THE YKI-CACTUS (IKBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA

Mapping Intimacies ◽

10.1101/2020.08.16.253005 ◽

2020 ◽

Author(s):

Kirti Snigdha ◽

Amit Singh ◽

Madhuri Kango-Singh

Keyword(s):

Tumor Progression ◽

Tumor Cells ◽

Critical Role ◽

Suppressor Gene ◽

Inflammatory Factors ◽

Oncogenic Signaling ◽

Jnk Pathway ◽

Target Matrix ◽

Necrosis Factor

AbstractPresence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved in Drosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We used Drosophila tumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms of RasV12 or its major effector Yorkie (Yki3SA) in polarity deficient cells mutant for tumor suppressor gene scribble (scrib) marked by GFP under nubGAL4 or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth of Yki3SAscribRNAi or RasV12scribRNAi tumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated in Yki3SAscribRNAi or RasV12scribRNAi tumors. Drosophila Cactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.

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NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽

10.3390/cancers13122999 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2999

Author(s):

Deborah Reynaud ◽

Roland Abi Nahed ◽

Nicolas Lemaitre ◽

Pierre-Adrien Bolze ◽

Wael Traboulsi ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Major Gene ◽

Critical Role ◽

Orthotopic Model ◽

Independent Manner ◽

Maternal Immune Response ◽

The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽

10.3390/metabo11030180 ◽

2021 ◽

Vol 11 (3) ◽

pp. 180

Author(s):

Christina Mertens ◽

Matthias Schnetz ◽

Claudia Rehwald ◽

Stephan Grein ◽

Eiman Elwakeel ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Lung Metastases ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Lipocalin 2 ◽

Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

International Journal of Molecular Sciences ◽

10.3390/ijms22094370 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4370

Author(s):

Cássia de Fáveri ◽

Paula M. Poeta Fermino ◽

Anna P. Piovezan ◽

Lia K. Volpato

Keyword(s):

Intracellular Signaling ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Critical Role ◽

Integrative Review ◽

Inflammatory Factors ◽

Resolvin D1 ◽

Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

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Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice

International Journal of Chronic Obstructive Pulmonary Disease ◽

10.2147/copd.s108919 ◽

2016 ◽

Vol Volume 11 ◽

pp. 1705-1712 ◽

Cited By ~ 7

Author(s):

Masaki Fujita ◽

Ouchi Hiroshi ◽

Satoshi Ikemage ◽

Eiji Harada ◽

Takemasa Matsumoto ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Pulmonary Emphysema ◽

Tumor Necrosis ◽

Critical Role ◽

Tumor Necrosis Factor Receptor ◽

Necrosis Factor

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P01.01 The role of exosome miRNA between tumor cells and microglias during the progression of medulloblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz126.079 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii24-iii24

Author(s):

Q Chang ◽

L Zhu ◽

N Li

Keyword(s):

Tumor Cells ◽

Critical Role ◽

Expression Level ◽

Migration And Invasion ◽

Specific Marker ◽

Migration Ability ◽

Daoy Cell ◽

Bv2 Cells ◽

Close Relationship

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant paediatric brain tumor. Recent studies show that M2 cells were relative more abundant in Shh subtype of MBs compared with other three subtypes. It’s known that M2 cells have close relationship with many tumors’ progression. But if they play any role in the progression of Shh subtype of MB is not yet clear. Many studies demonstrate that exosomes carring miRNAs have close relationship with tumor invasion. The aim of present study is to clarify the role of exosome miRNA between tumor cells and microglias during the progression of Shh subtype of medulloblastoma. MATERIAL AND METHODS Immunofluerescence staining using iNOS and Arg1, which is M1 and M2 specific marker, respectively, was performed in four subtypes of MBs. After coculture of exosomes extracted from Shh subtype of MB cell (DAOY) with microglia cell (BV2), Q-PCR and ELISA assay were done to evaluate the polarization status of the microglia. Transwell and scratch assay were then performed to detect the migration ability of DAOY cell after treatment of exosomes from polirized M2 cells. MiRNA sequencing by Ion Proton technology was then done to analyze the miRNAs expression level between Shh subtype and other subtype of MBs. Transformation assay was used to overexpress and inhibit the expression of these miRNAs respectively to further clarify the role of exosome miRNA in the polarization of BV2 cells. RESULTS M2 cells were observed more abundant than other three subtypes of tumors, supporting that M2 cells play some role in this subtype of MBs. Exosomes of DAOY cells can induce the polarization of M2 cells. The polarized M2 cells can improved the migration and invasion ability of DAOY cell. Dozens of miRNAs were identified with different expression level between Shh subtype of MBs and other subtype of MB cells. Among them, 4 miRNAs were reported to be related with polariztion of M2 in many other lesions. Three of the 4 miRNAs can induce the polarization of M2 in present study. CONCLUSION Our study demonstrated exosome miRNA play a critical role between tumor cells and microglias during the progression of Shh subtype of medulloblastoma.

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Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21103681 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3681

Author(s):

Momoko Nakao ◽

Tomomitsu Miyagaki ◽

Makoto Sugaya ◽

Shinichi Sato

Keyword(s):

Critical Role ◽

Skin Inflammation ◽

Interferon Α ◽

Toll Like Receptor ◽

Adaptive Immune ◽

Th17 Cytokines ◽

Factor Α ◽

Deficient Mice ◽

Necrosis Factor

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

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