Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high‐level immune infiltration status

Li, Hanning; Li, Xingrui; Lv, Zheng‐tao; Cai, Miaomiao; Wang, Ge; Yang, Zhaohui

doi:10.1002/cam4.3543

Cited by 22 publications

(23 citation statements)

References 48 publications

(89 reference statements)

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“…In particular, knockout of FRAS1 inhibits proliferation of gastric cancer cells through caspase activity increment and cell cycle arrest both in vitro and in vivo [49]. Conversely, increased expression of FREM1 in breast cancer is associated with a favorable prognosis and high-level immune infiltration status [50].…”

Section: Discussionmentioning

confidence: 99%

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

Zolotovskaia

Tkachev

Sorokin

et al. 2021

Cancers

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Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10−13, AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.

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Section: Discussionmentioning

confidence: 99%

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

Zolotovskaia

Tkachev

Sorokin

et al. 2021

Cancers

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“… 8 FREM1, in contrast, has been identified as an essential component for embryonic development and involves immune cell migration. 6 , 9 FREM1 gene (encoding 2179 amino acids) has ~15 splice variants, 10 , 11 including TILRR (encoding 715 amino acids). 6 As a shorter isoform of FREM1, the transcriptional start site of TILRR is present in an intronic segment between exons 24 to 25 of the FREM1 gene.…”

Section: Introductionmentioning

confidence: 99%

TILRR (Toll-like Interleukin-1 Receptor Regulator), an Important Modulator of Inflammatory Responsive Genes, is Circulating in the Blood

Kashem¹,

Yuan²,

et al. 2021

JIR

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Purpose TILRR (Toll-like interleukin-1 receptor regulator), a variant of FREM1 (Fras-related extracellular matrix 1), is a modulator of many genes in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and inflammatory responses. It enhanced the expression of multiple genes in the NF-κB signaling pathway and promoted the production of multiple pro-inflammatory cytokines/chemokines. TILRR is an extracellular matrix protein and expressed in cells and tissues, and has never been considered to exist in the blood. The study aimed to identify circulating TILRR protein in human plasma as a biomarker of systemic inflammation. Methods and Results We developed a multiplex bead array method (Bio-Plex) using 4 monoclonal antibodies targeting different protein domains of FREM1/TILRR to investigate whether TILRR can be detected in blood plasma. The results of the multiplex bead array method were validated by Western blot analysis of affinity-purified TILRR from patient plasma samples. We subsequently analyzed 640 plasma samples from women enrolled in the Pumwani Sex Worker cohort (PSWC) (Nairobi, Kenya). Our study showed that TILRR exists in all patient plasma samples, but its quantities vary greatly among the patients, ranging from 2.38 ng/mL to 5196.79 ng/mL. The plasma TILRR below 2.38 ng/mL can only be detected by affinity purification and Western blot analysis. Conclusion Our in-house developed multiplex bead array method can successfully quantify TILRR protein in plasma samples. Because TILRR is an important modulator of many inflammation-responsive genes, it may be an inflammation biomarker in blood and play a role in modulating systemic inflammation.

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“…Because FREM1 is an extracellular matrix protein and widely expressed in the regions of epithelial-mesenchymal interaction [3], its expression in epithelial tissues may promote immune cell infiltration. Using immunohistochemistry (IHC) and immunofluorescence (IF) assays, a study demonstrated that elevated expression of FREM1 in normal breast/mammary epithelial tissues is positively correlated with the in-filtration of several immune cells, such as CD4+, and CD8+T -cells, and M1 (inflammatory) macrophages [47]. In addition, analysis of breast cancer (BC) epithelial tissues showed that high FREM1-expressed BC tissues harbor abundant CD4+T memory cells (resting and activated), CD8+T-cells, M1 macrophages, resting dendritic cells, gamma-delta T cells (γδT), B-cells (naive and memory), plasma cells, and resting mast cells.…”

Section: Frem1 and Immune Cell Infiltrationmentioning

confidence: 99%

“…In addition, analysis of breast cancer (BC) epithelial tissues showed that high FREM1-expressed BC tissues harbor abundant CD4+T memory cells (resting and activated), CD8+T-cells, M1 macrophages, resting dendritic cells, gamma-delta T cells (γδT), B-cells (naive and memory), plasma cells, and resting mast cells. Contrastingly, low FREM1-expressed BC tissues tended to have a higher proportion of M2 (anti-inflammatory) macrophages, neutrophils, and resting NK (natural killer) cells [47]. It has also been shown that the RGD motif of ECM binds with integrins and promotes migration of effector T cells into the interstitial inflamed tissues [48].…”

Section: Frem1 and Immune Cell Infiltrationmentioning

confidence: 99%

“…Since cervical epithelial tissues express a high level of FREM1 mRNA [15], and TILRR is an isoform of FREM1 [60] and a major modulator of many inflammatory responsive genes in the NF-κB pathway [16], the expression of FREM1/TILRR in genital epithelial tissues may augment the inflammatory responses via NF-κB activation and the production of inflammatory mediators. We, therefore, propose a model depicting the potential roles of FREM1/TILRR in vaginal HIV-1 acquisition through mediating inflammation (Figure 4A-D) based on our in vitro studies [16,69], a genetic study [15] and a number of related publications [24,25,47,58,70]. , the high-level expression of FREM1/TILRR increases the production of pro-inflammatory cytokines/chemokines by epithelial cells [16].…”

Section: Potential Role Of Frem1 and Its Isoform Tilrr In Vaginal Hiv-1 Acquisitionmentioning

confidence: 99%

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The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation

Kashem

Liu

et al. 2021

IJMS

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FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.

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Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high‐level immune infiltration status

Abstract: Zhi-fang Yang 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 22 publications

References 48 publications

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

TILRR (Toll-like Interleukin-1 Receptor Regulator), an Important Modulator of Inflammatory Responsive Genes, is Circulating in the Blood

The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation

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