Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-κB pathway.

The insulin receptor (INSR) and insulin-like growth factor 1 receptor (IGF1R) have been reported to be involved in the tumorigenesis and metastasis of various malignancies. The aim of our study was to investigate and compare the effects of INSR and IGF1R on the tumorigenesis and metastasis of tongue squamous cell carcinoma (TSCC) and explore the possible mechanism(s) involved. We found that INSR had the same up-regulated expression pattern as IGF1R in TSCC tissues. INSR and IGF1R up-regulation were correlated with each other and associated with lymph node metastasis and poor prognosis. Functional studies established that knocking down either INSR or IGF1R dramatically impeded TSCC cell proliferation, migration, and invasion in vitro and tumorigenesis and tumor metastasis in vivo, whereas ectopic overexpression of INSR or IGF1R enhanced these activities. Both INSR and IGF1R directly targeted p65 and activated the NF-κB pathway; furthermore, C-myc was observed to directly bind to the INSR and IGF1R promoters and up-regulates INSR and IGF1R expression in TSCC. Thus, our current data demonstrate that both INSR and IGF1R are directly targeted by C-myc and exert similar effects to promote the tumorigenesis and metastasis of TSCC through the NF-κB pathway. Therefore, INSR and IGF1R may be therapeutic target genes and potential prognostic factors for TSCC.

Identification of a novel intergenic miRNA located between the human DDC and COBL genes with a potential function in cell cycle arrest.

Frequent abnormalities in 7p12 locus in different tumors like lung cancer candidate this region for novel regulatory elements. MiRNAs as novel regulatory elements encoded within the human genome are potentially oncomiRs or miR suppressors. Here, we have used bioinformatics tools to search for the novel miRNAs embedded within human chromosome 7p12. A bona fide stem loop (named mirZa precursor) had the features of producing a real miRNA (named miRZa) which was detected through RT-qPCR following the overexpression of its precursor. Then, endogenous miRZa was detected in human cell lines and tissues and sequenced. Consistent to the bioinformatics prediction, RT-qPCR as well as dual luciferase assay indicated that SMAD3 and IGF1R genes were targeted by miRZa. MiRZa-3p and miRZa-5p were downregulated in lung tumor tissue samples detected by RT-qPCR, and mirZa precursor overexpression in SW480 cells resulted in increased sub-G1 cell population. Overall, here we introduced a novel miRNA which is capable of targeting SMAD3 and IGF1R regulatory genes and increases the cell population in sub-G1 stage.

MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R.

Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive; however, recent studies have revealed that there are alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure and that one of the altered miRs is miR-145. We assessed the role of miR-145 and its target IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. Quantitative PCR, western blotting and 3'UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF1-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. An IGF1R target protector prevented the miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.

IGF/STAT3/NANOG/Slug Signaling Axis Simultaneously Controls Epithelial-Mesenchymal Transition and Stemness Maintenance in Colorectal Cancer.

Discovery of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are two milestones in people exploring the nature of malignant tumor in recent decades. Although some studies have presented the potential connections between them, the link details, underneath their superficial correlation, are largely unknown. In this study, we identified a small subpopulation of NANOG-positive colorectal cancer (CRC) cells, and demonstrated that they exhibited characteristics of CSCs and EMT traits simultaneously. Furthermore, we found that NANOG was a core factor in regulating both of EMT and stemness in CRC cells, NANOG modulate EMT and metastasis by binding to Slug promoter and transcriptionally regulate Slug expression. For the first time, we demonstrated that NANOG was regulated by extracellular IGF signaling pathway via STAT3 phosphorylation in CRC. This coincides with that IGF receptor IGF-1R is often increasing expressed in malignant metastasis colon cancer. Taken together, our data define the crucial functions of IGF/STAT3/NANOG/Slug signaling axis in the progression of CRC by operating EMT and CSCs properties, which make them served as potential therapeutic targets for treatment of CRC.

Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.

miR-494 suppresses tumor growth of epithelial ovarian carcinoma by targeting IGF1R.

A growing body of evidence suggests that microRNA-494 (miR-494) could act as tumor-suppressive or oncogenic microRNAs (miRNAs) in different types of tumors. However, the biological roles and underlying mechanisms of miR-494 remain unknown in human epithelial ovarian carcinoma (EOC). Therefore, the aims of this study were to investigate the miR-494 expression and the significance of its clinical diagnosis in patients suffering EOC and to analyze its role and underlying molecular mechanism on the carcinogenesis of EOC. Here, we found that miR-494 was significantly decreased in EOC cell lines and tissues and its expression was negatively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high pathological grade, and lymph node metastasis (all P < 0.01). Functional studies showed that overexpression of miR-494 in EOC cells could remarkably inhibit proliferation, colony formation, migration, and invasion and induce cell apoptosis, G0/G1 phase arrest. An in vivo analysis revealed that the overexpression of miR-494 suppressed tumor growth in a nude mouse xenograft model system. Bioinformatic assay and dual-luciferase assay confirmed that insulin-like growth factor 1 receptor (IGF1R) was as a direct target of miR-494 in EOC cells. Western blot assay showed that overexpression of miR-494 inhibited IGF1R expression and its downstream signal protein expression. In addition, downregulation of IGF1R has similar effects with miR-494 overexpression on EOC cells and overexpression of IGF1R effectively rescued the inhibition of overexpressed miR-494 in EOC cells. These data suggested that miR-494 functions as a tumor suppressor in EOC by targeting IGF1R.

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is the leading nongenetic cause of mental retardation. There are no treatments for FASD to date. Preclinical in vivo and in vitro studies could help in identifying novel drug targets as for other diseases. Here, we describe an ex vivo model that combines the physiological advantages of prenatal ethanol (EtOH) exposure in vivo with the uniformity of primary fetal hippocampal culture to characterize the effects of prenatal EtOH. The insulin signaling pathways are known to be involved in hippocampal functions. Therefore, we compared the expression of insulin signaling pathway genes between fetal hippocampi (in vivo) and primary hippocampal culture (ex vivo). The similarity of prenatal EtOH effects in these 2 paradigms would deem the ex vivo culture acceptable to screen possible treatments for FASD. METHODS: Pregnant Sprague-Dawley rats received 1 of 3 diets: ad libitum standard laboratory chow (control-C), isocaloric pair-fed (nutritional control), and EtOH containing liquid diets from gestational day (GD) 8. Fetal male and female hippocampi were collected either on GD21 (in vivo) or on GD18 for primary culture (ex vivo). Transcript levels of Igf2, Igf2r, Insr, Grb10, Rasgrf1, and Zac1 were measured by reverse transcription quantitative polymerase chain reaction. RESULTS: Hippocampal transcript levels differed by prenatal treatment in both males and females with sex differences observed in the expression of Igf2 and Insr. The effect of prenatal EtOH on the hippocampal expression of the insulin pathway genes was parallel in the in vivo and the ex vivo conditions. CONCLUSIONS: The similarity of gene expression changes in response to prenatal EtOH between the in vivo and the ex vivo conditions ascertains that these effects are already set in the fetal hippocampus at GD18. This strengthens the feasibility of the ex vivo primary hippocampal culture as a tool to test and screen candidate drug targets for FASD.

miR-96, miR-145 and miR-9 expression increases, and IGF-1R and FOXO1 expression decreases in peripheral blood mononuclear cells of aging humans.

BACKGROUND: In mammals, the IGF-1 pathway affects the phenotype of aging. Since the function of the immune system is modulated by IGF-1, it is plausible that immunosenescence might in part result from altered control by this pathway. We therefore examined whether the expression of IGF-1R, FOXO1, and FOXO3a in peripheral blood mononuclear cells (PBMC) changes with age and if this might be due to changes in the expression of select miRNAs. METHODS: The expression of IGF-1R, FOXO1, FOXO3a, as well as of miR-9, miR-96, miR-99a, miR-132, miR-145, and miR-182 was examined in PBMC of young (27.8 ± 3.7 years), elderly (65.6 ± 3.4 years), and long-lived (94.0 ± 3.7 years) Polish Caucasians using real-time PCR. mRNA/miRNA interactions were studied in HEK 293 cells using luciferase-expressing pmirGLO reporter vector. RESULTS: The median expression of IGF-1R decreased with age (p < 0.000001), as did the expression of FOXO1 (p < 0.000001), while the expression of FOXO3a remained stable. We also found an age-associated increase of the median expression of miR-96 (p = 0.002), miR-145 (p = 0.024) and miR-9 (p = 0.026), decrease of the expression of miR-99a (p = 0.037), and no changes regarding miR-132 and miR-182. Functional studies revealed that miR-96 and miR-182 interacted with human IGF-1R mRNA, and that miR-145 and miR-132 interacted with human FOXO1 mRNA. CONCLUSIONS: The age-associated higher expression of miR-96 and miR-145 might contribute to the lower expression of IGF-1R while the higher expression of miR-96, miR-145 and miR-9 might contribute to the lower expression of FOXO1 in peripheral blood mononuclear cells of aging humans. Sustained expression/function of FOXO3a but not of the other two genes might be important for the maintenance of the immune system function in these individuals.

Involvement of miR-143 in cisplatin resistance of gastric cancer cells via targeting IGF1R and BCL2.

We investigated the possible role of miR-143 in the development of cisplatin resistance in human gastric cancer cell line. miR-143 was detected by quantitative real-time PCR. Cisplatin resistance changes of cells was tested via MTT assay. Target genes of miR-143 were verified by dual-luciferase activity assay. Immunohistochemistry, immunofluorescence staining, Western blot, cell proliferation, and clonogenic and apoptosis assay were used to elucidate the mechanism of miR-143 in cisplatin resistance formation. miR-143 was downregulated in gastric cancer tissues and cell lines. It was also downregulated in cisplatin-resistant gastric cancer cell line SGC7901/cisplatin (DDP), which was concurrent with the upregulation of IGF1R and BCL2, compared with the parental SGC7901 cell line, respectively. Overexpressed miR-143 sensitized SGC7901/DDP cells to cisplatin. The luciferase activity suggested that IGF1R and BCL2 were both target genes of miR-143. Enforced miR-143 reduced its target proteins, inhibited SGC7901/DDP cells proliferation, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Our findings suggested that hsa-miR-143 could modulate cisplatin resistance of human gastric cancer cell line at least in part by targeting IGF1R and BCL2.

Evaluation of 99mTc-Z IGF1R:4551-GGGC affibody molecule, a new probe for imaging of insulin-like growth factor type 1 receptor expression.

Overexpression of insulin-like growth factor-1 receptor (IGF-1R) in several cancers is associated with resistance to therapy. Radionuclide molecular imaging of IGF-1R expression in tumors may help in selecting the patients that will potentially respond to IGF-1R-targeted therapy. Affibody molecules are small (7 kDa) non-immunoglobulin-based scaffold proteins that are well-suited probes for radionuclide imaging. The aim of this study was the evaluation of an anti-IGF-1R affibody molecule labeled with technetium-99m using cysteine-containing peptide-based chelator GGGC at C-terminus. ZIGF1R:4551-GGGC was efficiently and stably labeled with technetium-99m (radiochemical yield 97 ± 3%). (99m)Tc-ZIGF1R:4551-GGGC demonstrated specific binding to IGF-1R-expressing DU-145 (prostate cancer) and MCF-7 (breast cancer) cell lines and slow internalization in vitro. The tumor-targeting properties were studied in BALB/c nu/nu mice bearing DU-145 and MCF-7 xenografts. [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551 was used for comparison. The biodistribution study demonstrated high tumor-to-blood ratios (6.2 ± 0.9 and 6.9 ± 1.0, for DU-145 and MCF-7, respectively, at 4 h after injection). Renal radioactivity concentration was 16-fold lower for (99m)Tc-ZIGF1R:4551-GGGC than for [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551 at 4 h after injection. However, the liver uptake of (99m)Tc-ZIGF1R:4551-GGGC was 1.2- to 2-fold higher in comparison with [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551. A possible reason for the elevated hepatic uptake of (99m)Tc-ZIGF1R:4551-GGGC is a high lipophilicity of amino acids in the binding site of ZIGF1R:4551, which is not compensated in (99m)Tc-ZIGF1R:4551-GGGC. In conclusion, (99m)Tc-ZIGF1R:4551-GGGC can visualize the IGF-1R expression in human tumor xenografts and provides low retention of radioactivity in kidneys. Further development of this imaging agent should include molecular design aimed at reducing the hepatic uptake.

miR-133a suppresses ovarian cancer cell proliferation by directly targeting insulin-like growth factor 1 receptor.

The microRNA miR-133a is dysregulated in many types of cancer, but the underlying mechanism remains largely unknown. In this study, we showed that the expression level of miR-133a was reduced in ovarian cancer tissues compared with normal ovaries. Ectopic expression of miR-133a significantly inhibited ovarian cancer cell proliferation and colony formation, and induced G1-phase cell cycle arrest, whereas decreased miR-133a expression dramatically enhanced cell proliferation and colony formation. Importantly, miR-133a overexpression suppressed in vivo tumor growth in nude mice models. Through in silico search, we found that the 3'-untranslated region (UTR) of insulin-like growth factor 1 receptor (IGF1R) contains an evolutionarily conserved miR-133a binding site. miR-133a overexpression repressed IGF1R-3'UTR reporter activity, and reduced the mRNA and protein levels of endogenous IGF1R. Rescue experiments showed that ectopic expression of IGF1R significantly promoted the proliferation of ovarian cancer cells stably overexpressing miR-133a. Taken together, these findings indicate that miR-133a is an important regulator in ovarian cancer, and that its suppressive effects are mediated by targeting IGF1R.

Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers.

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility.

Captopril-dependent inhibition of collagen biosynthesis in cultured fibroblasts.

The mechanism underlying the dermatological manifestations that accompany captopril therapy is not known. The facts that prolidase plays an important role in collagen biosynthesis and that captopril directly inhibits prolidase activity led us to evaluate its effect on collagen biosynthesis in cultured human skin fibroblasts. Confluent fibroblasts were treated with milimolar concentrations (0.2-1 mM) of captopril (CAP) for 48 h. It was found that CAP-dependent decrease in prolidase activity was accompanied by parallel decrease in collagen biosynthesis. Since insulin-like growth factor receptor (IGF-IR) is the most potent regulator of both collagen biosynthesis and prolidase activity, and prolidase is regulated by beta1 integrin signaling, the effect of CAP on IGF-IR and beta1 integrin receptor expressions was evaluated. It was found that exposure of the cells to 0.3 mM CAP contributed to a decrease in IGF-IR, alpha2beta1 integrin receptor and MAPK/ERK1/2 expressions. The data suggest that CAP-dependent decrease of collagen biosynthesis in cultured human skin fibroblasts results from inhibition of prolidase activity that may occur through inhibition of alpha2beta1 integrin and IGF-IR signaling.

17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells.

Prostate carcinomas frequently express estrogen receptors (ER), irrespective of androgen receptor (AR) expression; however, the role of ERs and estrogens in prostate cancer is controversial. We found that 17beta-estradiol (E(2)) is able to markedly up-regulate insulin-like growth factor (IGF)-I receptor (IGF-IR) mRNA and protein expression in both AR-positive (LNCaP cells) and AR-negative (PC-3 cells) prostate cancer cells. This effect occurs not only via ERalpha but also via ERbeta stimulation and is specific for IGF-IR because it does not involve the cognate insulin receptor. IGF-IR up-regulation is associated with increased IGF-IR phosphorylation and with increased mitogenic and motogenic activities in response to IGF-I. IGF-IR up-regulation by E(2) does not require ER binding to DNA and is poorly sensitive to antiestrogen blockade, whereas it is associated with the activation of cytosolic kinase cascades involving Src, extracellular signal-regulated kinase (ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. In conclusion, our data indicate that estrogens may contribute to IGF system deregulation in prostate cancer through the activation of a nongenotropic pathway. Estrogens may have a role, therefore, in tumor progression to androgen independence. Inhibition of the IGF-IR or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in prostate cancer.

Correlation of IGF1R expression with ABCG2 and CD44 expressions in human osteosarcoma.

Osteosarcoma is the most common type of malignant bone tumors. Insulin Growth Factor 1 receptor (IGFR1) has been known as a prognostic factor for metastasis of osteosarcoma. ABC subfamily G member2 (ABCG2) is related to resistance to anti-cancer drug, and CD44 has a role in tumor growth and metastasis. The purpose of this study is to investigate the relationship among expression patterns of IGF1R, ABCG2, and CD44 in osteosarcoma. The expression levels of IGF1R, ABCG2, and CD44 proteins were determined in tissue arrays containing osteosarcoma tissues from 59 osteosarcoma patients. The expression pattern of IGF1R was highly correlated with the expression pattern of ABCG2 (r = 0.88) in overall osteosarcoma patients. According to pathological types, the expression pattern of IGF1R showed the higher correlation with ABGC2 (r = 0.90) and CD44 (r = 0.61) in osteoblatic type than in chondroblastic type. According to gender with pathologic type, the correlation between the expression patterns of IGF1R and CD44 was higher in male with osteoblatic type than in female with osteoblatic type. Among different age groups, the 1-10 years age group showed higher correlation in IGF1R versus CD44 (r = 0.90) and ABCG2 versus CD44 (0.80) than in other age groups. These results showed that the expression of IGF1R appears to be highly correlated with the expression of ABCG2 in osteosarcoma and with the expression of CD44 in osteosarcoma patients under age of 10, which suggests that ABCG2 and CD44 can be used as prognostic factors with IGF1R for specific prognosis and efficient treatment of osteosarcoma.

Expressions of insulin-like growth factor receptor-1 and cezanne-1 in lung adenocarcinoma.

IGF1R (insulin-like growth factor receptor-1) was confirmed to play a significant role in the development of cancer. Cezanne-1 overexpression was considered to be associated with enhancement of EGFR signaling pathway and reduced degeneration of EGFR. There was a close relationship between EGFR and IGFR as previous study showed. Dynamic balance between receptor ubiquitination and deubiquitination was critical in the process of termination of IGF signaling pathway. So we conducted an IHC staining to initially prove the correlation. Cezanne-1 and IGF1R expressions were evaluated in 103 patients with lung adenocarcinoma using immunohistochemical (IHC) analysis. The relationship between expressions of cezanne-1 and IGF1R were analyzed by χ2 test. Kaplan-Meier method was used to generate the survival curve, and the statistical difference was calculated by log-rank test. We also used data in R2 system to verify the relationship between IGF1R and cezanne-1. R2 system showed there was a close correlation between IGF1R and cezanne-1. Positive expression of cezanne-1 was detected in 64.1% patients. A significant association was shown between cezanne-1 and IGF1R expression (p < 0.001). Multivariate analysis confirmed that both cezanne-1 and IGF1R expressions were independent prognostic factors for OS. (HR 2.96, 95% CI 1.090-8.060, p = 0.033; HR 2.273, 95% CI 1.016-5.085, p = 0.046, respectively). Our findings indicated both cezanne-1 and IGF1R expressions were negative independent predictive factors for the prognosis of lung adenocarcinoma, respectively. There was a close positive interrelationship between cezanne-1 and IGF1R expression.

IGF1R+ Dental Pulp Stem Cells Enhanced Neuroplasticity in Hypoxia-Ischemia Model.

Until now, the surface markers of multipotent mesenchymal stem cells (MSCs) had not been fully identified. Here, we found that the IGF1 receptor (IGF1R), regarded as a pluripotent marker of embryonic stem cells (ESCs), was also expressed in human dental pulp derived-mesenchymal stem cells (hDSCs), which displayed a potential for both self-renewal and multipotency. hDSC-secreted IGF1 interacted with IGF1R through an autocrine signaling pathway to maintain this self-renewal and proliferation potential. Stereotaxic implantation of immunosorted IGF1R+ hDSCs in rats with neonatal hypoxia-ischemia (NHI) promoted neuroplasticity, improving the neurological outcome by increasing expression of the anti-apoptotic protein Bcl-2, which enhanced both neurogenesis and angiogenesis. In addition, treatment with IGF1R+ hDSCs significantly modulated neurite regeneration and anti-inflammation in vivo in NHI rats and in vitro in primary cortical cultures under oxygen/glucose deprivation. Autocrine regulatory expression of IGF1R contributed to maintaining the self-renewal capacity of hDSCs. Furthermore, implantation of IGF1R+ hDSCs increased neuroplasticity with neurite regeneration and immunomodulation in and the NHI rat model.

Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.

miR-422a Inhibits Glioma Proliferation and Invasion by Targeting IGF1 and IGF1R.

Glioma is a common type of malignant brain tumor characterized by aggressive metastasis capability. Recent evidence has suggested that noncoding RNAs, including microRNAs, have important functions in the pathophysiology of glioma development. In this study, we investigated the biological function of miR-422a in human glioma. We found that miR-422a was downregulated in glioma tissues. We also demonstrated that expression of miR-422a in glioma cells markedly suppressed cell proliferation, migration, and invasion. In addition, we identified insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) as inhibitory targets of miR-422a in glioma cells. We established that the expression levels of miR-422a were negatively correlated with the expression levels of IGF1/IGF1R and the clinical parameters in glioma patients. An IGFR inhibitor, AG1024, completely blocked the activity of miR-442a on glioma cell proliferation and invasion, which further confirmed that miR-422a functions through IGF1 and IGF1R.

Tumor suppressor role of miR-217 in human epithelial ovarian cancer by targeting IGF1R.

Accumulating evidence shows that microRNA-217 (miR-217) is frequently dysregulated in various cancers, and plays crucial roles in tumorigenesis and metastasis; however, the role and underlying molecular mechanism of miR-217 in human epithelial ovarian cancer (EOC) remains unclear. Here, we report that miR-217 expression was downregulated in EOC tissue and inversely correlated with advanced FIGO stage, high histological grading and lymph node metastasis (P<0.01). Function analysis revealed that the ectopic expression of miR-217 in EOC cells inhibited cell proliferation, migration and invasion in vitro, as well as suppressed tumor growth in vivo. Bioinformatics analysis and dual luciferase assays identified insulin-like growth factor 1 receptor (IGF1R) as a direct target of miR-217 in EOC cells. Western blot assay showed that overexpression of miR-217 in EOC cells inhibited IGF1R expression. In addition, downregulation of IGF1R mimicked the tumor-suppressive effects of miR-217 in EOC cells, whereas the reintroduction of IGF1R partially abrogated the suppression effect induced by miR-217 on EOC cells. Collectively, these results demonstrated that miR-217 plays a tumor suppressor role in human epithelial ovarian cancer by directly targeting IGF1R gene, suggesting a new potential therapeutic target in EOC.