Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus. / 人脐带间å 质干细胞通过IGF1R-CHK2-p53信号轴减轻2åž‹ç³–å°¿ç— é›„æ€§å¤§é¼ ç³–å°¿ç— è‚¾ç— .

Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however, the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study, a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose, interleukin-6 (IL-6), IL-10, glomerular basement membrane, and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of IGF1R, phosphorylated checkpoint kinase 2 (p-CHK2), and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red "O" staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane, increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2, and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells. When cisplatin was used to induce DNA damage, the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1, IGF1R, p-CHK2, and p-p53, and the level of 8-OHdG in the DM group increased significantly compared with those in the control group, and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy.

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME). METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance. RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice. CONCLUSIONS: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Side Effects and Adverse Events After Treatment With Teprotumumab for Thyroid Eye Disease: A Retrospective Observational Case Series.

As the use of teprotumumab for thyroid eye disease (TED) becomes more prolific, there remains a scarcity of literature regarding the associated side effects and adverse events of teprotumumab use. The authors present a single-center retrospective, observational case review of TED patients who received at least a single dose of teprotumumab infusion at the oculofacial plastic surgery service between February 2020 and July 2023. The most predominant recollected side effects were fatigue, brittle nails, dry eye symptoms, hair loss, muscle spasms, and dry mouth. Significant adverse events were limited to two cases of a blood clot and a single case of pulmonary embolism. This is the first retrospective study of patient-reported side effects and adverse events experienced by a cohort of teprotumumab users.

Clinical characteristics of and growth hormone treatment effects on short stature with type 1 insulin-like growth factor receptor (IGF1R) gene alteration.

Short stature with IGF-1 receptor (IGF1R) gene alteration is known as small-for-gestational-age (SGA) short stature with elevated serum IGF1 levels. Its prevalence and clinical characteristics remain unclear. No adapted treatment is available for short stature related to IGF1R gene alteration in Japan, and genetic testing is not yet widely accessible. We investigated short stature with IGF1R gene alterations and analyzed the clinical data of 13 patients using the results of questionnaires issued to the Japanese Society for Pediatric Endocrinology. Four cases were caused by a deletion of chromosome 15q26.3, and eight were caused by heterozygous pathogenic variants in the IGF1R gene. Cases with deletions showed a more severe degree of growth impairment (-4.5 ± 0.43 SD) than those caused by pathological variants (-2.71 ± 0.15 SD) and were accompanied by neurodevelopmental delay. However, cases caused by pathological variants lacked distinctive features. Only three of the 12 cases demonstrated serum IGF1 values exceeding +2 SD, and the other three had values below 0 SD. Four patients did not meet the criteria for SGA at birth. Six patients received GH therapy for SGA short stature and showed improvement in growth rate without any side effects or elevated serum IGF1 levels during treatment. Elevated IGF1 levels (over +2 SD) after GH treatment should be considered a suspicious finding. Owing to the lack of distinctive features, there was a possibility of undiagnosed cases of this condition. Promoting genetic testing and clinical trials on GH administration for this condition is recommended.

Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

PURPOSE: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab. DESIGN: Multicenter, retrospective, observational cohort study. PARTICIPANTS: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab. METHODS: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit. MAIN OUTCOME MEASURES: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement. RESULTS: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8). CONCLUSIONS: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Obesity and endocrine-related cancer: The important role of IGF-1.

Obesity is increasingly becoming a global epidemic of concern and is considered a risk factor for several endocrine-related cancers. Moreover, obesity is associated with cancer development and poor prognosis. As a metabolic abnormality, obesity leads to a series of changes in insulin, IGF-1, sex hormones, IGFBPs, and adipokines. Among these factors, IGF-1 plays an important role in obesity-related endocrine cancers. This review describes the role of obesity in endocrine-related cancers, such as prostate cancer, breast cancer and pancreatic cancer, focusing on the mechanism of IGF-1 and the crosstalk with estrogen and adipokines. In addition, this review briefly introduces the current status of IGF-1R inhibitors in clinical practice and shows the prospect of IGF-1R inhibitors in combination with other anticancer drugs.

AHNAK Contributes to Hepatocellular Carcinoma Growth by Interacting with IGF-1R.

Neuroblast differentiation-associated protein AHNAK, a large structural scaffold protein, remains mysterious in biological processes. AHNAK plays a suppressive or progressive role in different types of cancers. To investigate the role of the AHNAK in hepatocellular carcinoma (HCC), cell viability assays were performed to determine the cell proliferation of the stable AHNAK-knockdown HepG2 cell line; co-immunoprecipitation (Co-IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were performed on HCC and matched paracancerous (MPC) tissues. The Metascape platform was used for enrichment analyses; the "ComplexHeatmap" package was applied for cluster analyses and visualization. Co-IP, Western botting and immunofluorescence double staining were performed to assess the interactions between AHNAK and insulin-like growth factor 1 receptor (IGF-1R). AHNAK silencing reduced the viability of HepG2 cells; the interactome in HCC and MPC tissues enriched 204 pathways and processes, which partially reflected the signature of HCC field cancerization. AHNAK could co-localize and interact with IGF-1R. These results suggested that the AHNAK complex contributes to HCC growth, potentially by interacting with IGF-1R.

MicroRNA Associated with the Invasive Phenotype in Clear Cell Renal Cell Carcinoma: Let-7c-5p Inhibits Proliferation, Migration, and Invasion by Targeting Insulin-like Growth Factor 1 Receptor.

Differential microRNA (miRNA) expression can portend clear cell renal cell carcinoma (ccRCC) progression. In a previous study, we identified a subset of dysregulated miRNA in small renal masses, pT1 ccRCC (≤5 cm) that are associated with an aggressive phenotype. The present study investigated miRNA expression in clinical stage I (cT1) tumors (≤5 cm), comparing pathologic stage I (pT1) tumors to those upstaged to pathologic stage 3 (pT3) after surgery following identification of renal vein invasion or invasion into adjacent fat tissue within Gerota's fascia. Twenty cT1 tumors were examined in an miRNA screening, 10 pT1 and 10 pT3 tumors. The ccRCC cell lines 786-O and Caki-1 were used to assess the impact of let-7c-5p and its protein target insulin-like growth factor 1 receptor (IGF1R). Cells were transfected with pre-let-7c-5p and assessed through cell proliferation, migration, and invasion assays. IGF1R expression was evaluated through Simple Western, and interaction between let-7c-5p and IGF1R was confirmed via luciferase reporter assay. Screening identified 20 miRNA, including let-7c-5p, that were dysregulated between pT1 and pT3 upstaged tumors. This miRNA was also downregulated in our previous study of pT1 tumors that progressed to metastatic disease. Transfection of ccRCC cells with pre-let-7c-5p significantly inhibited proliferation, migration, invasion, and IGF1R expression. These findings suggest that miRNA dysregulation is involved in ccRCC progression, specifically through invasion, and that let-7c-5p downregulation contributes to the aggressiveness of small ccRCC tumors, in part, through its regulation of IGF1R.

The clinicopathological and prognostic significances of IGF-1R and Livin expression in patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC. METHODS: The present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC). RESULTS: The expression of insulin-like growth factor 1 receptor (IGF-1R) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan-Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA. CONCLUSION: IGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development.

Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study.

Background: Type 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities. Objectives: This study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study. Methods: A 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger. Results: INS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene. Conclusions: This study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

Various phenotypes of short stature with heterozygous IGF-1 receptor (IGF1R) mutations.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in normal fetal and postnatal growth. Over 30 pathogenic variants of IGF1R have been identified in patients with short stature. Yet, 20 years after the first report, a variety of phenotypes remain poorly defined. We analyzed the genetic and clinical data and responses to GH therapy in 11 patients using results from questionnaires. Eight of the 11 patients have already been reported in previous articles, and all of the identified mutations were heterozygous. The patients exhibited various phenotypes. At least two patients did not meet the criteria for GH treatment for small for gestational age (SGA) short stature, and two more patients showed lower serum IGF1 levels. Nine of the 11 patients had thin upper lips. Five patients with heterozygous IGF1R treated with GH exhibited similar height gains to those reported in previous Japanese studies on SGA short stature, which also led to extremely high serum IGF1 levels. Patients with short stature due to IGF1R mutations exhibit various phenotypes. Their presentation at diagnosis may be indistinguishable from common short stature. More specific clinical scoring that considers elevated IGF1 levels after GH treatment is needed to better detect IGF1R mutations.

MiR-448 suppresses cell proliferation and glycolysis of hepatocellular carcinoma through inhibiting IGF-1R expression.

Background: Microribonucleic acids (miRNAs) have been shown to play important roles in hepatocellular carcinoma (HCC) progression. MiR-448 has frequently been shown to be a tumor suppressor, and is abnormally expressed in HCC tumor tissues. However, little is known about the role of miR-448 in HCC development. In this article, the regulatory role of miR-448 on insulin-like growth factor 1 receptor (IGF-1R) in modulating hepatoma cell viability and glycolysis was investigated. Methods: The expression of miR-448 profiles in clinical tumor tissues and cell lines was examined using quantitative real-time polymerase chain reaction (qRT-PCR). HepG2 and Huh7 cells were transfected with miR-448 mimics, inhibitors, and scramble sequences. Cell viability and apoptosis were determined by a Cell Counting Kit-8 assay and a flow cytometry analysis. IGF-1R, a potential target of miR-448, was selected following a bioinformatic analysis, and the regulatory effects of miR-448 on IGF-1R expression was confirmed by luciferase reporter assay, qRT-PCR, and western blot. Glucose uptake, lactate production, and adenosine triphosphate (ATP) generation were detected by corresponding kits. Results: Decreased miR-448 expression was observed in both HCC patients' tumor tissues and hepatoma cells in vitro. The overexpression of miR-448 in HepG2 and Huh7 cells decreased cell viability and increased apoptosis. Additionally, the overexpression of miR-448 or the knockdown of IGF-1R lowered the level of glucose uptake, lactate production, and ATP generation, while the knockdown of miR-448 increased glycolysis. Further, aberrantly expressed miR-448 downregulated IGF-1R levels, while the inhibition of miR-448 resulted in the upregulation of IGF-1R in both HepG2 and Huh7 cells. In addition, miR-448 interacted with the wild-type 3'untranslated regions (3'UTRs) of IGF-1R, but had no effect on the mutant 3'UTRs. The expression of IGF-1R was increased in HCC patients' tumor tissues and serum, and was inversely correlated with miR-448 expression. Conclusions: The increased expression of miR-448 appears to downregulate the expression of IGF-1R by interacting with the 3'UTR in HCC progression. These findings highlight its role as a potential target for HCC therapy.

CircRASSF2 promotes IGF1R and osteosarcoma metastasis via sponging miR-6838-5p.

BACKGROUND: Osteosarcoma (OS) often occurs in children and adolescents and is highly malignant. Analyzing the pathogenesis of OS has great significance for prognosis and the discovery of new treatment strategies. METHODS: The effects and mechanism of circular RNA (circRNA) on OS were analyzed, as was the correlation between circRASSF2 and insulin-like growth factor 1 receptor (IGF1R) in data from The Cancer Genome Atlas (TCGA). The expression levels of microRNA (miR)-6838-5p and circRASSF2 in OS cells and osteoblasts were detected. The dual luciferase report was used to verify the targeting relationship. OS cells overexpressing circRASSF2, miR-6838-5p and/or IGF1R were constructed. The expression level of IGF1R and the biological behavior of the cells were detected. Eighty-two pairs of OS tissue and adjacent normal tissue samples were collected, and the levels of circRASSF2, miR-6838-5p, and IGF1R mRNA were detected by reverse transcription-quantitative PCR (RT-qPCR). RESULTS: Compared with osteoblasts, OS cells showed lower expression of miR-6838-5p and higher expression of circRASSF2. The dual luciferase report confirmed that miR-6838-5p targeted IGF1R. Overexpression of IGF1R significantly blocked the anticancer effects of miR-6838-5p. The dual luciferase report verified that circRASSF2 targeted miR-6838-5p, and promoted the expression of IGF1R. Overexpression of circRASSF2 not only promoted the malignant biological behavior of OS cells, but also blocked the anticancer effects of miR-6838-5p. In OS tissue, circRASSF2 and IGF1R were upregulated, and the two were positively correlated. MiR-6838-5p was downregulated, which negatively correlated with both circRASSF2 and IGF1R. High levels of circRASSF2 were associated with higher stage and metastasis of OS. CONCLUSIONS: In conclusion, the promoting effects of IGF1R on OS are targeted by miR-6838-5p. CircRASSF2 restored the expression of IGF1R by sponging miR-6838-5p, thereby promoting the progression of OS.

LncRNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) promotes the migration, invasion and epithelial-mesenchymal transition (EMT) through targeting miR-147a/insulin-like growth factor 1 receptor (IGF1R) pathway in cervical cancer tissues and cell model.

BACKGROUND: Two factors involved in regulation, long noncoding RNA Opa interacting protein 5-antisense RNA 1 (lncRNA OIP5-AS1) and microRNA-147a, were found in cervical cancer. Therefore, the investigation of the specific regulation of miR-147a by OIP5-AS1 was performed in cervical cancer. METHOD: The cervical cancer tissues were collected from patients with cervical cancer (n = 50). The expression of OIP5-AS1, miR-147a, proteins in epithelial-mesenchymal transition (EMT) process and insulin-like growth factor 1 receptor (IGF1R) were measured by quantitative real-time polymerase chain reaction (qRT-PCT) or western blotting. Cell motility and the relationship between OIP5-AS1 and miR-147a were detected or analyzed by wound healing test, Transwell assay, dual-luciferase reporter assay, RNA binding protein immunoprecipitation assay or Pearson correlation in OIP5-AS1, or miR-147a over-expressed and/or suppressed cervical cancer cells. RESULTS: OIP5-AS1 showed the high-expression and miR-147a showed the low-expression in tumor tissues collected from patients with cervical cancer and cell lines Hela, CaSki, Siha, and ME-180. The low-expression of OIP5-AS1 suppressed the motility of Caski cells, as well as up-regulated the level of E-cadherin, which a key protein in EMT. There were targeting sites between miR-147a and OIP5-AS1. OIP5-AS1 induced the down-regulation of miR-147a, so miR-147a was inversely correlated with OIP5-AS1. The down-regulation of miR-147a increased IGF1R and E-cadherin, and these increases were alleviated by OIP5-AS1 knockdown. CONCLUSION: LncRNA OIP5-AS1 promotes the migration, invasion and EMT of cervical cancer cells via targeting miR-147a/IGF1R pathway.

miR-520b Inhibits IGF-1R to Increase Doxorubicin Sensitivity and Promote Cell Apoptosis in Breast Cancer.

Doxorubicin (DOX) is currently one of the most widely used and effective drugs for the treatment of breast cancer, but drug resistance in breast cancer often leads to poor efficacy. MicroRNAs (miRNAs) are involved in the development and progression of various tumors and increasing number of studies have confirmed that abnormal miR-520b expression is closely associated breast cancer. We analyzed the clinical features, including miR-520b, of 30 patients with breast cancer. Further, we analyzed the interaction between miR-520b and insulin-like growth factor 1 receptor (IGF-1R) in breast cancer cell. miR-520b expression was significantly increased in chemotherapy-sensitive patients and was positively correlated with the chemotherapeutic efficacy in breast cancer. Cell proliferation assay confirmed that miR-520b promotes DOX-induced breast cancer cell apoptosis by regulating the PI3K/AKT signaling pathway. Moreover, bioinformatics method and dual luciferase reporter assay demonstrated that miR-520b negatively regulates IGF-1R, and IGF-1R overexpression and enhanced activity are closely associated with tumor development, progression, metastasis, and chemotherapy resistance. Similarly, cell proliferation assay showed that IGF-1R is negatively correlated with the efficacy of DOX chemotherapy and affects cell apoptosis mediated by the PI3K/AKT signaling pathway. On the contrary, miR-520b can downregulate the expression of IGF-1R. miR-520b increases DOX sensitivity and promotes cell apoptosis in breast cancer by inhibiting IGF-1R expression by the PI3K/AKT signaling pathway.

Insulin-like growth factor-1 receptor induces immunosuppression in lung cancer by upregulating B7-H4 expression through the MEK/ERK signaling pathway.

The Insulin-like growth factor-1/Insulin-like growth factor-1 receptor (IGF1/IGF1R) axis contributes to immunosuppression during tumor progression; however, the underlying mechanism remains unclear. In the present study, we found that IGF1 stimulation or IGF1R overexpression (IGF1R-OE) could upregulate the expression of B7-H4, while IGF1R inhibition downregulated B7-H4 in both A549 and SPC-A-1 lung cancer cell lines. IGF1R-OE conferred the inhibition of CD8+ T cells by cancer cells in vitro, and induction of B7-H4 expression was mediated by the activation of the MEK/ERK1/2 signaling pathway. The in vitro findings were further confirmed in vivo using a Lewis lung cancer mouse model. IGF1R-OE promoted tumor growth and inhibited tumor infiltration by CD8+ T cells in the mouse model. However, this effect was suppressed when B7-H4 was knocked down in IGF1R-OE cells. Our findings suggest that IGF1R could induce immunosuppression in lung cancer by upregulating the expression of B7-H4 through the MEK/ERK pathway. B7-H4 may therefore be a potential therapeutic target for lung cancer immunotherapy.

Effect of interfering IGF-1R by siRNA on cell cycle and apoptosis of hypoxic hepatocellular carcinoma HepG2 cells / 中国肿瘤生物治疗杂志

@# Objective: To explore the effect of interfering insulin-like growth factors-1 receptors (IGF-1R) by small interfering RNA (siRNA) on cell cycle and apoptosis of hypoxic hepatocellular carcinoma HepG2 cells. Methods: The hypoxic hepatocellular carcinoma model was established via cobalt chloride treatment. Three siRNAs targeting IGF1R gene and one negative control siRNA were designed and synthesized. They were transfected into hypoxic HepG2 cells, and 24 h later, the transfection efficiency was detected by fluorescent microscopy. The protein expression of IFG-1R was detected with Western blotting (WB) to screen the siRNA with highest transfection efficacy. The selected siRNA was used to transfect hypoxic HepG2 cells. The proliferation of hypoxic HepG2 cells was determined by MTT assay. Cell cycle distribution and apoptosis were analyzed by Flow cytometry. WB was performed to detect the proteinexpressionsofCDK1,CDK2andCaspase-3inHepG2cells. Results: The hypoxic hepatocellular carcinoma model was successfully established. IGF-1R-siRNA-2 showed the most effective interference efficiency and the most significant knockdown of IGF-1R (all P<0.01). The proliferation of HepG2 cells transfected with IGF-1R siRNA-2 was significantly suppressed (P<0.05 or P<0.01), the cell cycle was blocked at G0/G1 phase (P<0.05), and the apoptosis rate was increased up to (25.3±1.3)% P<0.01). In the meanwhile, the expressions of CDK1 and CDK2 were decreased and the expression of Caspase-3 was increased in hypoxic HepG2 cells after IGF-1R knockdown (P<0.05). Conclusion: Interfering IGF-1R by siRNA inhibits the malignant biological behaviors of hypoxic HepG2 cells via regulating cell cycle and apoptosis-related proteins. IGF-1R may be a potential target for the treatment of HCC.

Over-expression of miR-145-5p inhibits malignant biological behaviors of esophageal squamous cells carcinoma via down-regulating IGF1R / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To explore the mechanism of miR-145-5p on malignant biological behaviors, such as pro-liferation, invasion, migration and epithelial-mesenchymal transition (EMT), of esophageal squamous cell carcinoma (ESCC) TE-10 cells. Methods: The expression of miR-145-5p in ESCC cell lines and normal cells was detected by PCR. Dual luciferase reporter gene assay was used to detect the targeted regulation between miR-145-5p and insulin-like growth factor 1 receptor (IGF1R). The expres-sions of IGF1R protein and EMT related proteins were detected by Western blotting. Transwell assay and CCK-8 assay were carried out to detect the effects of miR-145-5p/IGF1R axis on the proliferation, migration andinvasionofTE-10 cells. Results: miR-145-5p was down-regulated in ESCC cell lines with the lowest expression in TE-10 cells (P<0.01orP<0.05).Over-expression of miR-145-5p significantly inhibited proliferation, invasion, migration and EMT of TE-10 cells (P<0.01 or P<0.05). Dual luciferase reporter gene assay con-firmed that miR-145-5p targetedly down-regulated IGF1R expression (P<0.01). The restora-tion experiments further confirmed that simultaneous over-expression of miR-145-5p and IGF1R significantly attenuated the promotion effect of IGF1R on proliferation, invasion, migration and EMT of TE-10 cells (P<0.01 or P<0.05). Conclusions: Over-expression of miR-145-5p inhibits proliferation, invasion, migration and EMT of ESCC TE-10 cells by down-regulating IGF1R.

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer.

BACKGROUND: Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC. METHODS: Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting. RESULTS: Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells in vitro. CONCLUSIONS: This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.