Mechanistic study on lncRNA XIST/miR-124-3p/ITGB1 axis in renal fibrosis in obstructive nephropathy.

OBJECTIVE: The purpose of this study was to investigate the role and possible mechanism of lncRNA XIST in renal fibrosis and to provide potential endogenous targets for renal fibrosis in obstructive nephropathy (ON). METHODS: The study included 50 cases of ON with renal fibrosis (samples taken from patients undergoing nephrectomy due to ON) and 50 cases of normal renal tissue (samples taken from patients undergoing total or partial nephrectomy due to accidental injury, congenital malformations, and benign tumors). Treatment of human proximal renal tubular epithelium (HK-2) cells with TGF-ß1 simulated renal fibrosis in vitro. Cell viability and proliferation were measured by CCK-8 and EdU, and cell migration was measured by transwell. XIST, miR-124-3p, ITGB1, and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, α-SMA, and fibronectin) were detected by PCR and immunoblot. The targeting relationship between miR-124-3p and XIST or ITGB1 was verified by starBase and dual luciferase reporter gene experiments. In addition, The left ureter was ligated in mice as a model of unilateral ureteral obstruction (UUO), and the renal histopathology was observed by HE staining and Masson staining. RESULTS: ON patients with renal fibrosis had elevated XIST and ITGB1 levels and reduced miR-124-3p levels. The administration of TGF-ß1 exhibited a dose-dependent promotion of HK-2 cell viability, proliferation, migration, and EMT. Conversely, depleting XIST or enhancing miR-124-3p hindered HK-2 cell viability, proliferation, migration, and EMT in TGF-ß1-damaged HK-2 cells HK-2 cells. XIST functioned as a miR-124-3p sponge. Additionally, miR-124-3p negatively regulated ITGB1 expression. Elevating ITGB1 weakened the impact of XIST depletion on TGF-ß1-damaged HK-2 cells. Down-regulating XIST improved renal fibrosis in UUO mice. CONCLUSION: XIST promotes renal fibrosis in ON by elevating miR-124-3p and reducing ITGB1 expressions.

MiRNA29a-3p Negatively Regulates ISL1-Integrin ß1 Axis to Suppress Gastric Cancer Progression.

Insulin gene enhancer protein 1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is closely related to the development of several cancers. We previously found that abnormally high ISL1 expression is involved in gastric cancer (GC) metastasis. However, the specific role of ISL1 and its regulatory mechanisms in GC metastasis warrant elucidation. In this study, we found that ISL1 is highly expressed in GC tissues and positively correlated with GC development, promoting cell migration and invasion in vivo and in vitro. Moreover, miRNA29a-3p can target ISL1 and thus inhibit GC cell migration. Furthermore, ISL1 upregulates ITGB1 by binding to its enhancer; nevertheless, ISL1-ITGB1 axis expression can be regulated using miRNA29a-3p. In GC cell nuclei, ISL1 and annexin A2 (ANXA2) form a transcriptional activator complex at the ITGB1 enhancer, thus promoting ITGB1 expression. In GC cell cytoplasm, the ISL1-ANXA2 complex synergistically activates matrix metalloproteinases, thus promoting cell migration. In conclusion, ISL1 is a potential therapeutic target for GC.

A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment.

Integrin ß1-mediated mast cell immune-surveillance of blood vessel content.

BACKGROUND: IgE-mediated degranulation of mast cells (MCs) provides rapid protection against environmental hazards, including animal venoms. A fraction of tissue-resident MCs intimately associates with blood vessels. These perivascular MCs were reported to extend projections into the vessel lumen and to be the first MCs to acquire intravenously injected IgE, suggesting that IgE loading of MCs depends on their vascular association. OBJECTIVE: We sought to elucidate the molecular basis of the MC-blood vessel interaction and to determine its relevance for IgE-mediated immune responses. METHODS: We selectively inactivated the Itgb1 gene, encoding the ß1 chain of integrin adhesion molecules (ITGB1), in MCs by conditional gene targeting in mice. We analyzed skin MCs for blood vessel association, surface IgE density, and capability to bind circulating antibody specific for MC surface molecules, as well as in vivo responses to antigen administered via different routes. RESULTS: Lack of ITGB1 expression severely compromised MC-blood vessel association. ITGB1-deficient MCs showed normal densities of surface IgE but reduced binding of intravenously injected antibodies. While their capacity to degranulate in response to IgE ligation in vivo was unimpaired, anaphylactic responses to antigen circulating in the vasculature were largely abolished. CONCLUSIONS: ITGB1-mediated association of MCs with blood vessels is key for MC immune surveillance of blood vessel content, but is dispensable for slow steady-state loading of endogenous IgE onto tissue-resident MCs.

Postoperative radiotherapy with docetaxel versus cisplatin for high-risk oral squamous cell carcinoma: a randomized phase II trial with exploratory analysis of ITGB1 as a potential predictive biomarker.

BACKGROUND: Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT). METHODS: In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III-IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin ß1 (ITGB1) expression was analyzed as a biomarker for efficacy. RESULTS: After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT. CONCLUSIONS: This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . NCT02923258 (date of registration: October 4, 2016).

Does rAj-Tspin, a novel peptide from A. japonicus, exert antihepatocellular carcinoma effects via the ITGB1/ZYX/FAK/AKT signaling pathway?

rAj-Tspin, a soluble recombinant peptide from Apostichopus japonicus, can inhibit the integrin ß1 (ITGB1)/FAK/AKT signaling pathway in hepatocellular carcinoma (HCC) via cell epithelial-mesenchymal transition (EMT) and apoptosis. Zyxin (ZYX) is a focal adhesion protein that is considered a novel mediator of EMT and apoptosis. However, the inhibitory mechanisms of rAj-Tspin in HCC and whether it is related to ZYX are unclear. We examined the antitumor effect of rAj-Tspin on the Huh7 human HCC cell line and on a nude mouse model generated via subcutaneous injection or orthotopic intrahepatic transplantation of Huh7 cells. Our results revealed that rAj-Tspin strikingly reduced the viability and promoted the apoptosis of Huh7 cells and inhibited HCC tumor growth in nude mice. rAj-Tspin inhibited ITGB1 and ZYX protein expression in vivo and in vitro in a dose-dependent manner. Mechanistically, the FAK/AKT signaling pathway and the proliferation and invasion of HCC cells were suppressed upon ITGB1 and ZYX knockdown. Moreover, the effect of ITGB1 overexpression on the growth of HCC cells was inhibited by rAj-Tspin. In contrast, the promoting effect of ITGB1 overexpression could be inhibited by ZYX knockdown. ZYX knockdown had no effect on ITGB1 expression. These findings suggest that ZYX is required for the indispensable role of ITGB1 in rAj-Tspin-alleviated HCC and provide an important therapeutic target for HCC. In summary, the anti-HCC effect of rAj-Tspin potentially involves the regulation of the ITGB1/ZYX/FAK/AKT pathway, which in turn impacts EMT and apoptosis.

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

BACKGROUND: Extracellular 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. METHODS: CAF 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). RESULTS: CAF-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. CONCLUSION: CAF-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.

Exosomes enriched by miR-429-3p derived from ITGB1 modified Telocytes alleviates hypoxia-induced pulmonary arterial hypertension through regulating Rac1 expression.

BACKGROUND: Recent studies have emphasized the critical role of Telocytes (TCs)-derived exosomes in organ tissue injury and repair. Our previous research showed a significant increase in ITGB1 within TCs. Pulmonary Arterial Hypertension (PAH) is marked by a loss of microvessel regeneration and progressive vascular remodeling. This study aims to investigate whether exosomes derived from ITGB1-modified TCs (ITGB1-Exo) could mitigate PAH. METHODS: We analyzed differentially expressed microRNAs (DEmiRs) in TCs using Affymetrix Genechip miRNA 4.0 arrays. Exosomes isolated from TC culture supernatants were verified through transmission electron microscopy and Nanoparticle Tracking Analysis. The impact of miR-429-3p-enriched exosomes (Exo-ITGB1) on hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) was evaluated using CCK-8, transwell assay, and inflammatory factor analysis. A four-week hypoxia-induced mouse model of PAH was constructed, and H&E staining, along with Immunofluorescence staining, were employed to assess PAH progression. RESULTS: Forty-five miRNAs exhibited significant differential expression in TCs following ITGB1 knockdown. Mus-miR-429-3p, significantly upregulated in ITGB1-overexpressing TCs and in ITGB1-modified TC-derived exosomes, was selected for further investigation. Exo-ITGB1 notably inhibited the migration, proliferation, and inflammation of PASMCs by targeting Rac1. Overexpressing Rac1 partly counteracted Exo-ITGB1's effects. In vivo administration of Exo-ITGB1 effectively reduced pulmonary vascular remodeling and inflammation. CONCLUSIONS: Our findings reveal that ITGB1-modified TC-derived exosomes exert anti-inflammatory effects and reverse vascular remodeling through the miR-429-3p/Rac1 axis. This provides potential therapeutic strategies for PAH treatment.

Autophagy Proteins and clinical data reveal the prognosis of polycystic ovary syndrome.

OBJECTIVE: We aimed to investigate the significance of autophagy proteins and their association with clinical data on pregnancy loss in polycystic ovary syndrome (PCOS), while also constructing predictive models. METHODS: This study was a secondary analysis. we collected endometrial samples from 33 patients with polycystic ovary syndrome (PCOS) and 7 patients with successful pregnancy control women at the Reproductive Center of the Second Hospital of Lanzhou University between September 2019 and September 2020. Liquid chromatography tandem mass spectrometry was employed to identify expressed proteins in the endometrium of 40 patients. R was use to identify differential expression proteins(DEPs). Subsequently, Metascape was utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Multivariate Cox analysis was performed to analyze autophagy proteins associated with reproductive outcomes, while logistic regression was used for analyzing clinical data. Linear correlation analysis was conducted to examine the relationship between autophagy proteins and clinical data. We established prognostic models and constructed the nomograms based on proteome data and clinical data respectively. The performance of the prognostic model was evaluated by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA). RESULTS: A total of 5331 proteins were identified, with 450 proteins exhibiting significant differential expression between the PCOS and control groups. A prognostic model for autophagy protein was developed based on three autophagy proteins (ARSA, ITGB1, and GABARAPL2). Additionally, another prognostic model for clinical data was established using insulin, TSH, TPOAB, and VD3. Our findings revealed a significant positive correlation between insulin and ARSA (R = 0.49), as well as ITGB1 (R = 0.3). Conversely, TSH exhibited a negative correlation with both ARSA (-0.33) and ITGB1 (R = -0.26). CONCLUSION: Our research could effectively predict the occurrence of pregnancy loss in PCOS patients and provide a basis for subsequent research.

miR-134-5p inhibits osteoclastogenesis through a novel miR-134-5p/Itgb1/MAPK pathway.

Osteoporosis affects approximately 200 million people and severely affects quality of life, but the exact pathological mechanisms behind this disease remain unclear. Various miRNAs have been shown to play a predominant role in the regulation of osteoclast formation. In this study, we explored the role of miR-134-5p in osteoclastogenesis both in vivo and in vitro. We constructed an ovariectomized (OVX) mouse model and performed microarray analysis using bone tissue from OVX mice and their control counterparts. Quantitative RT-PCR data from bone tissue and bone marrow macrophages (BMMs) confirmed the decreased expression of miR-134-5p in OVX mice observed in microarray analysis. In addition, a decrease in miR-134-5p was also observed during induced osteoclastogenesis of BMMs collected from C57BL/6N mice. Through transfection with miR-134-5p agomirs and antagomirs, we found that miR-134-5p knockdown significantly accelerated osteoclast formation and cell proliferation and inhibited apoptosis. Furthermore, a luciferase reporter assay showed that miR-134-5p directly targets the integrin surface receptor gene Itgb1. Cotransfection with Itgb1 siRNA reversed the effect of the miR-134-5p antagomir in promoting osteoclastogenesis. Moreover, the abundance levels of MAPK pathway proteins phosphorylated-p38 (p-p38) and phosphorylated-ERK (p-ERK) were significantly increased after transfection with the miR-134-5p antagomir but decreased after transfection with the miR-134-5p agomir or Itgb1 siRNA, which indicated a potential relationship between the miR-134-5p/Itgb1 axis and the MAPK pathway. Collectively, these results revealed that miR-134-5p inhibits osteoclast differentiation of BMMs both in vivo and in vitro and that the miR-134-5p/Itgb1/MAPK pathway might be a potential target for osteoporosis therapy.

CD248 promotes migration and metastasis of osteosarcoma through ITGB1-mediated FAK-paxillin pathway activation.

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. METHODS: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. RESULTS: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. CONCLUSION: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.

Introduced the ITGB1-DT as a novel biomarker associated with five potential drugs using bioinformatics analysis of breast cancer proteomics data and RT-PCR.

BACKGROUND: Breast cancer (BC) has been identified as a significant contributor to the rising number of female cancer deaths. As, it has become clear that breast cancer development depends on the interplay of several biological factors against a single molecule. This research aimed to use proteomics to gain a regulatory and metabolic understanding of BC pathophysiology. METHOD: For the study, a breast cancer proteomics dataset was downloaded from ProteomeXchange and then analyzed by employing MaxQuant and Perseus. Functional enrichment analysis through Metascape and Cytoscape software showed DEPs related biomedical phenomena with potential abruption. The expression of selected lncRNA in terms of the highest connectivity parameters was then quantitatively assessed through RT-PCR in 30 tumor tissues of breast cancer patients, as compared to the adjacent healthy ones. RESULT: The results indicated that among the 3048 identified proteins, 1149 were differentially expressed, which could be mainly enriched in several key terms. Furthermore, the obtained findings revealed that ITGB1-DT was significantly overexpressed in tumor tissues. Moreover, we found five potential compounds that could be attributed to ITGB1-DT targets (ATN-161, Firategrast, SB-683698, dabigatran-etexilate, and tranexamic-acid). CONCLUSION: These analyses proposed that ITGB1-DT could be employed as a differentiated factor to identify breast tumor tissues in healthy samples. Besides this, Firategrast could be introduced as a potential remedial agent for breast cancer patients. Overall, from the analysis of a proteomics dataset, an integrative map was generated, and a novel biomarker that may have been implicated in the early detection of BC was introduced.

Evaluation of ITGB1 expression as a predictor of the therapeutic effects of immune checkpoint inhibitors in gastric cancer.

BACKGROUND: Gastric cancer (CC) is a disease with high incidence and mortality rate. Immunotherapy is an important method for gastric cancer while lack of effective predictor. Integrins play an important role in the development. We aimed to explore the predictive value of ß1 integrin (ITGB1) as a predictor of immunnotherapy in gastric cancer. METHODS: Differential expression analysis was conducted using the Gene Expression Profiling Interactive Analysis (GEPIA) 2.0 and GEO databases. GEPIA data were used to evaluate the prognostic value of ITGB1 in gastric cancer (GC). Transcriptomic and clinical data of GC and normal tissues were downloaded from The Cancer Genome Atlas database, and the TIMER database was used to evaluate the association between ITGB1 and immune infiltration. Time-dependent receiver operating characteristic (ROC) curve analysis was used to determine the prognostic value of ITGB1. To verify ITGB1 expression at the protein level, immunohistochemical staining was conducted. In addition, to analyze the correlation of ITGB1 with PD-1 and PD-L1, we examined levels of PD-1 and PD-L1 by IHC and determined the predictive value of ITGB1 for anti-PD-1 therapy in GC by ROC curve analysis. RESULTS: Compared with normal tissues, analysis of GEPIA and data at protein levels showed significantly higher expression of ITGB1 in GC. In addition, higher expression of ITGB1 was associated with worse pathological G-staging and tumor T-staging, which suggested that ITGB1 is a risk factor for poor prognosis in GC. The level of ITGB1 expression was positively correlated with CD8 + T cells, neutrophils, macrophages, and dendritic cells. ITGB1 expression was also correlated with PD-L1 expression, and this was further verified at the protein level by immunohistochemical analysis. The area under the ROC curve was 0.808. CONCLUSION: ITGB1 may be a promising prognostic biomarker and effective predictor for anti-PD-1 therapy in GC. TRIAL REGISTRATION: Retrospectively registered.

Activin A increases human trophoblast invasion by upregulating integrin ß1 through ALK4.

Activin A promotes human trophoblast invasion during the first trimester of pregnancy and is associated with preeclampsia and pregnancy-induced hypertension (PE/PIH) in naturally conceived pregnancies. However, whether integrin ß1 mediates activin A-increased trophoblast invasion remains unknown and the evidence is limited regarding the predictive value of activin A for PE/PIH in women receiving in vitro fertilization (IVF) treatment. Here, we studied the role and underlying molecular mechanisms of integrin ß1 in activin A-promoted invasion in immortalized (HTR8/SVneo) and primary human extravillous trophoblast (EVT) cells. A nest case-control study was designed to investigate the predictive/diagnostic value of activin A in IVF pregnancies. Results showed that integrin ß1 expression increased after activin A treatment and knockdown of integrin ß1 significantly decreased both basal and activin A-increased HTR8/SVneo cell invasion. SB431542 (TGF-ß type I receptors inhibitor) abolished activin A-induced SMAD2/SMAD3 phosphorylation and integrin ß1 overexpression. Activin A-upregulated integrin ß1 expression was attenuated after the depletion of ALK4 or SMAD4 in both HTR8/SVneo and primary EVT cells. Furthermore, we found similar first-trimester activin A levels in IVF patients with or without subsequent PE/PIH. These results reveal that integrin ß1 mediates activin A-promoted trophoblast invasion through ALK4-activated SMAD2/3-SMAD4 pathway, and the predictive/diagnostic value of first-trimester maternal serum activin A for hypertensive disorders of pregnancy might be different in IVF population.

LncRNA LINC00115 facilitates lung cancer progression through miR-607/ITGB1 pathway.

Dysregulated long noncoding RNAs (lncRNAs) have potential roles in various cancer types. The objective of this study was to investigate the expression and the underlying role of long intergenic nonprotein coding RNA 115 (LINC00115) in lung cancer. The relative expression of LINC00115 and miR-607 in tumor tissues and cells was detected by real-time PCR. After overexpression or knockdown of LINC00115 expression in tumor cells, the changes in the proliferation, migration, and invasion capacities were detected via Counting Kit-8 (CCK-8) assay and transwell assays. The interplay among LINC00115, miR-607, and integrin ß1 (ITGB1) was confirmed by bioinformatics analyses and luciferase reporter assay. In addition, tumor cells with LINC00115 knockdown were injected into nude mice to investigate the effect of LINC00115 on tumorigenesis in vivo. LINC00115 was highly expressed in tumor tissues and cells. LINC00115 promoted the malignant properties of tumor cells. Investigation to its molecular mechanism revealed that LINC00115 functioned as a competitive endogenous RNA (ceRNA), regulating the expression of ITGB1 by sponging miR-607 to affect tumor growth. The LINC00115/miR-607/ITGB1 signaling axis might be a novel therapeutic target in lung cancer.

ITGB1-DT/ARNTL2 axis may be a novel biomarker in lung adenocarcinoma: a bioinformatics analysis and experimental validation.

BACKGROUND: Lung cancer is one of the most lethal malignant tumors that endangers human health. Lung adenocarcinoma (LUAD) has increased dramatically in recent decades, accounting for nearly 40% of all lung cancer cases. Increasing evidence points to the importance of the competitive endogenous RNA (ceRNA) intrinsic mechanism in various human cancers. However, behavioral characteristics of the ceRNA network in lung adenocarcinoma need further study. METHODS: Groups based on SLC2A1 expression were used in this study to identify associated ceRNA networks and potential prognostic markers in lung adenocarcinoma. The Cancer Genome Atlas (TCGA) database was used to obtain the patients' lncRNA, miRNA, and mRNA expression profiles, as well as clinical data. Informatics techniques were used to investigate the effect of hub genes on prognosis. The Cox regression analyses were performed to evaluate the prognostic effect of hub genes. The methylation, GSEA, and immune infiltration analyses were utilized to explore the potential mechanisms of the hub gene. The CCK-8, transwell, and colony formation assays were performed to detect the proliferation and invasion of lung cancer cells. RESULTS: We eventually identified the ITGB1-DT/ARNTL2 axis as an independent fact may promote lung adenocarcinoma progression. Furthermore, methylation analysis revealed that hypo-methylation may cause the dysregulated ITGB1-DT/ARNTL2 axis, and immune infiltration analysis revealed that the ITGB1-DT/ARNTL2 axis may affect the immune microenvironment and the progression of lung adenocarcinoma. The CCK-8, transwell, and colonu formation assays suggested that ITGB1-DT/ARNTL2 promotes the progression of lung adenocarcinoma. And hsa-miR-30b-3p reversed the ITGB1/ARNTL2-mediated oncogenic processes. CONCLUSION: Our study identified the ITGB1-DT/ARNTL2 axis as a novel prognostic biomarker affects the prognosis of lung adenocarcinoma.

KAT1 triggers YTHDF2-mediated ITGB1 mRNA instability to alleviate the progression of diabetic retinopathy.

Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness and visual impairment. This study focuses on the function of lysine acetyltransferase 1 (KAT1) in the progression of DR and the epigenetic mechanism. A mouse model with DR was induced by streptozotocin (STZ). Abundantly expressed genes in STZ-induced mice were analyzed. KAT1 was found to be significantly downregulated in the retinal tissues of model mice. Retinal microvascular endothelial cells (RMECs) and retinal Müller cells (rMCs) were cultured in high-glucose medium for in vitro studies. Upregulation of KAT1 suppressed inflammation, neovascularization, and vascular leakage in mouse retinal tissues, and it reduced the activity and inflammatory responses in rMCs, as well as the proliferation and metastatic potential of RMECs. KAT1 activated the transcription activity of YTHDF2 through histone acetylation of the promoter, and YTHDF2 triggered the instability of ITGB1 mRNA to induce mRNA degradation in an m6A manner. The activities of rMCs and RMECs were increased by sh-YTHDF2 but suppressed by sh-ITGB1. The FAK/PI3K/AKT signaling pathway was suppressed upon ITGB1 silencing. Collectively, this study demonstrated that KAT1 triggers YTHDF2-mediated ITGB1 mRNA instability to alleviate the progression of DR.

Silencing of Long Non-coding RNA TTN-AS1 Inhibits Hepatocellular Carcinoma Progression by the MicroRNA-134/ITGB1 Axis.

BACKGROUND: Hepatocellular carcinoma (HCC) causes considerable mortality worldwide. Long non-coding RNA (lncRNA) TTN-AS1 has been recently identified as an oncogene in several cancers, but its role in HCC and the molecules remain largely unknown. AIMS: The study aims to probe the function of lncRNA TTN-AS1 in HCC progression and the molecules involved. METHODS: Differentially expressed lncRNAs between HCC and the adjacent normal tissues were analyzed using a microarray. TTN-AS1 expression in HCC and normal tissues and cells was determined. Targeting relationships between TTN-AS1 and miR-134 and between miR-134 and ITGB1 were validated. Artificial up-regulation or down-regulation of TTN-AS1, miR-134 and ITGB1 was introduced in HCC cells to probe their effects on the biological behaviors of HCC cells. Xenograft tumors were induced in nude mice for in vivo experiments. RESULTS: TTN-AS1 and ITGB1 were highly expressed, while miR-134 was poorly expressed in HCC tissues. TTN-AS1 enforced ITGB1 expression through sequestering miR-134. Silencing of TTN-AS1 or over-expression of miR-134 inhibited proliferation, invasion, migration, and resistance to death of Huh7 cells. Following miR-134 silencing, further down-regulation of ITGB1 suppressed the malignant behaviors of HUH7 cells. The similar results were reproduced in vivo. CONCLUSION: The current study provided evidence that TTN-AS1 might promote HCC progression through sponging miR-134 and the following ITGB1 up-regulation. TTN-AS1 may serve as a potential target for HCC treatment.

Integrin ß1 regulates proliferation, apoptosis, and migration of trophoblasts through activation of phosphoinositide 3 kinase/protein kinase B signaling.

AIMS: Abnormal trophoblast invasion is one of the onsets of preeclampsia (PE). Studies found that integrin ß1 (ITGB1) is closely related to PE, but the role of ITGB1 in the progression of trophoblast remained unclear. Therefore, we studied the functional role of ITGB1 in PE and its effects on trophoblast. METHODS: ITGB1 expression in placenta tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of transfection on HTR-8/SVneo cells were analyzed by qRT-PCR and western blotting. After cell transfection, colony formation assay, flow cytometry, wound healing assay, and transwell assay were performed to detect cell proliferation, apoptosis, migration, and invasion. Western blotting assay was used for determining phosphoinositide 3 kinase (PI3K) and protein kinase B (Akt) signaling pathway. After inhibiting PI3K/Akt pathway, apoptosis-regulated proteins were detected by western blotting, and the effects of inhibitor on the migration and invasion changes were examined. RESULTS: ITGB1 was downregulated in placenta tissues from PE patients, as compared with normal. ITGB1 overexpression in HTR-8/SVneo cells enhanced cell proliferation, migration, and invasion, reduced cell apoptosis, and improved phosphorylation of PI3K and Akt. However, ITGB1 depletion resulted in an opposite effect to its overexpression. Inhibition of PI3K/Akt pathway completely blocked the effect of ITGB1 overexpression on cells, because we observed that apoptosis-regulated proteins were highly upregulated, and that cell migration and invasion were reduced. CONCLUSION: ITGB1 regulated HTR-8/SVneo cell progression by activation of the PI3K/Akt pathway.

GOLPH3 silencing inhibits adhesion of glioma U251 cells by regulating ITGB1 degradation under serum starvation.

GOLPH3, an oncoprotein, plays crucial roles in tumor etiology. Compelling evidences have demonstrated that GOLPH3 contributes to regulate tumor cell growth, migration and invasion under normal nutrient condition. However, the oncogenic activity of GOLPH3 under serum starvation remains largely unknown. In this study, we reported that GOLPH3 depletion led to marked reduction in adhesion of glioma U251 cells, particularly under serum deprivation. We found that silencing of GOLPH3 expression reduced the protein amount of ITGB1 only in serum-free medium. Further insights into the mechanism between GOLPH3 and ITGB1, we applied proteasome or lysosome inhibitor to block the degradation of ITGB1, and identified GOLPH3 silencing can prompt ITGB1 lysosomal degradation under serum starvation. Finally, we found the reductions in glioma cell adhesion and ITGB1 protein amount could be rescued by ITGB1 overexpression. Taken together, these results show that GOLPH3 contributes to the adhesion of glioma cells by regulating the lysosomal degradation of ITGB1 under serum starvation.