The Role of Apelin and Apelin Receptor Expression in Migration and Invasiveness of Colon Cancer Cells

Podgórska, Marta; Pietraszek-Gremplewicz, Katarzyna; Olszańska, Joanna; Nowak, Dorota

doi:10.21873/anticanres.14760

Cited by 14 publications

(10 citation statements)

References 38 publications

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“…However, further insight into tumor endothelium gene expression profile is essential. Certain authors found increased levels of APLN and APJ mRNA expression in colorectal cancer cell lines (Picault et al 2014;PodgOrska et al 2021;Podgorska, Pietraszek-Gremplewicz, and Nowak 2018), which contradicted the findings of this study. As a result, it is reasonable to conclude that the progressive reduction of apelinergic expression in cell culture is a limiting factor in accurately reflecting in vivo settings.…”

Section: Figure 2 Apj Surface Expression On Primary Aml Cells (A) Apj Expression From Aml Patients Whose Cells Were Isolated From Bone Macontrasting

confidence: 99%

“…Future experimental setups should be able to compensate for the loss of both Apelin and APJ. Several authors have partially corroborated the changes in cell migratory features that occur in response to modified apelinergic signaling throughout the course of this study (Podgorska, Pietraszek-Gremplewicz, and Nowak 2018), which is consistent with our findings.…”

Section: Functional Analysessupporting

confidence: 92%

“…The antagonism of APJ was shown to have a mild, but statistically insignificant, influence on the proliferation rates of these cell lines. These findings are in part consistent with prior research, which shown that inhibiting APJ leads to reduced tumor cell growth rates (Podgorska, Pietraszek-Gremplewicz, and Nowak 2018;Neelakantan et al 2019). However, this experimental setting clearly shown that the apelinergic system is not a vital element in tumor cell survival; rather, the involvement of this system as a helping element might be theorized.…”

Section: Functional Analysessupporting

confidence: 92%

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Expression of the apelinergic system and its influence on functional properties of tumor cells

Knežević

Wellbrock

Fuchs

et al. 2021

GenApp

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Small peptide Apelin and its cognate receptor APJ, are known to play a role in tumor angiogenesis and overall cancer progession. Certain authors suggest that the Apelin receptor is also a factor in cancer immunotherapy. In this article, our goal was to study the effects of in vitro targeting of the Apelin/APJ system on the tumor cells functional properties. Protein surface and mRNA expression of Apelin and APJ had been largely examined in various tumor-derived cell lines. In contrast to the tumor tissue, the results of this study demonstrated that most tumor cell lines exhibited somewhat moderate expression of Apelin/APJ. Similar effects of APJ stimulation and inhibition had been observed in in vitro functional assays, which was due to their unusually low expression levels. Low APJ expression in cell lines has been overcome by stable APJ overexpression. In such conditions, stimulation of apelinergic system APJ-overexpressed cells affected cell functional properties in comparison to the wildtype cell lines, where overexpression of APJ receptor resulted in increased migration. On the other hand, no effect on cell proliferation was observed. Consequently, Apelin/APJ signaling in tumor-derived cell lines is not expected to play a direct and crucial role in in vitro cancer survival. Further investigation should focus on in vivo role of the apelinergic system, as demonstrated in the recently published studies, where apelinergic system is claimed to be a promising target for anti-cancer therapy.

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Section: Figure 2 Apj Surface Expression On Primary Aml Cells (A) Apj Expression From Aml Patients Whose Cells Were Isolated From Bone Macontrasting

confidence: 99%

Section: Functional Analysessupporting

confidence: 92%

Section: Functional Analysessupporting

confidence: 92%

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Expression of the apelinergic system and its influence on functional properties of tumor cells

Knežević

Wellbrock

Fuchs

et al. 2021

GenApp

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“…MAGEC3 also upregulates a stress-related gene, WRNIP1 [27], a DNA replication gene, MCM7 [28], and cancer-related genes, XPO5 [29] and ZSCAN16 [30]. In addition, MAGEC3 downregulates genes that are shown to induce tumor progression, including APLMR [31,32], FBLN5 [33], and FNDC1 [34,35]. Gene set enrichment analysis (GSEA) showed that MAGEC3 significantly enriched E2F targets (NES = 3.63, FDR < 0.001), G2/M checkpoint (NES = 3.20, FDR < 0.001), and DNA repair (NES = 2.28, FDR < 0.001), whereas the epithelial to mesenchymal transition was downregulated (NES = −3.34, FDR < 0.001) (Figure 3B).…”

Section: Magec3 Expression Is Associated With Stress-related Processesmentioning

confidence: 99%

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Ellegate

Mastri

Isenhart

et al. 2022

Cancers

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Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially expressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA’s OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson’s r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.

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“…MAGEC3 also upregulates a stress related gene, WRNIP1 [16]; a DNA replication gene, MCM7 [17]; and cancer related genes, XPO5 [18] and ZSCAN16 [19]. In addition, MAGEC3 downregulates genes that are shown to induce tumor progression including APLMR [20,21], FBLN5 [22], and FNDC1 [23,24]. Gene set enrichment analysis (GSEA) showed that MAGEC3 significantly enriched E2F targets (NES=3.63, FDR<0.001), G2/M checkpoint (NES=3.20, FDR<0.001), and DNA repair (NES=2.28, FDR<0.001), whereas the epithelial to mesenchymal transition was downregulated (NES=-3.34, FDR<0.001) (Figure 2B).…”

Section: Magec3 Protein Expression Across Multiple Disease Sites Ffpe Blocks Were Available Frommentioning

confidence: 99%

MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

Ellegate

Mastri

Isenhart

et al. 2021

Preprint

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Rare variants in MAGEC3, members of the melanoma antigen gene family, are associated with BRCA-independent early onset ovarian cancers, while somatic mutations of this gene have been associated with kidney cancers. In this report, we quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in N=394 ovarian cancers and N=220 renal cell carcinomas. MAGEC3 protein levels fell into two categories – normal MAGEC3 and MAGEC3 loss – characterized by expression equivalent to normal tissue or significantly lower than normal tissue, respectively. Interestingly, cases with MAGEC3 loss demonstrated better overall survival in both ovarian cancers and renal cell carcinomas, which resembles patient outcomes with BRCA2 loss. MAGEC3 protein expression was associated with upregulation of pathways regulating G2/M checkpoint (NES: 4.13, FDR<0.001) and mitotic spindle formation (NES: 2.84, FDR<0.001). Increased CD8+ cell infiltration, coordinate expression of other cancer testis antigens, and tumor mutational burden were also associated with MAGEC3 expression. To emphasize the impact of these results, we built a prognostic RNA-based model using N=180 cancers of an independent cohort with matching transcriptomic data and tested its performance in two large public cohorts (N=282 ovary and N=606 kidney). Results based on predicted protein scores within these patients validated those discovered in patients with directly measured MAGEC3 protein. The RNA model was reproduced in independent cohorts implying a broader potential for MAGEC3-driven disease etiology and relevance to potential treatment selection.STATEMENT OF TRANSLATIONAL RELEVANCEMAGEC3 protein is expressed in multiple tissues and is dysregulated in cancer. In this work, we show that ovarian and kidney cancer patients with loss of MAGEC3 protein have favorable prognosis, indicating that MAGEC3 protein level may be used as a prognostic biomarker. Integrative genomic analysis of patients spanning more than nine cancer types showed an association between MAGEC3 protein and genes affecting stress response, including those involved in cell cycle and DNA damage repair. Additionally, it is correlated with tumor mutational burden in patients with mutated oncogenes. These associations suggest that MAGEC3 protein levels may be used to identify patients with deficient DNA damage repair mechanisms that can be targeted by PARP inhibitors. To operationalize this idea, we use machine learning to predict MAGEC3 protein levels from RNA sequencing data which can facilitate the identification of patients for treatment stratification according to their MAGEC3 status.

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The Role of Apelin and Apelin Receptor Expression in Migration and Invasiveness of Colon Cancer Cells

Cited by 14 publications

References 38 publications

Expression of the apelinergic system and its influence on functional properties of tumor cells

Expression of the apelinergic system and its influence on functional properties of tumor cells

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

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