Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression

Liu, Xiulan; Zhou, Zhongshi; Cheng, Qi; Wang, Hongjie; Cao, Hui; Xu, Qianqian; Tuo, Yali; Jiang, Li; Zhang, You; Ren, Hao; Xiang, Ming

doi:10.1038/cddis.2017.424

Cited by 27 publications

(25 citation statements)

References 43 publications

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“…Regenerating islet‐derived protein 3‐gamma (Reg3g) has been associated with colonic Paneth cell stemness and survival 28 . Two recent studies have revealed a novel immunosuppression role of Reg3g that weakens tumor‐specific antigenicity and suppresses antitumor effects of CD8+ T cells in murine models of pancreatic cancer, by activating the JAK2/STAT3 signaling pathway in DCs 29,30 . Lipocalin‐2/NGAL has been shown to be overexpressed in many solid cancers.…”

Section: Discussionmentioning

confidence: 99%

“…28 Two recent studies have revealed a novel immunosuppression role of Reg3g that weakens tumor-specific antigenicity and suppresses antitumor effects of CD8+ T cells in murine models of pancreatic cancer, by activating the JAK2/STAT3 signaling pathway in DCs. 29,30 Lipocalin-2/NGAL has F I G U R E 3 Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) detection of mRNA of selected genes/ proteins normalized to β-actin for validation of proteomic and microarray platforms. Missing columns were due to either missing hybridization probes (microarray) or lack of protein detection sensitivity by iTRAQ proteomics.…”

Section: Validation Of Differential Expression Of Selected Genes Anmentioning

confidence: 99%

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Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Zhang

Kim

et al. 2020

The Prostate

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Background The prostate‐specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene‐conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten‐KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures. Methods For proteomics, four pairs of whole prostates from tissue‐specific conditional knockout Pten‐KO mice (12‐15 weeks of age) and their respective wild‐type littermates housed in the same cages were analyzed by 8‐plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real‐time quantitative reverse transcription‐polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks. Results At the macromolecular level, proteomic and transcriptomic analyses complement and cross‐validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten‐KO prostate tumors. Suppressed expression patterns in the Pten‐KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor‐kappaB, and P53 in the Pten‐KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten‐KO prostate tumors. Conclusions Our work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho‐ and immunobiology of Pten‐loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.

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Section: Discussionmentioning

confidence: 99%

Section: Validation Of Differential Expression Of Selected Genes Anmentioning

confidence: 99%

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Zhang

Kim

et al. 2020

The Prostate

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“…Based on our previous work, and that of other labs, DC dysfunction in tumors might be a consequence of soluble factors secreted by cancer cell into the TME. These soluble factors include Reg3 g, IL-6, and IL-10 in tumor-conditioned medium (Liu et al, 2017a;Wang et al, 2016). To elucidate whether tumor-conditioned medium suppressed BMDC maturation via elevated H3K79me2-FOXM1 expression, we conducted an in vivo experiment pretreating BMDCs from wild-type mice with conditioned medium from Panc02 or CT-26 cells, mimicking TME, before pulsing them with EPZ or Thiostrepton.…”

Section: Tumor-conditioned Medium Inhibited Bmdc Maturation Via H3k79mentioning

confidence: 99%

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

et al. 2019

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Forkhead box transcription factor M1 ( FOXM 1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells ( DC s). Although previous work has shown that FOXM 1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM 1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM 1 in regulating bone marrow‐derived dendritic cell ( BMDC ) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM 1 retarded maturation phenotypes of BMDC s, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 ( IL ‐12) p70 in tumor‐bearing mice ( TBM ). Notably, FOXM 1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDC s. Increased H3K79me2 enrichment was observed at the FOXM 1 promoter in both BMDC s from TBM , and in BMDC s from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment ( TME ). Furthermore, inhibition of the H3K79 methyltransferase DOT 1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM 1 and partially reversed its immunosuppressive effects on BMDC s. Furthermore, we found that FOXM 1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDC s in vitro ; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM 1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM 1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDC s through the Wnt5a signaling pathway, and thus provide novel insights into FOXM 1‐based antitumor immunotherapy.

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“…4A). Notably, several of these genes such as Vsig4, Deptor, Reg3g, Hgfac, and Cxcl13 encode proteins with previously identified roles in promoting tumor invasion and migration or influencing immune responses (22)(23)(24) or denote protumorigenic macrophage phenotypes such as Cd163 and Vsig4 (25,26).…”

Section: Alterations In Macrophage Populations Distinguish Prostate Cmentioning

confidence: 99%

The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells

Bianchi‐Frias

Damodarasamy

Hernández

et al. 2019

Molecular Cancer Research

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The incidence of prostate cancer is directly linked to age, but age-associated changes that facilitate prostate cancer development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on prostate cancer behavior. Prostate cancer cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared with young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis, or angiogenesis. However, analysis of tumor-infiltrating immune cells by IHC and RNA sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling protumorigenic tumor-associated macrophages upon tumor cell engraftment. Older patients with prostate cancer (>60 years old) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset displayed higher expression of macrophage markers (CD163 and VSIG4) which associated with higher rates of biochemical relapse. Remodeling of the collagenous extracellular matrix (ECM) was associated with prostate cancer growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of prostate cancer cells Together, these results demonstrate that the aged prostatic microenvironment can regulate the growth and metastasis of malignant prostate cells, highlighting the role of resident macrophages and their polarization towards a protumorigenic phenotype, along with remodeling of the ECM. These findings demonstrate the importance of age-associated tumor microenvironment alterations in regulating key aspects of prostate cancer progression.

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Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression

Cited by 27 publications

References 43 publications

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Proteomic and transcriptomic profiling of Pten gene‐knockout mouse model of prostate cancer

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells

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