scholarly journals ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Dafeng Xu ◽  
Yu Wang ◽  
Jincai Wu ◽  
Zhensheng Zhang ◽  
Jiacheng Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aerobic Glycolysis ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
Integrated Analysis ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
In Vivo Experiments

AbstractHepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.

scholarly journals Exosomal DLX6-AS1 from hepatocellular carcinoma cells induces M2 macrophage polarization to promote migration and invasion in hepatocellular carcinoma through microRNA-15a-5p/CXCL17 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Lin-pei Wang ◽  
Jing Lin ◽  
Xiao-qiu Ma ◽  
Dong-yao Xu ◽  
Chun-feng Shi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Mesenchymal Transition ◽  
M2 Macrophage Polarization ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) cells-secreted exosomes (exo) could stimulate M2 macrophage polarization and promote HCC progression, but the related mechanism of long non-coding RNA distal-less homeobox 6 antisense 1 (DLX6-AS1) with HCC-exo-mediated M2 macrophage polarization is largely ambiguous. Thereafter, this research was started to unearth the role of DLX6-AS1 in HCC-exo in HCC through M2 macrophage polarization and microRNA (miR)-15a-5p/C-X-C motif chemokine ligand 17 (CXCL17) axis. Methods DLX6-AS1, miR-15a-5p and CXCL17 expression in HCC tissues and cells were tested. Exosomes were isolated from HCC cells with overexpressed DLX6-AS1 and co-cultured with M2 macrophages. MiR-15a-5p/CXCL17 down-regulation assays were performed in macrophages. The treated M2 macrophages were co-cultured with HCC cells, after which cell migration, invasion and epithelial mesenchymal transition were examined. The targeting relationships between DLX6-AS1 and miR-15a-5p, and between miR-15a-5p and CXCL17 were explored. In vivo experiment was conducted to detect the effect of exosomal DLX6-AS1-induced M2 macrophage polarization on HCC metastasis. Results Promoted DLX6-AS1 and CXCL17 and reduced miR-15a-5p exhibited in HCC. HCC-exo induced M2 macrophage polarization to accelerate migration, invasion and epithelial mesenchymal transition in HCC, which was further enhanced by up-regulated DLX6-AS1 but impaired by silenced DLX6-AS1. Inhibition of miR-15a-5p promoted M2 macrophage polarization to stimulate the invasion and metastasis of HCC while that of CXCL17 had the opposite effects. DLX6-AS1 mediated miR-15a-5p to target CXCL17. DLX6-AS1 from HCC-exo promoted metastasis in the lung by inducing M2 macrophage polarization in vivo. Conclusion DLX6-AS1 from HCC-exo regulates CXCL17 by competitively binding to miR-15a-5p to induce M2 macrophage polarization, thus promoting HCC migration, invasion and EMT.

scholarly journals Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages

2020 ◽  
Vol 8 (1) ◽  
pp. e000489 ◽  
Author(s):  
Marta Di Martile ◽  
Valentina Farini ◽  
Francesca Maria Consonni ◽  
Daniela Trisciuoglio ◽  
Marianna Desideri ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Macrophage Polarization ◽  
Melanoma Cells ◽  
Response To Therapy ◽  
Major Constituent ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

BackgroundA bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression.MethodsTHP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice.ResultsHigher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4+IFNγ+and CD8+IFNγ+effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment.ConclusionsTaken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies.

scholarly journals Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yohei Kawai ◽  
Yuji Narita ◽  
Aika Yamawaki-Ogata ◽  
Akihiko Usui ◽  
Kimihiro Komori
Keyword(s):  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Gene Expressions ◽  
Arginase 1 ◽  
M2 Macrophage Polarization

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

scholarly journals Tiliroside Ameliorates Ulcerative Colitis by Restoring the M1/M2 Macrophage Balance via the HIF-1α/glycolysis Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongda Zhuang ◽  
Qi Lv ◽  
Chao Zhong ◽  
Yaru Cui ◽  
Luling He ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Therapeutic Approach ◽  
Activity Index ◽  
Aerobic Glycolysis ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Inflammatory Status ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory

Macrophages polarized to different phenotypes critically contribute to colitis development by coordinating inflammatory and anti-inflammatory processes. Herein, targeting the balance between the pro-inflammatory M1 and the anti-inflammatory M2 macrophage phenotypes can be a novel therapeutic approach for colitis. In the present study, we firstly demonstrated that tiliroside possessed the ability to alleviate the clinical symptoms of colitis as evidenced by decreased disease activity index (DAI) scores, longer colon length, reduced myeloperoxidase (MPO) activity, and improvement of colonic pathological damage in vivo. Furthermore, we showed that tiliroside modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in colonic lamina propria but has little effect on the T cell population and epithelial barrier function in colitis mice. The macrophage depletion study further showed the protective effect of tiliroside was macrophage dependent in vivo. Mechanistically, our study demonstrated that tiliroside regulated cellular metabolism by inhibiting aerobic glycolysis in LPS and IFNγ stimulated macrophages. At the molecular level, tiliroside facilitated the proteasomal degradation of HIF-1α and downregulated mRNA expressions of HIF-1α dependent glycolytic enzymes in macrophages. Collectively, our data highlight the aberrant M1/M2 macrophage polarization in the initiation and development of ulcerative colitis and put forth the stage for considering tiliroside as a metabolic regulator in reprogramming macrophage polarization, which may serve as a promising therapeutic approach for treatment of inflammation-associated and metabolic disorders.

scholarly journals MSC-derived miR-181b Overexpressing Exosomes Enhanced Osteointegration by Enhancing M2 Polarization of Macrophages via Targeting the PRKCD/AKT Pathway

2020 ◽  
Author(s):  
Wei Liu ◽  
Muyu Yu ◽  
Feng Chen ◽  
Dong Xie ◽  
Longqing Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
Fluorescent Labeling ◽  
M2 Macrophage ◽  
Implant Loosening ◽  
M2 Polarization ◽  
Tnf Α

Abstract Background: Many patients suffer from implant loosening after the implantation of titanium alloy caused by immune response to the foreign bodies and this could inhibit osteogenesis, which could possibly give rise to poor osteointegration and there is currently no appropriate solution in clinical practice. Exosomes overexpressing miRNA has been proven to be a suitable candidate for solving this problem. In this study, we explored whether miR-181b could exert beneficial effect on promoting M2 macrophage polarization, thus inhibiting inflammation as well as promoting osteogenesis and elaborated the underlying mechanism in vitro. Furthermore, we aimed to find whether exosomes overexpressing miR-181b (Exo-181b) could enhance osteointegration in vivo.Methods: In vitro and in vivo studies were carried out for assessing the anti-inflammatory and pro-osteogenesis effect of miR-181b. In vitro, ELISA was applied for the detection of the inflammation factors levels including IL-6, TNF-α, as well as IL-10 and the percentage of M1 or M2 polarization was determined by flow cytometry. Also, qRT-PCR was used for the detection of the relative gene expression of the CCR7, CD206, Arg-1, iNOS, VEGF and BMP-2 genes. Western blotting was applied for detecting the protein expression of PRKCD, AKT and p-AKT. In vivo, we established air pouch model for evaluating the effect of Exo-181b on macrophage polarization and distal femoral bone defect model was established for determining the osteointegration effect of Exo-181b by MicroCT, sequential fluorescent labeling and histological analysis. Results: In vitro, we firstly verified that miR-181b significantly enhanced M2 polarization and inhibited inflammation by suppressing PRKCD and activating p-AKT. Then, in vivo, we verified that Exo-181b enhanced M2 polarization, reduced the inflammatory response and enhanced osteointegration. Conclusions: MiR-181b could suppress inflammatory response by regulating the PRKCD/AKT signaling pathway and promoting M2 polarization, which further promoting osteogenesis of hBMSC in vitro and Exo-181b could promote osteointegration in vivo.

scholarly journals A novel delivery nanobiotechnology: engineered miR-181b exosomes improved osteointegration by regulating macrophage polarization

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wei Liu ◽  
Muyu Yu ◽  
Feng Chen ◽  
Longqing Wang ◽  
Cheng Ye ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
M2 Macrophage ◽  
Implant Loosening ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
Osteogenesis In Vitro

Abstract Background Many patients suffer from implant loosening after the implantation of titanium alloy caused by immune response to the foreign bodies and this could inhibit the following osteogenesis, which could possibly give rise to aseptic loosening and poor osteointegration while there is currently no appropriate solution in clinical practice. Exosome (Exo) carrying miRNA has been proven to be a suitable nanocarrier for solving this problem. In this study, we explored whether exosomes overexpressing miR-181b (Exo-181b) could exert beneficial effect on promoting M2 macrophage polarization, thus inhibiting inflammation as well as promoting osteogenesis and elaborated the underlying mechanism in vitro. Furthermore, we aimed to find whether Exo-181b could enhance osteointegration. Results In vitro, we firstly verified that Exo-181b significantly enhanced M2 polarization and inhibited inflammation by suppressing PRKCD and activating p-AKT. Then, in vivo, we verified that Exo-181b enhanced M2 polarization, reduced the inflammatory response and enhanced osteointegration. Also, we verified that the enhanced M2 polarization could indirectly promote the migration and osteogenic differentiation by secreting VEGF and BMP-2 in vitro. Conclusions Exo-181b could suppress inflammatory response by promoting M2 polarization via activating PRKCD/AKT signaling pathway, which further promoting osteogenesis in vitro and promote osteointegration in vivo. Graphic abstract

scholarly journals Long Non-Coding RNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Jianfei Tu ◽  
Fazong Wu ◽  
Li Chen ◽  
Liyun Zheng ◽  
Yang Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Function ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
M2 Macrophage ◽  
Metabolic Dysfunction ◽  
Downstream Target ◽  
M2 Polarization

LncRNAs can act crucial roles in multiple tumors including cholangiocarcinoma (CCA). M2 polarization of macrophages is crucial for their biological roles in immunologic tolerance, which is able to induce tumorigenesis. Given that increasing evidence have suggested that lncRNAs could participate in modulating immune cell differentiation and function. Our current study was aimed to identify the underlying mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in CCA progression via regulating M2 macrophage polarization. PCAT6 has been reported as an oncogene in many cancers. In our work, we observed increased expression of PCAT6 in CCA patients. PCAT6 expression in various types of immune cells derived from CCA patients was tested by quantitative real-time PCR (qRT-PCR). It was revealed that PCAT6 was highly expressed in macrophages, which indicated that PCAT6 might regulate the function of macrophages to promote CCA progression. Then, via establishing CCA xenograft mouse model, we found loss of PCAT6 obviously triggered the immune response and reduced the in vivo tumor growth. In addition, overexpression of PCAT6 led to the M2 polarization of THP-1-differentiated macrophages. Moreover, miR-326 was predicted and proved as a target for PCAT6. In addition, down-regulation of PCAT6 repressed M2 polarization of macrophages, which was reversed by miR-326 inhibitors. The increase of PCAT6 induced the accumulation of ROS, mitochondrial and metabolic dysfunction in macrophages and mimics of miR-326 exhibited an opposite process. RohA has been recognized as a significant regulator of immune cell function. In our current work, we observed that RohA function as a downstream target for miR-326. In conclusion, our study highlighted a significant role of PCAT6/miR-326/RohA in immune response of macrophages in CCA and indicated PCAT6 as a potential target of immunotherapy in CCA.

scholarly journals Cerebral Injury Promotes Regeneration of The Brachial Plexus

2020 ◽  
Author(s):  
fan su ◽  
Guobao Wang ◽  
Tie Li ◽  
Wendong Xu
Keyword(s):  
Brachial Plexus ◽  
Macrophage Polarization ◽  
Enrichment Analysis ◽  
Nerve Transfer ◽  
Underlying Mechanism ◽  
Cerebral Injury ◽  
M2 Macrophage ◽  
Electrophysiological Recordings ◽  
Injury Models

Abstract Background: Our previous trial of contralateral seventh cervical nerve transfer (CC7) for spastic arm paralysis suggested that regeneration of the C7 nerve seems to be faster in patients undergoing nerve transfer due to cerebral injury compared to patients receiving surgery due to brachial plexus injury (BPI). This finding needs to be further verified, and the underlying mechanism remains largely unknown. The present study compared C7 regeneration between two groups of patients and animal models. Proteomics was utilized to reveal the mechanism mediating the promotion of C7 nerve regeneration.Methods: We assessed Tinel’s sign in the arm after C7 transfer and compared the latency to the appearance of Tinel’s sign to evaluate regeneration. Traumatic brain injury (TBI) and BPI were induced in C57 mice to establish injury models. C7 regeneration was assessed by electrophysiology and histology. Enrichment analysis of the differentially expressed proteins identified by proteomics suggested altered inflammation related to TBI. qPCR and histology were performed to assess the inflammatory environment in the C7 nerve. We evaluated the influence of the contributing factor serum amyloid protein A1 (SAA1) on the regenerative ability and inflammatory response of the C7 nerve by electrophysiology, qPCR and histology.Results: Faster C7 regeneration was identified in patients, which was further confirmed in mouse models by electrophysiological recordings and histology. Altered systemic inflammation, which led to increased M2 macrophage activation, may represent an underlying mechanism of increased regeneration. In mice, SAA1 facilitated C7 regeneration and interfered with macrophage polarization in vivo.Conclusions: Altered inflammation promoted the regenerative capacity of the C7 nerve by altering macrophage behavior, and SAA1 may be a therapeutic target to improve the recovery of injured peripheral nerves.

scholarly journals Ovarian Cancer Cell-Derived Exosomal miR-205 Promotes M2 Macrophage Polarization and Ovarian Cancer Cell Metastasis By Activating The AKT/mTOR Signalling Pathway

2021 ◽  
Author(s):  
Liuqing He ◽  
Quan Chen ◽  
Di Wu ◽  
Wei Zhu ◽  
Qifeng Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Ovarian Cancer Cell ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Qrt Pcr ◽  
M2 Macrophage Polarization

Abstract Background: Tumour-associated macrophages (TAMs) are the most abundant immune cells in the tumour environment and are considered to be similar to M2 macrophages, which facilitate cancer progression. Exosomes, as important mediators of cell-to-cell communication, can alter the phenotype of TAMs by transferring microRNAs (miRNAs) that influence targets and signalling pathways. However, the exact mechanisms by which cancer-derived exosomal miRNAs facilitate the development and metastasis of ovarian cancer (OC) remain unclear.Methods: In situ hybridization and immunohistochemistry were performed to examine the relationship between miR-205 and CD163 in OC. Exosome labelling experiments and qRT-PCR were used to detect the transfer of miR-205 from OC cells to macrophages. The effects of exosomal miR-205-induced macrophages on OC cell migration, invasion and EMT were assessed by in vitro assays in a co-culture model. Western blotting and qRT-PCR experiments were performed to investigate the role of the PI3K/AKT/mTOR axis in M2 macrophage polarization induced by exosomal miR-205. An in vivo mouse tumour model was used to evaluate the effects of M2 macrophages induced by exosomal miR-205.Results: We found that miR-205 expression levels were associated with M2 macrophage infiltration in patients with OC. miR-205 could be transported from OC cells to macrophages via exosomes and altered the macrophage phenotype. Moreover, macrophages that received exosomal miR-205 further enhanced the invasion, migration and EMT of OC cells. Decreased PTEN levels caused by exosomal miR-205 could increase the activation of AKT and mTOR as well as the expression of several immunosuppressive factors. In contrast, inhibition of miR-205 or restoration of PTEN effectively decreased cancer-mediated M2-type polarization, improving the infiltration of inflammatory factors in the tumour environment. Exosomal miR-205 derived from OC cells was found to induce M2-type polarization of macrophages and promote cancer progression in vivo.Conclusions: These results suggest a novel mechanism by which exosomal miR-205 induces M2 macrophage polarization and facilitates OC progression by targeting the PI3K/AKT/mTOR axis. Targeting exosomal miR-205 may offer a potential diagnosis and treatment strategy for OC.

scholarly journals Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Theodora Katopodi ◽  
Savvas Petanidis ◽  
Kalliopi Domvri ◽  
Paul Zarogoulidis ◽  
Doxakis Anestakis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Lung Tumor ◽  
Quantitative Polymerase Chain Reaction ◽  
Macrophage Polarization ◽  
Metastatic Potential ◽  
Intratumoral Heterogeneity ◽  
M2 Macrophage

AbstractIntratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

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