NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

Smith, Shannon M.; Lyu, Yi Lisa; Cai, Li

doi:10.1371/journal.pone.0106966

Cited by 93 publications

(76 citation statements)

References 46 publications

(65 reference statements)

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“…Among the different genes found to be up-regulated in RL cells obtained from co-cultures with neutrophils and vincristine ( Supplementary Table 2 ), CD44 was among the most strongly over-expressed. As CD44 is another adhesion molecule involved in regulating cell proliferation [ 32 – 34 ], we used blocking antibody recognizing CD44 and observed abrogation of the neutrophil-induced protection of RL cell proliferation in the presence of vincristine (Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding

et al. 2017

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Innate immune cells constitute a substantial proportion of the cells within the tumor microenvironment. Besides the contribution of the microenvironment to tumor proliferation and survival, there is direct evidence that interactions between tumor cells and their microenvironment alter sensitivity to anti-cancer agents. Neutrophils, a key player in the innate immune system, have been less studied than many other immune cells regarding their impact on cancer cell response to anti-cancer agents. In our 2D and 3D coculture systems, human neutrophils and differentiated HL60 cells attenuated the sensitivity of various lymphoma cell lines to several anti-cancer agents, including targeted therapies. Neutrophil-induced protection was dependent on cell-cell interaction between CD11b and ICAM-1 expressed by neutrophils and B cells, respectively and was shown to be Mcl-1-dependent. The protective effect of neutrophils was validated in vivo using immune-compromised mice inoculated with human NHL with our without neutrophils then followed by treatment with chemotherapy. Similar findings were made on primary cells purified from patients with chronic lymphocytic leukemia, treated with fludarabine or targeted agents in the presence of autologous neutrophils. In a clinical study, patients with non-Hodgkin's lymphoma with increased neutrophil counts displayed a reduced response rate to therapy. These findings reveal a novel protective mechanism of neoplastic B cells involving innate immune cells which could be pharmacologically targeted to enhance the antitumor effect of therapy.

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Section: Resultsmentioning

confidence: 99%

Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding

et al. 2017

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“…In HuH7 and mNeat1v1-overexpressing HepG2 cells, the expression of CD44s was observed, while other splicing variants were not detected. It has been reported that CD44 expression in tumor cells is regulated by transcription factors and miRNAs [33][34][35][36][37]. A lncRNA, gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC), also induces CD44 expression by suppressing miR-221, a CD44-targeting miRNA [33].…”

Section: Discussionmentioning

confidence: 99%

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

Koyama

Tsuchiya

Amisaki

et al. 2020

IJMS

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CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner.

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“…Elastase‐cleaved CD40 signaling is mediated through the binding and interactions of TRAF1 and 2 within the intracellular domain of CD40, resulting in nuclear translocation, upregulation of NFκB transcriptional activity, and an increase in the expression of NFκB target genes. We investigated the effects of HNE on the expression levels of several NFκB target genes known to be involved in promoting breast cancer cell migration ( ICAM‐1 , CXCR4 , CD44 ) . MDA‐MB‐231 cells were treated with 100 n m HNE for different lengths of time, and gene expression was assessed by RT‐qPCR.…”

Section: Resultsmentioning

confidence: 92%

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

2018

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Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides, named loggerpeptins A-C (1-3), along with molassamide (4), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFκB activation, we assessed the effects of 4 on the expression of target genes, including ICAM-1. ICAM-1 is also a direct target of elastase and, in our studies, compound 4 attenuated both elastase-induced ICAM-1 gene expression and ICAM-1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase-mediated migration of highly invasive triple-negative breast cancer cells.

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NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

Cited by 93 publications

References 46 publications

Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding

Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

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