scholarly journals IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells

2021 ◽  
Vol 9 (6) ◽  
pp. e002856
Author(s):  
Ksenia Magidey-Klein ◽  
Tim J Cooper ◽  
Ksenya Kveler ◽  
Rachelly Normand ◽  
Tongwu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Data Analysis ◽  
Conditioned Medium ◽  
Mononuclear Cells ◽  
Fluorescent Protein ◽  
Metastatic Potential ◽  
Loss Of Function ◽  
Tumor Spread ◽  
Hematopoietic Stem ◽  
Proteomic Screen

BackgroundMetastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored.MethodsWe used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets.ResultsMice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)–IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors—through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness.ConclusionsOur study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.

Shp-2 Heterozygous Hematopoietic Stem Cells Have Deficient Repopulating Activity Due to a Self-Renewal Defect.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1690-1690
Author(s):  
Rebecca J. Chan ◽  
Yanjun Li ◽  
Chris Shelley ◽  
Mervin C. Yoder
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Tyrosine Phosphatase ◽  
Embryonic Stem ◽  
Low Density ◽  
Loss Of Function ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Split Dose ◽  
Significant Difference

Abstract The protein tyrosine phosphatase, Shp-2, has been shown to be necessary for normal hematopoiesis based on embryonic stem (ES) cell-based assays; however, due to the early lethality of the homozygous Shp-2 mutant mice (Shp-2−/−) the role of Shp-2 in adult hematopoietic stem cell (HSC) function has never been examined. The Shp-2 heterozygous mice (Shp-2+/−) bear a mutant allele of the Shp-2 gene resulting in the production of a mutant protein lacking amino acids 46–110, which confers a loss of function. To test the hypothesis that Shp-2 is required for normal HSC activity, we compared the competitive repopulating ability of Shp-2+/− bone marrow-derived cells with WT cells. Total adult bone marrow low density mononuclear cells were isolated from Shp-2+/− and WT littermate controls (test cells, C57Bl/6 background, CD45.2+), mixed with a common pool of competitor (comp) cells (BoyJ background, CD45.1+), and administered to lethally irradiated (1100 cGy split dose) Gpi/BoyJ recipients. Based on peripheral blood chimerism, the repopulating ability of the Shp-2+/− cells was significantly lower than that of the WT cells (Figure 1, *p<0.0001 Shp-2+/− v. WT at ratio 1:2; **p=0.001 Shp-2+/− v. WT at ratio 1:1). We next converted the chimerism to repopulating units using the formula [competitor number x 105] X [% 45.2]/100 − [% 45.2] to quantitatively asses the repopulating defect in Shp-2+/− HSCs. We observed that the repopulating units of the Shp-2+/− cells was approximately 3-fold lower than that of the WT cells at both cell doses administered (Figure 2, *p=0.003 Shp-2+/− v. WT at ratio 1:2; **p=0.03 comparing Shp-2+/− v. WT at ratio 1:1). Multi-lineage analysis using two color fluorescence cytometry revealed a significantly lower contribution of Shp-2+/− cells to all lineages tested (B220, GR1, Mac, and CD4/8) compared to WT cells. As Shp-2 has been shown to participate in cell migration, we sought to rule out a homing deficiency of the Shp-2+/− HSCs. We performed short term homing assays and observed no difference in spleen-homed or bone marrow-homed Shp-2+/− and WT lin- cells twenty hours following transplantation. To evaluate self-renewal potential, we conducted serial transplantation experiments. Total bone marrow low density mononuclear cells were isolated from primary or seconary recipient mice with equal chimerism and transplanted into lethally irradiated (1100 cGy split dose) Gpi/BoyJ recipients. While no significant difference was observed between Shp-2+/− and WT engraftement in secondary transplants, eight weeks following tertiary transplantation, engraftment of the Shp-2+/− cells is significantly lower than that of the WT cells (WT 68.9% +/− 9.5 v. Shp-2+/− 26.1% +/− 11.7, n=6, p<0.0001) suggesting that a self-renewal defect contributes to the decreased HSC activity of the Shp-2+/− cells. These data demonstrate that Shp-2 function is not only necessary within the progenitor compartment to support proficient hematopoiesis, but is also needed within the HSC compartment to support normal HSC self-renewal. These findings provide insight into how oncogenic Shp-2 potentially may contribute to the dysregulation of hematopoiesis and the pathogenesis of childhood leukemias.

Hematopoietic Origin of Fibroblasts and Their Precursors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 672-672 ◽  
Author(s):  
Yasuhiro Ebihara ◽  
Masahiro Masuya ◽  
Russell Owens ◽  
Su Yang ◽  
Richard P. Visconti ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mononuclear Cells ◽  
Fluorescent Protein ◽  
Mesangial Cells ◽  
Pcr Analysis ◽  
Glomerular Mesangial Cells ◽  
General Belief ◽  
Hematopoietic Stem ◽  
Steel Factor ◽  
Cd34 Cells

Abstract Recent studies indicate that hematopoietic stem cells (HSCs) are capable of reconstituting a number of non-hematopoietic organs and tissues. To define the potential of the HSC precisely, we initiated transplantation studies of a clonal population of cells derived from a single HSC. We used the bone marrow (BM) of transgenic enhanced green fluorescent protein (EGFP) mice as the source of donor HSCs. We demonstrated the HSC origin of glomerular mesangial cells (Masuya et al, Blood 101: 2215, 2003) and brain microglial cells and pericyte-like perivascular cells (Hess et al, Exp Neurol 186: 134, 2004). These observations and the fact that glomerular mesangial cells and pericytes are considered myofibroblasts suggested that fibroblasts are also derived from HSCs. In this abstract, we present evidence for HSC origin of fibroblasts and their precursors, BM fibroblast colony-forming units (CFU-F) and peripheral blood (PB) fibrocytes. Lin−Sca-1+c-Kit+CD34− cells from the BM of adult EGFP mice were individually sorted into 96 well Corning plates and cultured for 7 days in the presence of Steel factor and IL-11 or Steel factor and G-CSF. Viable clones consisting of fewer than 20 cells were individually transplanted into lethally irradiated mice. EGFP+ mononuclear cells were sorted from the BM cells of recipients showing high-level, multilineage hematopoietic reconstitution and assayed for CFU-F in Retronectin-treated tissue culture plates. Colonies consisting of more than 50 adherent cells were all EGFP+. The majority of the cells comprising the colonies were fibroblast-like, exhibited spindle-shaped or polygonal cytoplasm and had clear, ovoid nuclei. Flow cytometric analyses revealed that these cells expressed collagen-1 and discoidin domain receptor 2 (DDR2) and exhibited a decreased intensity of CD45. RT-PCR analysis of these cells revealed the presence of mRNA for procollagen 1 alpha-1, vimentin, fibronectin and DDR2. Next we analyzed the PB for donor origin fibrocytes, a fibroblast-like cell type that expresses both fibroblastic and hematopoietic phenotypes in culture. When nucleated PB cells from clonally engrafted mice were cultured on fibronectin-coated dishes, proliferation of EGFP+ fibroblast-like cells was detected. Only one-third of the EGFP+ cells expressed CD45 and most of the EGFP+ cells expressed both collagen-I and DDR2. Similar results were obtained with EGFP+ cells from mice transplanted with 100 uncultured Lin−Sca-1+c-Kit+CD34− cells or 1x106 BM nucleated cells. These studies excluded the effects of short-term culture on HSC differentiation and established the HSC origin of CFU-F and fibrocytes. Classic studies of CFU-F by Friedenstein and others have led to the general belief that mesenchymal stem cells (MSCs), rather than HSCs, generate a number of tissues including adipocytes, osteoblasts, chondrocytes, myocytes and vascular endothelial cells. Here we unequivocally demonstrated that CFU-F are of HSC origin, warranting a re-evaluation of the relationship between HSCs and MSCs.

The Hematopoietic Stem Cell Is a Source of Endothelial Cells in Cancer Vasculogenesis and Depends on SDF-1.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3722-3722
Author(s):  
Christopher R. Cogle ◽  
Adam Brank ◽  
Dietmar Siemann ◽  
Edward W. Scott
Keyword(s):  
Lung Cancer ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Blood Vessels ◽  
Fluorescent Protein ◽  
Treated Group ◽  
Control Cohort ◽  
Hematopoietic Stem ◽  
Green Fluorescent ◽  
Cxcr4 Axis

Abstract Cancer growth and metastasis depend upon a rich supply of oxygen and nutrients from blood vessels. Previously we found that the hematopoietic stem cell (HSC) is capable of contributing to vasculogenesis in settings of physiologic repair, and given the relative hypoxia within tumor microenvironments, we subsequently hypothesized that the HSC also acts as a pathologic hemangioblast. First, we injected cancers (lung, pancreatic, melanoma, lymphoma) into cohorts of C57BL/6 mice which were previously transplanted green fluorescent protein (GFP)-tagged whole bone marrow. All cancer specimens demonstrated blood vessels with marrow-derived endothelial cells. Approximately 25% of tumor vessels contained marrow-derived endothelial cells as demonstrated by GFP, CD31 and vWF expression. We further questioned whether the tumor neovasculogenesis is from a clonal, self-renewing HSC. Single HSC transplanted mice were used as donors for secondary transplant mice in order to select for the true HSC. Lung cancers grown in recipients of single cell and serially transplanted hematopoietic stem cells (n=9) demonstrate clonal, donor-derived endothelial cells in 5% of tumor vasculature, matching hematopoietic engraftment. Thus, our results indicate that the self-renewing, clonal adult HSC exhibits pathologic hemangioblast activity. We further hypothesized that factors that affect leukocyte trafficking likely affect the pathologic hemangioblast activity of HSC. To test this hypothesis, we made slight modifications to our transplant and tumor inoculation model by administering GCSF and SCF to mobilize marrow derived EPC. Over the ensuing 14 days, the tumors in the cytokine treated group grew at a much faster rate and to a much larger size than tumors in the control mice. After 14 days of cytokine treatment and tumor growth, microvessel density was not different between cytokine treated mice (n=4) and control mice (n=4); however, marrow-derived tumor vasculogenesis was markedly elevated in the cytokine treated compared to controls (63% vs. 26%). Given that the SDF1/CXCR4 axis is pivotal for marrow cell homing and migration, we hypothesized that blocking this axis would block marrow-derived blood vessels in cancer. To test this hypothesis, we transplanted green fluorescent protein (GFP) marrow into wild-type C57BL/6 mice and then inoculated these mice with lung cancer. An experimental cohort of mice (n=4) received intra-tumoral anti-SDF1. A control cohort included mice receiving intra-tumoral PBS (n=4). Over the ensuing 14 days, tumors in the anti-SDF1 treated group grew at a much slower rate and to a much smaller size, if at all. After 14 days of injections and tumor growth, microvessel density was markedly decreased in the anti-SDF1 cohort compared to the control cohort. Moreover, marrow-derived tumor vasculogenesis was decreased in the anti-SDF1 treated tumors compared to controls (18% of vessels with marrow-derived endothelial cells vs. 26%, respectively). Lung cancer cells grew normally in vitro in the presence of anti-SDF-1. In conclusion, the results of our studies indicate that the HSC contributes to blood vessels within a variety of cancers and that strategies targeting HSC and EPC mobilization and homing potentially represent excellent ant-neoplastic opportunities. Indeed, perturbing the SDF1/CXCR4 axis inhibits marrow-derived tumor vasculogenesis. These studies serve as the preclinical basis for anti-SDF-1 antibody therapy as an adjunct to anti-cancer therapy.

Tumor Vasculogenesis Can Be Derived from the Hematopoietic Stem Cell.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1806-1806
Author(s):  
Jacklyn Otero ◽  
Kathryn J. Russell ◽  
DongTao Fu ◽  
Wenyin Shi ◽  
Marda L. Jorgensen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Blood Vessels ◽  
Hematopoietic Stem Cell ◽  
Fluorescent Protein ◽  
Treated Group ◽  
Recovery Phase ◽  
Hematopoietic Stem ◽  
Tumor Vessels

Abstract Blood vessel development is essential to cancer growth and metastasis. Based on our recent findings that the hematopoietic stem cell (HSC) provides functional hemangioblast activity in repairing the ischemic retina, we questioned if the HSC also acts as a pathologic hemangioblast - contributing to tumor vasculogenesis. Using a transplant model of green fluorescent protein (GFP) marrow into wild-type C57BL/6 mice, we injected lung cancer (LLC) and allowed the tumor to grow for 14 days. All tumor specimens demonstrated tumor vessels with marrow-derived endothelial cells. Approximately 25% of tumor vessels contained marrow-derived endothelial cells as demonstrated by GFP, CD31 and vWF expression. Confocal microscopy was used to identify true marrow-derived endothelial cells lining the vascular lumen versus marrow-derived pericytes juxtaposed to endothelial cells. We further questioned whether the tumor neovasculogenesis is from a clonal, self-renewing HSC. Lung cancers grown in recipients of single cell and serially transplanted hematopoietic stem cells (n=9) demonstrate clonal, donor-derived endothelial cells in 5% of tumor vasculature, matching hematopoietic engraftment. Our results indicate that the self-renewing, clonal adult hematopoietic stem cell exhibits pathologic hemangioblast activity, capable of producing both blood and blood vessels within tumors. Given that the HSC and its EPC progeny can contribute to tumor vasculogenesis, we further hypothesized that factors that affect leukocyte trafficking likely affect the pathologic hemangioblast activity of HSC. Thus, we made slight modifications to our transplant and tumor inoculation model by administering GCSF and SCF to mobilize marrow derived EPC. Over the ensuing 14 days, the tumors in the cytokine treated group grew at a much faster rate and to a much larger size than tumors in the control mice. After 14 days of cytokine treatment and tumor growth, microvessel density was not different between cytokine treated mice (n=4) and control mice (n=4); however, marrow-derived tumor vasculogenesis was markedly elevated in the cytokine treated compared to controls (63% vs. 26%). In conclusion, the HSC contributes to blood vessels within lung cancer and strategies targeting HSC/EPC mobilization (such as during the recovery phase of chemotherapy) potentially represent excellent ant-neoplastic opportunities.

Levels interleukine-4 and interleukin-17 (IL-4, IL-17) of blood in patients with habitual recurrent pregnancy loss, which occurred in a loop in vitro fertilization

2016 ◽  
pp. 137-139
Author(s):  
K.P. Golovatyuk ◽  
Keyword(s):  
In Vitro Fertilization ◽  
Conditioned Medium ◽  
Mononuclear Cells ◽  
Recurrent Miscarriage ◽  
Interleukin 4 ◽  
Control Group ◽  
Interleukin 17 ◽  
Vitro Fertilization ◽  
Blood Mononuclear Cells

The objective: was to investigate the levels of cytokines IL-4 and IL-17 in serum and conditioned medium cultures of blood mononuclear cells (MNC) and evaluation association between their products and miscarriage, which occurred in IVF cycles. Patients and methods. We observed 240 patients with recurrent miscarriage, came in IVF cycles, and 100 apparently healthy fertile women in the control group. The concentrations of IL-4 and IL-17 in serum and conditioned medium of MNC cultures were determined. Results. The levels of IL-4 in the serum and conditioned medium in spontaneous and stimulated mitogen secretion was not significantly different from those in the control group, whereas IL-17 levels were higher than those in the control group serum, in conditioned media of stimulated and non-stimulated MNCs. Conclusion. Disregulation of activity of circulating blood mononuclear cells in women with recurrent miscarriage that followed IVF, is accompanied by increased secretion of IL-17 and almost constant production of IL-4 on the back of high stimulation index of production of these cytokines. Key words: in vitro fertilization, miscarriage, interleukin-4, interleukin-17, serum stimulated and non-stimulated mononuclear blood.

scholarly journals LncRNA PCAT1 Interacts with DKC1 to Regulate Proliferation, Invasion and Apoptosis in NSCLC Cells via the VEGF/AKT/Bcl2/Caspase9 Pathway

2021 ◽  
Vol 30 ◽  
pp. 096368972098607
Author(s):  
Shi-Yuan Liu ◽  
Zhi-Yu Zhao ◽  
Zhe Qiao ◽  
Shao-Min Li ◽  
Wei-Ning Zhang
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Apoptosis ◽  
Rna Binding ◽  
A549 Cells ◽  
Nonsmall Cell Lung Cancer ◽  
Nsclc Cell ◽  
Loss Of Function ◽  
Proliferation And Invasion

Long noncoding RNAs (lncRNAs) are increasingly recognized as indispensable components of the regulatory network in the progression of various cancers, including nonsmall cell lung cancer (NSCLC). The lncRNA prostate cancer associated transcript 1 (PCAT1) has been involved in tumorigenesis of multiple malignant solid tumors, but it is largely unknown that what is the role of lncRNA-PCAT1 and how it functions in the progression of lung cancer. Herein, we observed that lncRNA PCAT1 expression was upregulated in both human NSCLC tissues and cell lines, which was determined by qualitative polymerase chain reaction analysis. Then, gain-and loss-of-function manipulations were performed in A549 cells by transfection with a specific short interfering RNA against PCAT1 or a pcDNA-PCAT1 expression vector. The results showed that PCAT1 not only promoted NSCLC cell proliferation and invasion but also inhibited cell apoptosis. Bioinformatics and expression correlation analyses revealed that there was a potential interaction between PCAT1 and the dyskerin pseudouridine synthase 1 (DKC1) protein, an RNA-binding protein. Then, RNA pull-down assays with biotinylated probes and transcripts both confirmed that PCAT1 directly bounds with DKC1 that could also promote NSCLC cell proliferation and invasion and inhibit cell apoptosis. Moreover, the effects of PCAT1 and DKC1 on NSCLC functions are synergistic. Furthermore, PCAT1 and DKC1 activated the vascular endothelial growth factor (VEGF)/protein kinase B (AKT)/Bcl-2/caspase9 pathway in NSCLC cells, and inhibition of epidermal growth factor receptor, AKT, or Bcl-2 could eliminate the effect of PCAT1/DKC1 co-overexpression on NSCLC cell behaviors. In conclusion, lncRNA PCAT1 interacts with DKC1 to regulate proliferation, invasion, and apoptosis in NSCLC cells via the VEGF/AKT/Bcl-2/caspase9 pathway.

scholarly journals Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1

2021 ◽  
Vol 22 (13) ◽  
pp. 7100
Author(s):  
Yohan Seo ◽  
Sung Baek Jeong ◽  
Joo Han Woo ◽  
Oh-Bin Kwon ◽  
Sion Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Throughput Screening ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Small Cell ◽  
Channel Activity ◽  
Small Cell Lung ◽  
Protein Levels

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

scholarly journals LINC01089 functions as a ceRNA for miR-152-3p to inhibit non‐small lung cancer progression through regulating PTEN

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huixian Zhang ◽  
Hao Zhang ◽  
Xingya Li ◽  
Siyuan Huang ◽  
Qianqian Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Expression Level ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Protein Coding ◽  
Tensin Homolog ◽  
Pten Mrna

Abstract Background Long non-coding RNAs (lncRNAs) have been reported to exert crucial functions in regulating the progression of human cancers. However, the function and mechanism of long intergenic non-protein coding RNA 01089 (LINC01089) in non-small cell lung cancer (NSCLC) have not been revealed. Methods The expression level of LINC01089, microRNA (miRNA, miR)-152-3p and phosphatase and tensin homolog deleted onc hromosome ten (PTEN) mRNA was detected by quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function models were established with NSCLC cell lines, the proliferation, migration and invasion of NSCLC cells were detected by cell counting kit-8 (CCK-8) assay, scratch healing assay, Transwell assay, respectively. Dual luciferase reporter assay was employed to validate the binding relationship between miR-152-3p and LINC01089 or the 3’UTR of PTEN. Western blot was used to detect PTEN expression in NSCLC cells after LINC01089 and miR-152-3p were selectively modulated. Results LINC01089 was down-regulated in NSCLC tissues and cells. Functional experiments showed that knockdown of LINC01089 could promote the proliferation, migration and invasion of NSCLC cells, while over-expression of LINC01089 had the opposite effects. miR-152-3p was identified as a functional target for LIN01089, and miR-152-3p could reverse the function of LINC01089. Additionally, LINC01089 could up-regulate the expression level of PTEN via repressing miR-152-3p. Conclusions Down-regulation of LINC01089 promoted the progression of NSCLC through regulating miR-152-3p/PTEN axis.

scholarly journals Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Donghong Zhang ◽  
Jinfeng Ning ◽  
Imoh Okon ◽  
Xiaoxu Zheng ◽  
Ganesh Satyanarayana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epigenetic Modification ◽  
Suppressor Gene ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Lung Cancer Patients ◽  
Lkb1 Tumor Suppressor ◽  
And Migration

AbstractOncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

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