive of poor survival in lung cancer (9). However, there is still a lack of insightful understanding of the role of AGR2 in EGFR-TKI-resistant NSCLC cells. There are 19 members of zinc-dependent metalloproteases in the family of a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) (10). Recent reports suggest the critical roles of ADAMTSs in angiogenesis and cancer (11). They also play an important role in the modulation of extracellular matrix. For instance, ADAMTS-1 metallopro...

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Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma

Cited by 18 publications

References 48 publications

Prognostic values of GMPS, PR, CD40, and p21 in ovarian cancer

Prognostic values of GMPS, PR, CD40, and p21 in ovarian cancer

Integrative analysis of AGR2 based on data mining reveals new insights in breast cancer

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

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