scholarly journals Salmonella Impacts Tumor-Induced Macrophage Polarization, and Inhibits SNAI1-Mediated Metastasis in Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2894
Author(s):  
Christian R. Pangilinan ◽  
Li-Hsien Wu ◽  
Che-Hsin Lee
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Lung Metastases ◽  
Macrophage Polarization ◽  
Interleukin 1 ◽  
Mammalian Target Of Rapamycin ◽  
High Mobility ◽  
Treated Group ◽  
Mesenchymal Transition ◽  
Oxide Synthase

Targeting metastasis is a vital strategy to improve the clinical outcome of cancer patients, specifically in cases with high-grade malignancies. Here, we employed a Salmonella-based treatment to address metastasis. The potential of Salmonella as an anticancer agent has been extensively studied; however, the mechanism through which it affects metastasis remains unclear. This study found that the epithelial-to-mesenchymal transition (EMT) inducer SNAI1 was markedly reduced in Salmonella-treated melanoma cells, as revealed by immunoblotting. Furthermore, wound healing and transwell assays showed a reduced in vitro cell migration following Salmonella treatment. Transfection experiments confirmed that Salmonella acted against metastasis by suppressing protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, which in turn inhibited SNAI1 expression. Since it is known that metastasis is also influenced by inflammation, we partly characterized the immune infiltrates in melanoma as affected by Salmonella treatment. We found through tumor-macrophage co-culture that Salmonella treatment increased high mobility group box 1 (HMGB1) secretion in tumors to coax the polarization of macrophages in favor of an M1-like phenotype, as shown by increased inducible nitric oxide synthase (iNOS) expression and Interleukin 1 Beta (IL-1β) secretion. Data from our animal study corroborated the in vitro findings, wherein the Salmonella-treated group obtained the lowest lung metastases, longer survival, and increased iNOS-expressing immune infiltrates.

scholarly journals High-Mobility Group Nucleosome-Binding Protein 1 Mediates Renal Fibrosis Correlating with Macrophages Accumulation and Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy Mice Model

2019 ◽  
Vol 44 (3) ◽  
pp. 331-343
Author(s):  
Jiali Yu ◽  
Rong Dong ◽  
Jingjing Da ◽  
Jiayu Li ◽  
Fuxun Yu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Binding Protein ◽  
High Mobility ◽  
Treated Group ◽  
High Mobility Group ◽  
Mesenchymal Transition ◽  
Collagen Expression ◽  
Nucleosome Binding

Background/Aim: Renal fibrosis is essential for the progression of diabetic nephropathy (DN). Macrophages accumulate in diabetic kidneys and are involved in epithelial-to-mesenchymal transition (EMT), a vital mechanism leading to renal fibrosis. Recently, high-mobility group nucleosome-binding protein 1(HMGN1) was documented in promoting the recruitment and activation of antigen-presenting cells. In this study, we first reported its roles in renal fibrosis and the underlying mechanism associated with macrophage filtration and EMT. Methods: Twenty C57BL/6J mice were administered streptozotocin (STZ) to induce diabetes for 6 weeks and then divided into 4 groups: normal control group; DN group; benazepril-treated group, and insulin-treated group. Blood glucose, creatinine, and albumin in urine, hematoxylin and eosin, and Sirius red staining of kidney tissues were used to assess the renal pathology. ELISA, immunochemistry, and in situ hybridization were performed to determine the expression of HMGN1, CD68, F4/80, α-smooth muscle actin, and E-cadherin. Results: The renal expression levels of HMGN1, macrophage markers, and EMT makers were increased in DN group, and insulin treatment could reduce the overexpression of these indicators with a better effect than benazepril treatment. Both treatments could not obviously ameliorate urine albumin-to-creatinine ratio, collagen expression, and renal histological changes in STZ-induced diabetic mice. Correlation analysis indicated that there was a relationship among HMGN1, macrophage markers, EMT markers, and collagen expression in DN mice. Conclusion: HMGN1 may promote macrophages accumulation and EMT, suggesting a potential therapeutic target for preventing renal fibrosis development in DN.

scholarly journals Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts

2014 ◽  
Vol 306 (6) ◽  
pp. L534-L542 ◽  
Author(s):  
Luai Huleihel ◽  
Ahmi Ben-Yehudah ◽  
Jadranka Milosevic ◽  
Guoying Yu ◽  
Kusum Pandit ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
High Mobility ◽  
Lung Fibroblasts ◽  
Phenotypic Properties ◽  
Mesenchymal Transition ◽  
Junction Protein ◽  
Primary Fibroblasts

MicroRNAs are small noncoding RNAs that inhibit protein expression. We have previously shown that the inhibition of the microRNA let-7d in epithelial cells caused changes consistent with epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. The aim of this study was to determine whether the introduction of let-7d into fibroblasts alters their mesenchymal properties. Transfection of primary fibroblasts with let-7d caused a decrease in expression of the mesenchymal markers α-smooth muscle actin, N-cadherin, fibroblast-specific protein-1, and fibronectin, as well as an increase in the epithelial markers tight junction protein-1 and keratin 19. Phenotypic changes were also present, including a delay in wound healing, reduced motility, and proliferation of fibroblasts following transfection. In addition, we examined the effects of transfection on fibroblast responsiveness to TGF-β, an important factor in many fibrotic processes such as lung fibrosis and found that let-7d transfection significantly attenuated high-mobility group-A2 protein induction by TGF-β. Our results indicate that administration of the epithelial microRNA let-7d can significantly alter the phenotype of primary fibroblasts.

scholarly journals NRBP2 Functions as a Tumor Suppressor and Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyu Li ◽  
Bingxiong Liu ◽  
Chenyuan Li ◽  
Si Sun ◽  
Hanpu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mammalian Target Of Rapamycin ◽  
Tumor Model ◽  
Adenosine Monophosphate ◽  
Prognostic Indicator ◽  
Mesenchymal Transition

Nuclear Receptor Binding Protein 2 (NRBP2), one of the pseudokinases discovered during a screen of neural differentiation genes, inhibits tumor progression in medulloblastoma and hepatocellular carcinoma. However, the role and the mechanism of NRBP2 in the regulation of the progression of breast cancer (BC) have not been reported. In our study, NRBP2 was downregulated in human BC tissues compared with the corresponding normal tissues. Moreover, bioinformatics and cellular experiments illustrated that a lower level of NRBP2 contributed to a poor prognosis for patients with BC. In addition, we characterized the NRBP2-overexpressing BC cells and found that NRBP2 overexpression dramatically suppressed cell proliferation and invasion and inhibited the epithelial-mesenchymal transition (EMT) in cells in vitro, whereas knockdown of NRBP2 reversed these effects. Furthermore, overexpression of NRBP2 in the orthotopic breast tumor model significantly reduced lung metastatic nodules in nude mice. Mechanistically, NRBP2 regulated the activation of the 5′-adenosine monophosphate (AMP)-activated protein kinase/ mammalian target of rapamycin (AMPK/mTOR) signaling pathway. Moreover, the inhibition of cell proliferation, invasion and the EMT by NRBP2 overexpression was partially rescued after treatment with an AMPK inhibitor. Conversely, mTOR-specific inhibitors eliminated the effects of NRBP2 knockdown on increasing cell proliferation, invasion and the EMT, which suggested the anti-tumor effect of NRBP2, which may be partially related to the regulation of the AMPK/mTOR pathway. Taken together, NRBP2, a novel and effective prognostic indicator, inhibited the progression of BC and may become a potential therapeutic target for BC.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals Plasticity in Neuroblastoma Cell Identity Defines a Noradrenergic-to-Mesenchymal Transition (NMT)

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2904
Author(s):  
Margot Gautier ◽  
Cécile Thirant ◽  
Olivier Delattre ◽  
Isabelle Janoueix-Lerosey
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Biochemical Properties ◽  
Poor Overall Survival ◽  
Cell Identity ◽  
Mesenchymal Transition ◽  
Neuroblastoma Cell Lines

Neuroblastoma, a pediatric cancer of the peripheral sympathetic nervous system, is characterized by an important clinical heterogeneity, and high-risk tumors are associated with a poor overall survival. Neuroblastoma cells may present with diverse morphological and biochemical properties in vitro, and seminal observations suggested that interconversion between two phenotypes called N-type and S-type may occur. In 2017, two main studies provided novel insights into these subtypes through the characterization of the transcriptomic and epigenetic landscapes of a panel of neuroblastoma cell lines. In this review, we focus on the available data that define neuroblastoma cell identity and propose to use the term noradrenergic (NOR) and mesenchymal (MES) to refer to these identities. We also address the question of transdifferentiation between both states and suggest that the plasticity between the NOR identity and the MES identity defines a noradrenergic-to-mesenchymal transition, reminiscent of but different from the well-established epithelial-to-mesenchymal transition.

Epicardial Cells of Human Adults Can Undergo an Epithelial-to-Mesenchymal Transition and Obtain Characteristics of Smooth Muscle Cells In Vitro

Stem Cells ◽  
2007 ◽  
Vol 25 (2) ◽  
pp. 271-278 ◽  
Author(s):  
John van Tuyn ◽  
Douwe E. Atsma ◽  
Elizabeth M. Winter ◽  
Ietje van der Velde-van Dijke ◽  
Daniel A. Pijnappels ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Muscle Cells ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Human Adults

735 Impact of reversing an epithelial-to-mesenchymal transition program on tumor metabolism and immune suppression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A779-A779
Author(s):  
Michelle Williams ◽  
Jessica Christenson ◽  
Kathleen O’Neill ◽  
Sabrina Hafeez ◽  
Nicole Spoelstra ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Survival ◽  
Conditioned Medium ◽  
Mammary Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Raw264.7 Macrophages ◽  
Mammary Carcinoma Cells

BackgroundTo identify novel molecular mechanisms used by triple negative breast cancer (TNBC) to facilitate metastasis, we manipulated oncogenic epithelial-to-mesenchymal transition (EMT) by restoring the microRNA-200c (miR-200c), termed ‘the guardian of the epithelial phenotype.’ We identified several tumor cell catabolizing enzymes, including tryptophan 2,3-dioxygenase (TDO2) and heme oxygenase-1 (HO-1). The Richer lab has published that TDO2 promotes anchorage independent cell survival during TNBC metastasis via its catabolite kynurenine, which also induces CD8+ T cell death. Similarly, published studies have demonstrated that HO-1 supports BC anchorage independent survival. However, effects of the HO-1 catabolite bilirubin on the tumor microenvironment had not been studied. We postulated that TNBC utilize targetable catabolizing enzymes, like HO-1, to simultaneously support tumor cell survival and dampen the anti-tumor immune response.MethodsTo test our hypothesis in an immune competent mouse model, Met-1 mammary carcinoma cells from a late stage MMTV-PyMT tumor were engineered to inducibly express miR-200c. Tumor cell infiltrates were analyzed by immunohistochemistry (IHC), flow cytometry and multispectral fluorescence. RAW264.7 mouse macrophages were cultured with conditioned medium from carcinoma cells ± miR-200c or the HO-1 competitive inhibitor tin mesoporphyrin (SnMP). RAW264.7 macrophages were also treated with 0–20 µM bilirubin and macrophage polarization and efferocytic capacity, the ability to engulf dead tumor cells, were assessed using qRT-PCR and IncuCyte assays.ResultsMiR-200c restoration to Met-1 orthotopic tumors decreased growth by 45% and increased infiltration of CD11c+ dendritic cells and activation, determined by CD44 expression, of CD4+ and CD8+ T cells. While the number of F4/80+ macrophages was unchanged by miR-200c, the percent of M1 anti-tumor macrophages (F4/80+iNOS+/total cells) increased by >6-fold in miR-200c+tumors. RAW264.7 macrophages cultured with conditioned medium from miR-200c-restored mammary carcinoma cells had a 25–95% decrease in M2 pro-tumor genes (Arg1, Il4 and Il13) and a 15–55% increase in M1 genes (Nos2, Tnfa and Cxcl10). A similar decrease in M2 (30–50%) and increase M1 (35–160%) genes was seen in macrophages cultured with conditioned medium from SnMP treated mammary carcinoma cells. Conversely, bilirubin treatment alone enhanced M2 macrophage polarization and inhibited efferocytosis in a dose-dependent manner.ConclusionsUse of miR-200c to reverse EMT revealed that HO-1 promotes simultaneous TNBC cell survival and immune suppression. These studies are the first to show that tumor cell-HO-1 activity and subsequent bilirubin production may alter macrophage function in the tumor microenvironment. This finding could be clinically relevant since HO-1 inhibitors like SnMP are already FDA approved for treatment of other diseases.

scholarly journals Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5194
Author(s):  
Paola Pontrelli ◽  
Francesca Conserva ◽  
Rossella Menghini ◽  
Michele Rossini ◽  
Alessandra Stasi ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Selective Inhibition ◽  
Collagen I ◽  
Protein Accumulation ◽  
Mesenchymal Transition ◽  
Collagen Iii ◽  
Proximal Tubular Epithelial Cells

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.

scholarly journals Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 259
Author(s):  
Monish Ram Makena ◽  
Myungjun Ko ◽  
Donna Kimberly Dang ◽  
Rajini Rao
Keyword(s):  
Breast Cancer ◽  
Secretory Pathway ◽  
Histone Deacetylase Inhibitors ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Subtype ◽  
Survival Prognosis ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Canonical Wnt

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

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