Interleukin 7 induces the growth of breast cancer cells through a wortmannin-sensitive pathway

Al-Rawi, Mahir A.; Rmali, Khaled A.; Mansel, Robert Edward; Jiang, Wen Guo

doi:10.1002/bjs.4449

Cited by 27 publications

(20 citation statements)

References 35 publications

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“…Of note, NF-κB complex took part in a hub of the network with the majority of genes regulating the complex to be downregulated. Also, many cancer-related genes such as IL7, S100B and IER3 showed an altered expression pattern 28–30 . Based on the knowledge that FLRT2 is responsible for cellular growth and proliferation, cellular adhesion, and movement, the deregulated genes associated with those pathways were arranged in heat maps (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

Bae

Kim

Lee

et al. 2017

Sci Rep

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To identify dysregulated genes by abnormal methylation and expression in breast cancer, we genome-wide analyzed methylation and expression microarray data from the Gene Expression Omnibus and the Cancer Genome Atlas database. One of the genes screened in silico, FLRT2, showed hypermethylation and downregulation in the cancer dataset and the association was verified both in cultured cell lines and cancer patients’ tissue. To investigate the role of FLRT2 in breast cancer, its expression was knocked down and upregulated in mammary cell lines, and the effect was examined through three levels of approach: pathway analysis; cell activities such as proliferation, colony formation, migration, and adhesion; target gene expression. The top pathway was “Cellular growth and proliferation”, or “Cancer”-related function, with the majority of the genes deregulated in a direction pointing to FLRT2 as a potential tumor suppressor. Concordantly, downregulation of FLRT2 increased cell proliferation and cell migration, while overexpression of FLRT2 had the opposite effect. Notably, cell adhesion was significantly decreased by FLRT2 in the collagen I-coated plate. Taken together, our results provide insights into the role of FLRT2 as a novel tumor suppressor in the breast, which is inactivated by hypermethylation during tumor development.

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Section: Resultsmentioning

confidence: 99%

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

Bae

Kim

Lee

et al. 2017

Sci Rep

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“…Stimulation with exogenous IL-7 induced activation of AKT and JNK, as well as upregulated the expression of CyclinD1 and MMP-9, in HBX-positive cells. In addition to tumor cells, IL-7 was reported to be expressed in immune cells, fibroblasts, and other stromal cells in vivo [43]. This suggests that in the hepatoma microenvironment, IL-7, secreted by the tumor, as well as by other types of cells, contributes to the abnormal activation of IL-7R in hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Kong

Zhou

et al. 2016

J Exp Clin Cancer Res

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BackgroundInterleukin-7 receptor (IL-7R) is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC) are still unclear.MethodsGene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV) plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX). The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-κB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP)-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA). Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated.ResultsThe expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells.ConclusionsOur data demonstrate that HBX can upregulate IL-7R via NF-κB and Notch1 pathways to facilitate the activation of intracellular pathways and expression of associated molecules, and contribute to proliferation and migration of hepatoma cells.

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“…Recurrence-Free Probability IL-7R has been shown to induce tumor growth and lymphangiogenesis through upregulation of VEGF-D. 34,35 Its ligand, IL-7, is produced by stromal and epithelial cells and plays a central role in T-cell development, in addition to providing a potent lymphocyte-survival factor through the JAK-STAT pathway. 36 The role of the IL-7/IL-7R axis in the tumor immune microenvironment in lung ADC warrants more investigation.…”

Section: Prognostic Immune Markers In Stage I Lung Adenocarcinomamentioning

confidence: 99%

Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence

Suzuki

Kadota

Sima

et al. 2013

JCO

185

182

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A B S T R A C T PurposeMounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC). Patients and MethodsUsing tissue microarray and immunohistochemistry, we investigated eight types of tumorinfiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts). ResultsAlthough a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P ϭ .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P ϭ .004). High expression of tumor interleukin-12 receptor ␤2 (IL-12R␤2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P ϭ .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P ϭ .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors Յ 2 cm. ConclusionOur investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.

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Interleukin 7 induces the growth of breast cancer cells through a wortmannin-sensitive pathway

Abstract: IL-7 induced the growth of breast cancer cells in vitro through a wortmannin-sensitive pathway. This may have an important impact on research into breast cancer development and progression.

Cited by 27 publications

References 35 publications

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence

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