Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

Fuady, Jerry H.; Bordoli, Mattia R; Abreu-Rodríguez, Irene; Kristiansen, Glen; Hoogewijs, David; Stiehl, Daniel P.; Wenger, Roland H.

doi:10.2147/hp.s54404

Cited by 12 publications

(9 citation statements)

References 53 publications

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“…We previously reported a HIF-2 specific regulation of WISP-2 expression in breast cancer cells [ 35 ]. Because WISP-2 is a known ERα target gene [ 36 ], we aimed for the analysis of the cooperation between estrogen and oxygen signaling.…”

Section: Resultsmentioning

confidence: 99%

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

et al. 2016

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The involvement of estrogen (E2) and hypoxia in tumor progression is well established. Hypoxia has been reported to activate and degrade estrogen receptor alpha (ERα) in breast cancer cells. Furthermore, E2 has been shown to regulate hypoxia-inducible factor (HIF)-1α protein, but its role in HIF-2α regulation remains largely unexplored. In this study, we found that both HIF-2α mRNA and protein were down-regulated in ER positive but not ER negative breast cancer cells upon treatment with E2. The analysis of 690 samples derived from 608 mixed and 82 triple-negative breast cancer patients revealed that high nuclear HIF-2α tumor levels are associated with a worse prognosis specifically in human epidermal growth factor receptor 2 (HER2) and hormone receptor positive patients. Consistently, ERα/HER2 positive breast cancer cells displayed less pronounced downregulation of HIF-2α by E2. Experiments using a histone deacetylase inhibitor indicate that the E2 mediated decrease in HIF-2α mRNA is due to transcriptional repression. A functional estrogen response element (ERE) was identified in the first intron of the gene encoding HIF-2α (EPAS1), suggesting transcriptional co-repressor recruitment by ERα. Our results demonstrate a novel modulation of HIF-2α in breast cancer cells, explaining the opposing regulation between HIF-1α and HIF-2α in hormone-responsive breast cancer.

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Section: Resultsmentioning

confidence: 99%

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

et al. 2016

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“…SOD3/HIF-2α appears to trigger WNT activation through the autocrine secretion of specific WNT ligands. HIF-2α also transactivates the WISP2 promoter in human EC, 37 which suggests a common regulatory mechanism in humans. Analyses in human CRC support this hypothesis, as SOD3 levels correlated with the percentage of β-cateninstained EC.…”

Section: Sod3/hif-2α/wnt Pathway Induces Laminin α4mentioning

confidence: 93%

“…21 A search for genes whose expression has been reported specifically regulated by HIF-2α identified six potential candidates (including VEC) by which SOD3 might regulate T cell transmigration. We focused on WNT1inducible signaling pathway protein 2 (WISP2/CCN5), a non-conventional WNT ligand of the CCN (cysteine-rich 61 (Cyr61/CCN1)/connective tissue growth factor (CTGF/ CCN2)/nephroblastoma overexpressed gene (NOV/ CCN3)) family, since WISP2 modifies the perivascular environment through its interaction with the integrin α v β 3 35 36 ; WISP2 also modulates the immune cell infiltrate in breast tumors, 37 although to our knowledge, specific effects on T cell migration have not been described.…”

Section: Sod3-hif-2α Upregulates Wnt Ligands In Ecmentioning

confidence: 99%

SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells

Carmona-Rodríguez

Martínez-Rey

Fernández-Aceñero

et al. 2020

J Immunother Cancer

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BackgroundTumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium.ResultsHere we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell–inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program.ConclusionOur findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically “cold” into “hot” tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type–specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.

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“…CCN5 has been implicated as having an important role in carcinogenesis, with particular relevance to human breast disease [ 38 , 41 , 45 – 48 ]. In most studies, CCN5 expression has been shown to correlate inversely with the aggressiveness of cancers in breast [ 38 , 49 , 50 ], pancreas [ 51 , 52 ], salivary gland [ 53 ], gallbladder [ 54 ] and gastric tissue [ 55 ], suggesting tumor suppressor/anti-invasive activity [ 38 , 41 , 52 ]. Thus, at least in BC, CCN5 can be considered a good prognostic marker [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

“…CCN5 regulation in ER-α-positive cells is estrogen, an insulin-like growth factor and HIF-α2-dependent, and its expression has been found to participate in controlling proliferation as well as the aggressive phenotypes of these cells [ 38 , 44 , 50 ]. Thereby, CCN5 depletion in ER-α-positive cells promotes estrogen-independent growth, epithelial-mesenchymal transition (EMT), and stemness, consistent with more invasive phenotypes and display similarities to TNBC.…”

Section: Introductionmentioning

confidence: 99%

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway

et al. 2018

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BackgroundIn menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity.MethodsWe analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells.ResultsPresent studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways.ConclusionsThese studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.

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Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

Cited by 12 publications

References 53 publications

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway

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