Beta1 Integrin Expression Research Articles

Extracellular vesicles derived from stored red blood cell suspensions enhance invasion and migration of lung cancer cells by miR1246 and miR150-3p.

Aged red blood cell (RBC) transfusions in lung cancer patients are often related to cancer recurrence and shorter lifespans. Extracellular vesicles (EVs) accumulated in stored RBC suspensions may be one of the important influential factors. This study aims to investigate how EVs derived from RBC suspensions affect the progress of lung cancer through the most enriched microRNAs (miRNAs) previously reported in our research. EVs derived from stored RBC suspensions in Weeks 1, 3 and 5 were harvested via ultracentrifugation. Lung adenocarcinoma H1975 cells were co-cultured with EVs and transfected with miR1246 and miR150-3p mimics to evaluate alterations in their proliferation, invasion and migration abilities in vitro. Proteomics and bioinformatics were performed to predict the signalling pathway related to invasion and migration of H1975, which were verified by western blotting (WB) and flow cytometry. EVs derived from stored RBC suspensions in Weeks 3 and 5 could significantly enhance the invasion and migration ability of H1975 cells and also increase the expression of miR1246 and miR150-3p. After transfection with miR1246 and miR150-3p mimics, invasion, migration and proliferation of H1975 cells were obviously enhanced. Proteomics analysis demonstrated that EVs co-cultivation and miRNA transfection groups were both enriched in cell adhesion molecules. WB and cytometry indicated that integrin beta-1 (ITGB1) and Rap1b were increased. EVs derived from stored RBC suspensions can enhance invasion and migration ability of lung cancer cells via the most accumulated miR1246 and miR150-3p, which may increase the expression of ITGB1 through Rap1 signalling pathway.

IL-10 promotes mast cell homeostasis and differentiation towards a mucosal mast cell phenotype

Abstract We recently demonstrated an unexpected role for IL-10 in driving mast cell (MC) activation and proliferation. IL-10 stimulation significantly enhanced IgE-mediated MC activation, upregulated FceRI expression, and promoted MC-mediated food allergy. Surprisingly, IL-10 also amplified cytokine production in un-activated MCs and enhanced their proliferation and survival, suggesting a role for IL-10 in MC homeostasis. Herein, we demonstrate that IL-10 can significantly expand MC proliferation and activity during homeostatic conditions. Treatment with IL-10 enhanced the proliferation and survival of both IL-3 and IL-3+SCF cultured bone marrow-derived MCs (BMMCs). This corresponded with a dramatic increase in cytokine production in IL-10-treated cells, along with upregulation of FceRI expression. While SCF was dispensable for the increased FceRI, it significantly enhanced cytokine production compared to cells cultured in IL-3 alone. Further analysis revealed a distinctive mucosal MC phenotype in IL-10-treated cells, characterized by beta7-integrin expression and enhanced secretion of murine MC protease-1. Lastly, autocrine IL-10 also supported MC expansion and function, as blocking IL-10 signaling attenuated MC expansion, inducing apoptosis, and decreasing cytokine production. Taken together, these data suggest an important role for IL-10 in maintaining MC responses during physiological conditions.

COMPARISON OF THE EFFECTS OF DOCETAXEL and AMYGDALIN TREATMENT ON CELL DEATH, INTEGRIN-α and INTEGRIN-β EXPRESSIONS IN DU145 PROSTATE CANCER CELL LINE

OBJECTIVE: Prostate cancer (PC) ranks second among cancer-related deaths in men, and most deaths are caused by metastasis. Integrins, which are cell surface receptors, play an important role in cancer metastasis. It has been shown that integrin alpha2beta1 expression is effective in cell adhesion, migration, and invasion by increasing binding to collagen I in metastatic PCs. Docetaxel chemotherapy is used in PC, but it is ineffective in advanced stages. Amygdalin is a cyanogenic glycoside commonly found in fruit seeds, there is conflict in the literature regarding its effectiveness in cancer treatment. We aimed to compare the effects of Amygdalin and Docetaxel treatments on the DU145 prostate cancer cell line on integrinalfa2 (ITGA2) and integrinbeta1 (ITGB1) expressions, as well as their effects on cell death, Caspase-3, and Beclin-1. MATERIAL AND METHODS: Propagated DU145 cells were divided into four groups. Amygdalin was given to the first group, Docetaxel was given to the second group, and Amygdalin andDocetaxel were given together to the third group. They were exposed to the active substances for 24 hours. The fourth group (Control) was not given any substance. mRNA levels of ITGA2 and ITGB1 genes were determined by the Real-time PCR method. Caspase-3 and Beclin-1 staining were performed immunocytochemically to evaluate cell death. RESULTS: There was an increase in ITGA2 and ITGB1 expressions in the groups administered by Amygdalin and by Docetaxel (P<0.05). The decrease in ITGB1 expression was significant in the group given Amygdalin+Docetaxel (P<0.001). Caspase-3 (P<0.05) and Beclin-1 (P<0.05) immunoreactivities were observed to increase in all three groups compared to the control group. CONCLUSIONS: It was observed that Docetaxel increased cell death more than Amygdalin in DU145 PC cells, and when Amygdalin and Docetaxel were used together, ITGA2 and ITGB1 expressions were significantly reduced. Our results suggest that dual treatment of Amygdalin and Docetaxel may prevent prostate cancer metastases.

Exosomes derived from ITGB1 modified Telocytes alleviates LPS-induced inflammation and oxidative stress through YAP1/ROS axis

AimsPrevious studies have demonstrated a significant upregulation of Integrin Beta 1 (ITGB1) in Telocytes. This study aims to explore the roles and underlying mechanisms of ITGB1 in inflammation and oxidative stress following Lipo-polysaccharide (LPS) administration in Telocytes. MethodsWe observed an increase in reactive oxygen species (ROS) production, accompanied by a reduction in ITGB1 levels post-LPS treatment. ResultsNotably, inhibiting ROS synthesis markedly reduced LPS-induced ITGB1 expression. Additionally, ectopic ITGB1 expression mitigated LPS-induced inflammation and oxidative stress, evident through decreased levels of pro-inflammatory markers such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, IL-6, and Monocyte Chemoattractant Protein (MCP)-1. Depletion of endothelial Yes-Associated Protein 1 (YAP1) notably diminished the levels of inflammatory markers and ROS production. Furthermore, exosomes secreted by ITGB1-modified Telocytes promoted Human Umbilical Vein Endothelial Cells (HUVECs) proliferation and inhibited apoptosis. In vivo experiments revealed that exosomes from ITGB1-modified Telocytes modulated functional and structural changes, as well as inflammatory responses in Acute Lung Injury (ALI). ConclusionThese findings highlight the critical role of the YAP1/ROS axis in LPS-induced Telocyte injuries, underlining the therapeutic potential of targeting ITGB1 for mitigating inflammation and oxidative stress in these cells.

Cancer-associated fibroblast-derived extracellular vesicles promote lymph node metastases in oral cavity squamous cell carcinoma by encapsulating ITGB1 and BMI1

BackgroundExtracellular vesicles (EVs) have been revealed to facilitate the development of oral squamous cavity cell carcinoma (OCSCC), while its supporting role in lymph node metastases is under continuous investigation. This study aimed to examine the function of cancer-associated fibroblasts (CAF)-derived EVs (CAF-EVs) during lymph node metastasis in OCSCC and the mechanisms.MethodsCAF were isolated from OCSCC tissues of patients, and CAF-EVs were extracted and identified. EdU, colony formation, wound healing, and Transwell assays were performed. The OCSCC cells before and after CAF-EVs treatment were injected into mice to probe the effects of CAF-EVs on tumor growth and lymph node metastasis, respectively. The effect of CAF-EVs treatment on transcriptome changes in OCSCC cells was analyzed. Clinical data of patients with OCSCC were analyzed to determine the prognostic significance of the selected genes. Finally, loss-of-function assays were conducted to corroborate the involvement of polycomb complex protein BMI-1 (BMI1) and integrin beta1 (ITGB1).ResultsCAF-EVs promoted the malignant behavior of OCSCC cells and accelerated tumor growth and lymph node metastasis in mice. CAF-EVs significantly increased the expression of BMI1 and ITGB1, and the expression of BMI1 and ITGB1 was negatively correlated with the overall survival and relapse-free survival of OCSCC patients. Knockdown of BMI1 or ITGB1 in OCSCC cells abated the promoting effects of CAF-EVs in vitro and in vivo.ConclusionCAF-EVs elicited the metastasis-promoting properties in OCSCC by elevating BMI1 and ITGB1, suggesting that BMI1 and ITGB1 could be potential biomarkers and therapeutic targets for OCSCC.

Upregulation of Integrin beta-3 in astrocytes upon Alzheimer's disease progression in the 5xFAD mouse model

Integrins are receptors that have been linked to various brain disorders, including Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. While Integrin beta-3 (ITGB3) is known to participate in multiple cellular processes such as adhesion, migration, and signaling, its specific role in AD remains poorly understood, particularly in astrocytes, the main glial cell type in the brain. In this study, we investigated alterations in ITGB3 gene and protein expression during aging in different brain regions of the 5xFAD mouse model of AD and assessed the interplay between ITGB3 and astrocytes. Primary cultures from adult mouse brains were used to gain further insight into the connection between ITGB3 and amyloid beta (Aβ) in astrocytes. In vivo studies showed a correlation between ITGB3 and the astrocytic marker GFAP in the 5xFAD brains, indicating its association with reactive astrocytes. In vitro studies revealed increased gene expression of ITGB3 upon Aβ treatment. Our findings underscore the potential significance of ITGB3 in astrocyte reactivity in the context of Alzheimer's disease.

The role of thrombomodulin in modulating ITGB3 expression and its implications for triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) compared to other BC subtypes in clinical settings. Currently, there are no effective therapeutic strategies for TNBC treatment. Therefore, there is an urgent need to identify suitable biomarkers or therapeutic targets for TNBC patients. Thrombomodulin (TM) plays a role in cancer progression and metastasis in many different cancers. However, the role of TM in TNBC is not yet fully understood. First, silenced-TM in MDA-MB-231 cells caused an increase in proliferative and metastatic activity. In contrast, overexpression of TM in Hs578T cells caused a reduction in proliferation, invasion, and migration rate. Using RNA-seq analysis, we found that Integrin beta 3 (ITGB3) expression may be a downstream target of TM. Furthermore, we found an increase in ITGB3 levels in TM-KD cells by QPCR and western blot analysis but a decrease in ITGB3 levels in TM-overexpressing cells. We found phospho-smad2/3 levels were increased in TM-KD cells but decreased in TM-overexpressing cells. This implies that TM negatively regulates ITGB3 levels through the activation of the smad2/3 pathway. Silencing ITGB3 in TM-KD cells caused a decrease in proliferation and migration. Finally, we found that higher ITGB3 levels were correlated with poor overall survival and relapse-free survival in patients with TNBC. Our results indicated a novel regulatory relationship between TM and ITGB3 in TNBC.

ITGB3 Promotes the Progression of JAK2V617F-Positive Myeloproliferative Neoplams By Regulating Calreticulin to Inhibit Cellular Autophagy

O bjectives: Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain, of which integrin beta 3 (ITGB3) was known to participate in cell adhesion as well as cell-surface mediated signaling and plays vital roles in different tumors. However, the role of ITGB3 in JAK2V617F-positive classical myeloproliferative neoplasms (cMPNs) remians unclear, and the aim of this study was to explore the effect of ITGB3 on cellular autophagy in JAK2V617F-positive cMPN cell line and its underlying mechanisms. Methods: ITGB3 expression in bone marrows from JAK2V617F-positive cMPN patients compared to normal controls were detected by quantitative reverse-transcription PCR (qPCR) and further validated by western blotting. Cell models of cMPNs were constructed using human HEL cell lines carrying JAK2V617F mutation and cytokine-dependent wild type BaF3 cells (Jak2 V617F BaF3 cells) with ectopic expression of Jak2 V617F seperately to perform phenotype and mechanism investigation. The putative targets of STAT5a on the promoters of ITGB3 were disclosed by public databases and a dual-luciferase reporter assay and chromatin immunoprecipitation assay (ChIP) was used to analyze the binding of STAT5a to ITGB3 promoter region. To observe the role of ITGB3 played in cMPN progression, stable-transfected HEL cell line with ITGB3 knockdown or overexpression were established by lentivirus packaging and cell transfection. Cell phenotype including cell proliferation, apoptosis and cell cycle distribution were detected by soft agar colony formation assay, BrdU staining, flow cytometry and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The variations of autophagic flux after ITGB3 dysregulation in HEL cells was analyzed using mRFP-GFP-LC3 adenovirus transfection and fluorescence microscopy, and LC3-II/I ratio as well as autophagy-related protein were detected by western blotting. Transmission electron microscopy was used to observe the formation of intracellular autophagosomes and autophagic lysosomes. RNA sequencing and GSEA analysis were applied to predict the downstream pathway and putative targets of ITGB3. Western blotting, immunofluorescence and qPCR were performed to detect the transcription and expression levels of genes. Results: 1.Western blotting and qRT-PCR detection showed increased expression of ITGB3 in bone marrow of JAK2V617F-positive cMPN patients compared to normal controls (A-B). Also, the evaluation of ITGB3 in a variety of myeloid tumor cell lines (HEL, HL60, K562, KG-1a) and wild-type BaF3 cells as well as Jak2 V617F BaF3 cells revealed that ITGB3 protein level is the highest in HEL (which harboring the JAK2V617F) and Jak2 V617F BaF3 cells (C-F). 2. Dual-luciferase reporter assay showed that STAT5a significantly induced the transcription activities of promoters of ITGB3 and inhibition of STAT5a reduced the transcription activities of promoters of ITGB3 (G-H). ITGB3 knockdown (I) in HEL cells reduced the proliferation capacity (J-L), promoted early apoptosis (M-O) and caused cell cycle arrest (P-Q). While ITGB3 overexpression in HEL cells (R) reduced the cell cycle arrest (S) and apoptosis (T-U). 3. Autophagic flux analysis showed that ITGB3 knockdown promoted the autophagic flux in HEL cells (V-X). Inhibition of ITGB3 increases the synthesis and degradation of autophagosomes and accelerates the process of cellular autophagy (Y-Z). Further identification of DEGs in ITGB3-dysregulated HEL cells (AA-AB) reveals that ITGB3 inhibits the expression of calreticulin (AC-AE), and ITGB3 might be involved in the regulation of autophagy in HEL cells through the regulation of calreticulin. Conclusions: 1. ITGB3 is significantly activated in HEL cell lines carrying the JAK2V617F mutation. 2. ITGB3 protein acts as a pro-oncogene in JAK2V617F-positive myeloproliferative neoplams progression by regulating calreticulin to inhibit autophagy, which deserves more in-depth study in JAK2V617F mutation-positive cMPNs.

ITGB4 Serves as an Identification and Prognosis Marker Associated with Immune Infiltration in Small Cell Lung Carcinoma.

Integrin beta 4 (ITGB4) is a vital factor for numerous cancers. However, no reports regarding ITGB4 in small cell lung carcinoma (SCLC) have been found in the existing literature. This study systematically investigated the expression and clinical value of ITGB4 in SCLC using multi-center and large-sample (n = 963) data. The ITGB4 expression levels between SCLC and control tissues were compared using standardized mean difference and Wilcoxon rank-sum test. The clinical significance of the gene in SCLC was observed using Cox regression and Kaplan-Meier curves. ITGB4 is overexpressed in multiple cancers and represents significant value in distinguishing among cancer samples (AUC = 0.91) and predicting the prognoses (p < 0.05) of patients with different cancers. In contrast, decreased ITGB4 mRNA expression was determined in SCLC (SMD < 0), and this finding was further confirmed at protein levels using in-house specimens (p < 0.05). This decrease in expression may be attributed to the regulatory role of estrogen receptor 1. ITGB4 may participate in the progression of SCLC by affecting several signaling pathways (e.g., tumor necrosis factor signaling pathway) and a series of immune cells (e.g., dendritic cells) (p < 0.05). The gene may serve as a potential marker for predicting the disease status (AUC = 0.97) and prognoses (p < 0.05) of patients with SCLC. Collectively, ITGB4 was identified as an identification and prognosis marker associated with immune infiltration in SCLC.

Photosensitizing deep-seated cancer cells with photoprotein-conjugated upconversion nanoparticles

To resolve the problem of target specificity and light transmission to deep-seated tissues in photodynamic therapy (PDT), we report a cancer cell-targeted photosensitizer using photoprotein-conjugated upconversion nanoparticles (UCNPs) with high target specificity and efficient light transmission to deep tissues. Core-shell UCNPs with low internal energy back transfer were conjugated with recombinant proteins that consists of a photosensitizer (KillerRed; KR) and a cancer cell-targeted lead peptide (LP). Under near infrared (NIR)-irradiating condition, the UCNP-KR-LP generated superoxide anion radicals as reactive oxygen species via NIR-to-green light conversion and exhibited excellent specificity to target cancer cells through receptor-mediated cell adhesion. Consequently, this photosensitizing process facilitated rapid cell death in cancer cell lines (MCF-7, MDA-MB-231, and U-87MG) overexpressing integrin beta 1 (ITGB1) receptors but not in a cell line (SK-BR-3) with reduced ITGB1 expression and a non-invasive normal breast cell line (MCF-10A). In contrast to green light irradiation, NIR light irradiation exhibited significant PDT efficacy in cancer cells located beneath porcine skin tissues up to a depth of 10 mm, as well as in vivo tumor xenograft mouse models. This finding suggests that the designed nanocomposite is useful for sensing and targeting various deep-seated tumors.

Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that exhibits aggressive tumor phenotypes, including rapid metastasis and tumor recurrence. Integrins belong to the family of transmembrane glycoproteins involved in regulating cell adhesion, proliferation, and differentiation through cell-cell and cell-extracellular matrix interactions. Aberrant β1 integrin signaling has been implicated in cancer invasion and metastasis processes. The present work aimed to investigate the role of β1 integrin in TNBC cancer progression using a mouse 4T1 cell line as a model system. We have sorted a subset of tumor-initiating cells (TICs) from the 4T1 cell line based on CD133 positivity by flow cytometry. RT-PCR and protein analysis studies showed the transcriptional upregulation of β1 integrin and its downstream target focal adhesion kinase in 4T1-TICs compared to parental 4T1 cells. In addition, the expression of β1 receptors in TICs is significantly higher than in parental population cells. Furthermore, in vitro cellular assays revealed that CD133+ TICs have higher clonogenic ability, invasion, and sphere formation potential. These findings suggest that β1 integrin has a potential role in TNBC invasion and metastasis. Hence, β1 integrin could be a possible factor for future targeted cancer therapies.

Calcitriol Suppressed Isoproterenol-induced Proliferation of Cardiac Fibroblasts via Integrin β3/FAK/Akt Pathway.

Cardiac fibroblasts (CFs) proliferation and extracellular matrix deposition are important features of cardiac fibrosis. Various studies have indicated that vitamin D displays an anti-fibrotic property in chronic heart diseases. This study explored the role of vitamin D in the growth of CFs via an integrin signaling pathway. MTT and 5-ethynyl-2'-deoxyuridine assays were performed to determine cell viability. Western blotting was performed to detect the expression of proliferating cell nuclear antigen (PCNA) and integrin signaling pathway. The fibronectin was observed by ELISA. Immunohistochemical staining was employed to evaluate the expression of integrin β3. The PCNA expression in the CFs was enhanced after isoproterenol (ISO) stimulation accompanied by an elevated expression of integrin beta-3 (β3). The blockade of the integrin β3 with a specific integrin β3 antibody reduced the PCNA expression induced by the ISO. Decreasing the integrin β3 by siRNA reduced the ISO-triggered phosphorylation of FAK and Akt. Both the FAK inhibitor and Akt inhibitor suppressed the PCNA expression induced by the ISO in the CFs. Calcitriol (CAL), an active form of vitamin D, attenuated the ISO-induced CFs proliferation by downregulating the integrin β3 expression, and phosphorylation of FAK and Akt. Moreover, CAL reduced the increased levels of fibronectin and hydroxyproline in the CFs culture medium triggered by the ISO. The administration of calcitriol decreased the integrin β3 expression in the ISO-induced myocardial injury model. These findings revealed a novel role for CAL in suppressing the CFs growth by the downregulation of the integrin β3/FAK/Akt pathway.

Primary immunodeficiency in a patient with Kabuki syndrome

Kabuki syndrome is a well-known disease characterized by postnatal growth failure, dysmorphic facial features, skeletal abnormalities, and mental retardation associated with one of the pathogenic mutations in the KMT2D or KDM6A genes. At least 50% of individuals with Kabuki syndrome tend to develop recurrent infections and immune abnormalities, primarily hypogammaglobulinemia. The article describes the clinical course of resistant infectious syndrome in an 18-month-old child without typical dysmorphic and dermatoglyphic manifestations characteristic of Kabuki syndrome. A long history of resistant bacterial infection, enterocolitis, microcephaly, autistic-like behavior, hyperkinetic disorder, CT scan patterns of granulomatous lymphocytic interstitial lung disease (GLILD), suggested the immunodeficiency as part of a hereditary genetically determined syndrome. At the same time, the patient did not experience hypogammaglobulinemia characteristic of Kabuki syndrome. The upper normal response to previously received vaccination and a polyclonal repertoire of B-lymphocytes indicated the absence of disturbances in the humoral immunity. Immunophenotyping revealed the absence of T-regulatory cells (CD4+CD25++CD127–) as well as effector NK cells (CD16+CD56+CD3–) in the peripheral blood. The significant reduction of CD4+CD3+ T-lymphocytes and CD4+/CD8+ index was observed. In addition, no expression of integrin-beta (CD18) on neutrophils revealed.Conclusion. In children under the age of 2, Kabuki syndrome may present difficulties for clinical diagnosis due to the absence of distinctive phenotypic signs. Patients with mental disorders, congenital malformations, recurrent infections suspected of immunodeficiency should be carried out using molecular genetic exploration, including testing for mutations in the KMT2D and KDM6A.

Integrin beta1 (ITGB1) as a prognostic marker in esophageal adenocarcinoma

Today, individual prognosis in patients with adenocarcinoma of the esophagus (EAC) is based on post-surgical TNM staging and valid biomarkers are still not implemented. Integrin beta1 (ITGB1) is widely expressed in epithelial cells and promotes cell adhesion and growth. Its impact on tumor progression was described for different tumor entities before, data on its function as a potential biomarker in EAC is not available. Aim of the study is to evaluate the expression level of ITGB1 in a large collective of EAC and its impact on patients´ prognosis. 640 patients with esophageal adenocarcinoma were analyzed immunohistochemically for ITGB1. The data was correlated with long term outcome, clinical, pathological and molecular data (TP53, HER2/neu, c-myc, GATA6, PIK3CA and KRAS). Of 640 patients to be analyzed, 127 (19.8%) showed expression of ITGB1. ITGB1 expression was associated with lymph node metastasis, expression of integrin alphaV and KRAS mutation status. Patients with high ITGB1 expression showed impaired overall survival (22.5 months (95% CI 15.3–29.7 months), vs. 34.1 months (95% CI 25.3–42.4 months), P = 0.024). This effect was particularly evident in the group of patients undergoing primary surgery without prior neoadjuvant therapy (10.2 months (95% CI 1.9–41.7 months) vs. 31.4 months (95% CI 21.1–144.2 months, P = 0.008). ITGB1 was also an independent prognostic marker in multivariable analysis (HR 1.696 (95% CI 1.084–2.653, P = 0.021) in patients that underwent primary surgery. We demonstrate for the first time the prognostic significance of ITGB1 expression in a large EAC patient population.

The Profile and Clinical Significance of ITGB2 Expression in Non-Small-Cell Lung Cancer.

Integrins are involved in extracellular and intracellular signaling and are often aberrantly expressed in tumors. Integrin beta 2 (ITGB2) has previously been demonstrated to be correlated with the host defense. However, the expression profile and role of ITGB2 in non-small-cell lung cancer (NSCLC) remain unclear. Here, we found that the genetic alterations in ITGB2 was predominated by gene mutation and copy number deletion using cBioPortal analysis, and its expression was downregulated in the NSCLC tissues, as validated by the UALCAN, TCGA, and GEO databases and our tissue samples. Kaplan-Meier (KM) plotter analysis revealed that patients with a lower ITGB2 expression had a shorter overall survival (OS) time (p = 0.01). Moreover, 1089 differentially expressed genes (DEGs) in the NSCLC tissues were screened using the TCGA database. The GO and KEGG enrichment analysis showed that the DEGs were closely associated with immune processes and cell adhesion. The protein-protein interaction (PPI) network revealed that 10 of 15 EMT-related genes among the DEGs might lead to the metastasis of NSCLC. Concomitantly, the expression of ITGB2 was positively correlated with the infiltration of Treg cells and Myeloid-derived suppressor cells (MDSC). Biologically, the ectopic expression of ITGB2 significantly inhibited the proliferation and metastasis of NSCLC cells. Mechanistically, we demonstrated that ITGB2 suppressed the expression of N-cadherin, Vimentin, Slug, Snail, and Twist, while it promoted E-cadherin expression, according to gain-of-function studies. In conclusion, ITGB2 can inhibit the proliferation and migration of NSCLC cells, leading to a poor prognosis, via epithelial-mesenchymal transition (EMT) signaling.

Uterine administration of C-X-C motif chemokine ligand 12 increases the pregnancy rates in mice with induced endometriosis

To study the effect of intrauterine injection of C-X-C motif chemokine ligand 12 (CXCL12), also known as a stem cell chemoattractant (stromal cell-derived factor 1), on fertility and endometrial receptivity in mice with endometriosis. Laboratory study. Academic Medical Center. Fifty-six mice underwent chemotherapy and bone marrow transplantation. Thirty-six of these mice underwent either surgery to induce endometriosis (n = 20) or sham surgery (n = 16). Injection of CXCL12 as a potential therapeutic agent to improve fertility in endometriosis. Pregnancy rate, bone marrow-derived cell (BMDC) recruitment and endometrial receptivity markers. The mice with or without endometriosis received a single uterine injection of either CXCL12 or placebo. Uterine injection of CXCL12 increased the pregnancy rates in a mouse model of endometriosis. Mice were euthanized after delivery, and implantation markers homeobox A11, alpha-v beta-3 integrin, and progesterone receptor were analyzed by immunohistochemistry, whereas green fluorescent protein positive BMDC recruitment was quantified by immunohistochemistry and immunofluorescence. The sham surgery groups without endometriosis had the highest cumulative pregnancy rate (100%) regardless of CXCL12 treatment. The endometriosis group treated with placebo had the lowest pregnancy rate. An increased pregnancy rate was noted in the endometriosis group after treatment with CXCL12. There was also an increase in BMDC recruitment and endometrial expression of progesterone receptor and alpha-v beta-3 integrin in the endometriosis group that received CXCL12 compared with that in the endometriosis group that received placebo. Uterine injection of CXCL12 increased the pregnancy rates in a mouse model of endometriosis. These results suggest that CXCL12 has a potential role as a therapeutic agent in women with infertility related to endometriosis and potentially other endometrial receptivity defects.

ITGB4 deficiency induces DNA damage by downregulating HDAC1 in airway epithelial cells under stress stimulation.

DNA damage in airway epithelia under exogenous disruptors can trigger various pulmonary diseases. Integrin beta 4 (ITGB4) is a structural adhesion molecule, which is indicated to regulate the process of DNA damage in airway epithelia for its unique long cytoplasmic domain subunit. The expression level of ITGB4 and the degree of DNA damage were observed in the house dust mite (HDM)-stressed model and ozone-challenged model, respectively. Besides, ITGB4 conditional knockout mice and ITGB4-deficient airway epithelial cells were constructed to observe the influence of ITGB4 deficiency on DNA damage. Furthermore, the influence of ITGB4 deficiency on HDAC1 expression in airway epithelia was determined under stress stimulation. Finally, corresponding intervention strategies were carried out to verify the involvement of the ITGB4-mediated HDAC1 pathway in DNA damage of airway epithelial cells. HDM stress and ozone challenge reduced the expression of ITGB4, which is accompanied by the increased expression of 8-oxoG and γ-H2AX both in vivo and in vitro. Moreover, ITGB4 deficiency in airway epithelia aggravates the degree of DNA damage under HDM stimulation and ozone stress, respectively. Furthermore, ITGB4 deficiency downregulated the expression of HDAC1 during DNA damage, and restoring HDAC1 can reverse the enhanced DNA damage in airway epithelial cells after exogenous stress. This study confirmed the involvement of ITGB4 in the regulation of DNA damage through mediating HDAC1 in airway epithelial cells under exogenous stress. These results supply some useful insights into the mechanism of DNA damage in airway epithelial cells, which would provide possible targets for early prediction and intervention of pulmonary diseases.

Recent advances in "sickle and niche" research - Tribute to Dr. Paul S Frenette.

SummaryIn this retrospective, we review the two research topics that formed the basis of the outstanding career of Dr. Paul S. Frenette. In the first part, we focus on sickle cell disease (SCD). The defining feature of SCD is polymerization of the deoxygenated mutant hemoglobin, which leads to a vicious cycle of hemolysis and vaso-occlusion. We survey important discoveries in SCD pathophysiology that have led to recent advances in treatment of SCD. The second part focuses on the hematopoietic stem cell (HSC) niche, the complex microenvironment within the bone marrow that controls HSC function and homeostasis. We detail the cells that constitute this niche, and the factors that these cells use to exert control over hematopoiesis. Here, we trace the scientific paths of Dr. Frenette, highlight key aspects of his research, and identify his most important scientific contributions in both fields.

Preclinical study of a new matrix to help the ocular surface in dry eye disease

Dry eye disease (DED), a multifactorial disease of the tears and ocular system, causes loss of tear film homeostasis with damage to the ocular surface. This study aimed to assess whether a peculiar matrix based on sodium hyaluronate (HA), xanthan gum (XNT), glycine (GLY) and betaine (BET) as osmoprotectants, could be involved in biological responses. Wound healing assay on human corneal epithelial (HCE) cells in monolayer showed a synergistic effect of the combination of HA + XNT (**p ≤ 0.01) together with an efficient extracellular matrix remodeling of the formulation in SkinEthic™ HCE 3D-model sought by integrin beta-1 (ITGβ1) expression and morphological analysis by hematoxylin and eosin (H&E), compared to a reference marketed product. The synergistic effect of HA + XNT + GLY + BET showed an antioxidant effect on HCE cells (***p ≤ 0.001). Real-time PCR analysis showed that the combination of GLY + BET seemed to ameliorate the effect exhibited by the single osmoprotectants in reducing tumor necrosis factor-alpha (TNFα, #p ≤ 0.05), interleukin-1 beta (IL1β, ####p ≤ 0.0001) and cyclooxygenases-2 (COX2, ####p ≤ 0.0001) genes in SIRC cells under hyperosmotic stress. Furthermore, pretreatment with XNT, alone and in combination (##p ≤ 0.01), reduced COX2 expression in human non-small cell lung cancer cells (A549). Finally, the formulation was well-tolerated following q.i.d. ocular administration in rabbits during a 28-day study. Due to the synergistic effect of its components, the matrix proved able to repair the ocular surface restoring cell homeostasis and to protect the ocular surface from pro-inflammatory pathways activation and oxidative damage, thus behaving as a reactive oxygen species (ROS) scavenger.

The proliferative and multipotent epidermal progenitor cells for human skin reconstruction in vitro and in vivo.

ObjectivesThe skin exhibits tremendous regenerative potential, as different types of progenitor and stem cells regulate skin homeostasis and damage. However, in vitro primary keratinocytes present with several drawbacks, such as high donor variability, short lifespan, and limited donor tissue availability. Therefore, more stable primary keratinocytes are needed to generate multiple uniform in vitro and in vivo skin models.ResultsWe identified epidermal progenitor cells from primary keratinocytes using Integrin beta 1 (ITGB1) an epidermal stem cell marker markedly decreased after senescence in vitro. Epidermal progenitor cells exhibited unlimited proliferation and the potential for multipotent differentiation capacity. Moreover, they could completely differentiate to form an organotypic skin model including conversed mesenchymal cells in the dermis and could mimic the morphologic and biochemical processes of human epidermis. We also discovered that proliferation and the multipotent differentiation capacity of these cells relied on ITGB1 expression. Eventually, we examined the in vitro and in vivo wound healing capacity of these epidermal progenitor cells.ConclusionsOverall, the findings suggest that these stable and reproducible cells can differentiate into multiple lineages, including human skin models. They are a potentially powerful tool for studying skin regeneration, skin diseases, and are an alternative for in vivo experiments.