Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

Jeon, Youkyoung; Park, Sae-Gwang; Choi, Il‐Whan; Lee, Soo-Woong; Lee, Sang Min; Choi, Inhak

doi:10.1016/j.bbrc.2015.02.098

Cited by 29 publications

(19 citation statements)

References 24 publications

(28 reference statements)

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“…The transcriptional regulation of VTCN1 is not well understood compared to that of PD‐L1 . Recently, HIF1A has been shown to induce VTCN1 in multiple myeloma, cervical, and breast cancer cell lines (Jeon et al , ), which may be a part of the mechanism by which VTCN1 is regulated in IMA. As shown in Fig C, a transcription factor ELF3 , which is expressed in human IMA, was highly correlated with VTCN1 in both the 105 human NSCLC cell lines (Klijn et al , ) and the 230 TCGA LUAD cases (Cancer Genome Atlas Research Network, ), suggesting that ELF3 may be a regulator of VTCN1 .…”

Section: Discussionmentioning

confidence: 99%

Gene signature driving invasive mucinous adenocarcinoma of the lung

et al. 2017

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Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin‐producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7‐H4 (but not PD‐L1/B7‐H1). Importantly, induction of FOXA3 or SPDEF along with mutant KRAS in lung epithelium was sufficient to develop benign or malignant mucinous lung tumors, respectively, in transgenic mice. FOXA3 and SPDEF induced MUC5AC and MUC5B, while HNF4A induced MUC3 in human mucinous lung cancer cells harboring a KRAS mutation. ChIP‐seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the mucin genes MUC5AC and MUC5B, which were bound by SPDEF, were required for the expression of the mucin genes. Here, we report the molecular signature and gene regulatory network driving mucinous lung tumors.

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Section: Discussionmentioning

confidence: 99%

Gene signature driving invasive mucinous adenocarcinoma of the lung

et al. 2017

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“…In addition, culture of lung cell carcinoma (LCC) cell line with TAM‐derived IL‐10 or TNFα resulted in the surface B7S1 expression on tumor cells . Hypoxia is another factor that upregulates B7S1 transcription in primary CD138 + multiple myeloma cells and cancer cell lines . Hypoxia‐inducible factor‐1alpha (HIF‐1alpha) can bind to proximal hypoxia‐response element sites within the B7S1 gene promoter.…”

Section: B7s1 In Cancer Immunotherapymentioning

confidence: 99%

New checkpoints in cancer immunotherapy

Dong

2017

Immunological Reviews

128

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Summary Immune responses must be fine‐tuned to allow effective clearance of invading pathogens, while maintain tolerance to self‐antigens. T cells are the major effector cells for fighting and killing tumor cells. Immune checkpoints play a pivotal role in T cell activation, and determine the functional outcome of T cell receptor (TCR) signaling. The blockade of immune checkpoints CTLA‐4 and PD‐1 has already been one of the most successful cancer immunotherapies. In this review, we will focus on three novel inhibitory B7 family checkpoint molecules, B7‐H3, B7S1 and VISTA. The aim of this article is to summarize their expressions in tumors as well as their roles in controlling and suppressing T cell immune responses and anti‐tumor immunity. These pathways may be explored in future cancer immunotherapy.

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“…For example, the multiple myeloma bone marrow microenvironment has been shown to be hypoxic . A recent study demonstrated that hypoxia upregulated B7‐H4 expression in primary CD138‐positive multiple myeloma cells and cancer cell lines . While most of the discussed studies focused on the triggering factors involved in B7‐H4 expression, the signaling pathways that participate in B7‐H4 expression remain largely unknown.…”

Section: B7‐h4 Expression and Cancermentioning

confidence: 99%

“…Similarly, B7‐H4 expression by tumor cells is a putative mechanism by which these cells evade anti‐tumor immune responses. In the majority of breast and ovarian cancers, B7‐H4 mRNA is expressed at approximately twofold or greater than the level expressed within normal tissue, and B7‐H4 protein is present in half of early stage and two‐thirds of late stage ovarian tumors . Additionally, tissues from breast, uterus, ovary, colon, and pancreas tumors showed a statistically significant increase in the percentage of cells expressing B7‐H4 .…”

Section: Functional Connection Between B7‐h4 and Tregsmentioning

confidence: 99%

“…76 A recent study demonstrated that hypoxia upregulated B7-H4 expression in primary CD138-positive multiple myeloma cells and cancer cell lines. 77 While most of the discussed studies focused on the triggering factors involved in B7-H4 expression, the signaling pathways that participate in B7-H4 expression remain largely unknown. The complexity of the tumor microenvironment may significantly affect B7-H4 expression and distinct molecular mechanisms of such regulation also require further elucidation.…”

Section: B7-h4 Expression and Cancermentioning

confidence: 99%

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Potential targeting of B7‐H4 for the treatment of cancer

Podojil

Miller

2017

Immunological Reviews

125

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Summary Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor-specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7-H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7-H4 is supported by the high levels of B7-H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7-H4 has been associated with decreased inflammatory CD4+ T-cell responses and a correlation between B7-H4-expressing tumor-associated macrophages and FoxP3+ regulatory T cells (Tregs) within the tumor microenvironment. Since B7-H4 is expressed on tumor cells and tumor-associated macrophages in various cancer types, therapeutic blockade of B7-H4 could favorably alter the tumor microenvironment allowing for antigen-specific clearance tumor cells. The present review highlights the therapeutic potential of targeting B7-H4.

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Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

Cited by 29 publications

References 24 publications

Gene signature driving invasive mucinous adenocarcinoma of the lung

Gene signature driving invasive mucinous adenocarcinoma of the lung

New checkpoints in cancer immunotherapy

Potential targeting of B7‐H4 for the treatment of cancer

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