Insulin-like Growth Factor II Research Articles

Addition of IMP3 to L1CAM for discrimination between low- and high-grade endometrial carcinomas: a European Network for Individualised Treatment of Endometrial Cancer collaboration study

Discrimination between low- and high-grade endometrial carcinomas (ECs) is clinically relevant but can be challenging for pathologists, with moderate interobserver agreement. Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofoetal protein that is associated with nonendometrioid endometrial carcinomas but has been limited studied in endometrioid carcinomas. The aim of this study is to investigate the diagnostic and prognostic value of IMP3 in the discrimination between low- and high-grade ECs and its added value to L1CAM. IMP3 and L1CAM expression was assessed in tumors from 378 patients treated for EC at 1 of 9 participating European Network for Individualised Treatment of Endometrial Cancer centers. IMP3 was expressed in 24.6% of the tumors. In general, IMP3 was more homogeneously expressed than L1CAM. IMP3 expression was significantly associated with advanced stage, nonendometrioid histology, grade 3 tumors, deep myometrial invasion, lymphovascular space invasion, distant recurrences, overall mortality, and disease-related mortality. Simultaneous absence of IMP3 and L1CAM expression showed the highest accuracy for identifying low-grade carcinomas (area under the curve 0.766), whereas simultaneous expression of IMP3 and L1CAM was strongly associated with high-grade carcinomas (odds ratio 19.7; 95% confidence interval 9.2-42.2). Even within endometrioid carcinomas, this combination remained superior to IMP3 and L1CAM alone (odds ratio 8.6; 95% confidence interval 3.4-21.9). In conclusion, IMP3 has good diagnostic value and together with L1CAM represents the optimal combination of diagnostic markers for discrimination between low- and high-grade ECs compared to IMP3 and L1CAM alone. Because of the homogenous expression of IMP3, this marker might be valuable in preoperative biopsies when compared to the more patchy L1CAM expression.

Glucoregulatory activity of vesiculin in insulin sensitive and resistant mice

Pancreatic islet-derived peptide hormones play key roles in the maintenance of systemic energy homeostasis and glucose balance and defects in their regulation are strongly implicated in the pathogenesis of obesity and diabetes. Peptides have also been used as lead compounds for therapeutics targeting metabolic disease. It is therefore important to understand the activity and function of islet hormones in both their target tissues and the whole organism. Insulin-like growth factor II (IGF-II) is an insulin homolog secreted by the islet β-cells. Vesiculin is a newly discovered peptide hormone, processed from IGF-II and secreted from islet β-cells in response to glucose. We postulated that vesiculin might act to regulate systemic glucose metabolism. Here we report our original investigations of vesiculin’s activity in relation to glucoregulation. Vesiculin and IGF-II displayed similar dose-response relationships for lowering blood glucose in insulin-responsive FVB/n mice. By contrast, the ability of IGF-II to lower blood glucose was blunted in insulin-resistant triprolyl human-amylin transgenic mice, whereas vesiculin’s ability to lower blood glucose remained unaffected. We also confirmed the ability of vesiculin to bypass insulin resistance in a second mouse model. In vitro analysis of signalling by vesiculin and IGF-II indicates that, like IGF-II, vesiculin signals through the IR/ IGF1R. Overall, we show that removal of only four amino acids from IGF-II has generated a peptide hormone with different bioactivity relevant to blood-glucose regulation. Investigating the differences among vesiculin, IGF-II and insulin signalling and activity may provide new insights into insulin resistance and potentially inform the design of novel therapeutics

Regulation of embryo survival in cattle

Evidence is presented that bovine somatotrophin (bST) treatment of lactating dairy cows enhances both expression of oviductal insulin-like growth factor II (IGF-II) mRNA and endometrial insulin-like growth factor binding protein 3 (IGFBP-3) mRNA between day 3 and day 7 of the oestrous cycle. mRNA encoding growth hormone (GH) receptor in endometrial tissues increased between day 3 and day 7 of the oestrous cycle. The changes induced by bST treatment may contribute to stimulation of embryo development and increase pregnancy rates in lactating dairy cows. Additive effects of bST and rb interferon tau (rbIFN-tau) to inhibit phorbol ester induction of prostaglandin F2alpha secretion in immortalized bovine endometrial cells indicates that there is interplay between their signal transduction pathways. Non-lactating dairy cows were killed at day 17 after oestrus to evaluate the effects of pregnancy status (cyclic versus pregnant) and bST (bST versus control) treatment on endometrial gene expression. Distinctly different mRNA and protein responses were detected between cyclic and pregnant cows that were related to luteolytic-antiluteolytic drive (that is expression of progesterone receptor, oxytocin receptor, oestradiol receptor alpha and prostaglandin GH synthase 2 (PGHS-2)). The bST-induced changes in PGHS-2 protein (+), oxytocin receptor mRNA (+) and oestrogen receptor alpha protein (+) may potentially affect the mechanisms associated with maintenance of pregnancy. Two experiments were conducted to evaluate whether ovarian follicular suppression induced by biodegradable deslorelin implants would reduce either early or late embryo losses. A 450 microg deslorelin implant used to induce ovulation in a timed insemination programme decreased subsequent follicular development and tended to reduce early embryo losses, whereas a 2.1 mg deslorelin implant failed to reduce late embryonic losses when inserted on day 27 of pregnancy.

Insulin-like Growth Factor II: An Essential Adult Stem Cell Niche Constituent in Brain and Intestine.

SummaryTissue-specific stem cells have unique properties and growth requirements, but a small set of juxtacrine and paracrine signals have been identified that are required across multiple niches. Whereas insulin-like growth factor II (IGF-II) is necessary for prenatal growth, its role in adult stem cell physiology is largely unknown. We show that loss of Igf2 in adult mice resulted in a ∼50% reduction in slowly dividing, label-retaining cells in the two regions of the brain that harbor neural stem cells. Concordantly, induced Igf2 deletion increased newly generated neurons in the olfactory bulb accompanied by hyposmia, and caused impairments in learning and memory and increased anxiety. Induced Igf2 deletion also resulted in rapid loss of stem and progenitor cells in the crypts of Lieberkühn, leading to body-weight loss and lethality and the inability to produce organoids in vitro. These data demonstrate that IGF-II is critical for multiple adult stem cell niches.

A preliminary study on abnormal expression of long noncoding RNA CTD- 2012K14.6 in placentas and its role in inducing macrosomia

Objective To explore the role of long noncoding RNA (lncRNA) CTD-2012K14.6 in the development of gestational diabetes mellitus (GDM) related macrosomia. Methods The quantitative real-time PCR (qRT-PCR) was performed to measure the expression of CTD-2012K14.6 in placentas of women with or without GDM, and the quantity of CTD-2012K14.6 expression and its association with fetal weights were analyzed; Bioinformatic analysis was performed to predict the downstream molecules. CTD-2012K14.6 over-expressing lentiviral and siRNA was constructed in human trophoblastic cell line HTR-8/SVneo cells, qRT-PCR and Western blot (WB) were used to invest its effect in modulating the expression of downstream molecules. Results The expression of CTD-2012K14.6 in GDM placentas was significantly higher than that in normal controls (1.70±0.63 vs 1.00±0.56, t=3.68, P<0.01), and positively correlated with fetal weight (r=0.8501, P<0.01); on-line analysis showed that CTD-2012K14.6 was located at chr16: 67, 549, 214-67, 563, 958, which was located in the intron of CCCTC-binding factor(CTCF); Up-regulating CTD-2012K14.6 could significantly reduce the expression of CTCF mRNA and protein, and increase the expression of insulin-like growth factor-Ⅱ(IGF-Ⅱ) mRNA and protein, while down-regulating CTD-2012K14.6 could significantly increase the expression of CTCF mRNA and protein, and reduce the expression of IGF-Ⅱ mRNA and protein. Conclusion The CTD-2012K14.6 may play an important role in the pathogenesis of GDM related macrosomia by upregulating the expression of CTCF and IGF-Ⅱ. Key words: Gestational diabetes mellitus; Macrosomia; Long noncoding RNA CTD-2012K14.6; CCCTC-binding factor; Insulin-like growth factor 2

Insulin-like growth factor-II mRNA-binding protein 3 immunocytochemical expression in direct endometrial brushings: Possible diagnostic help in endometrial cytology.

This study evaluated the immunocytochemical (ICC) expression of IMP3 in direct endometrial brushings processed as liquid-based cytology (LBC) samples of endometrioid adenocarcinoma (EAC), serous carcinoma (ESC) and surface papillary syncytial change (SPSC) with endometrial glandular and stromal breakdown (EGBD) to exploit its possible differential diagnostic aid. In total, 333 samples of LBC samples were obtained from selected outpatients in parallel with Pipelle endometrial sampling. They consisted of 97 EAC (83 grade 1: EAC-1, 14 EAC-3), 35 ESC and 201 benign endometrial samples (51 proliferative, 42 secretory, 38 atrophic, 70 SPSC with EGBD). ICC expression of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) was manually performed on Papanicolaou-stained LBC samples. The ESC samples showed positive staining cells in 100%, EAC-3 in 28.5%, and EAC-1 in 2.4% cases. All the benign endometrium samples were negative. Only ESC cases showed strong immunoreactivity (≥3+) in more than 50% of tumour cells with an average frequency of 80%. IMP3 is a helpful immunomarker to distinguish ESC from EAC and SPSC in endometrial cytology.

Data Independent Acquisition Mass Spectrometry Can Identify Circulating Proteins That Predict Future Weight Loss with a Diet and Exercise Programme.

We investigated biological determinants that would associate with the response to a diet and weight loss programme in impaired glucose regulation (IGR) people using sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry (MS), a data acquisition method which complement traditional mass spectrometry-based proteomics techniques. Ten women and 10 men with IGR underwent anthropometric measurements and fasting blood tests. SWATH MS was carried out with subsequent immunoassay of specific peptide levels. After a six-month intervention, 40% of participants lost 3% or more in weight, 45% of patients remained within 3% of their starting weight and 15% increased their weight by 3% or more. Hemoglobin A1c (HbA1C) level was reduced with weight loss with improvements in insulin sensitivity. SWATH MS on pre-intervention samples and subsequent principal component analysis identified a cluster of proteins associated with future weight loss, including insulin-like growth factor-II (IGF-II) and Vitamin D binding protein. Individuals who lost 3% in weight had significantly higher baseline IGF-II levels than those who did not lose weight. SWATH MS successfully discriminated between individuals who were more likely to lose weight and potentially improve their sensitivity to insulin. A higher IGF-II baseline was predictive of success with weight reduction, suggesting that biological determinants are important in response to weight loss and exercise regimes. This may permit better targeting of interventions to prevent diabetes in the future.

Alteration of oncogenic IGF-II gene methylation status associates with hepatocyte malignant transformation

BackgroundOncogenic insulin-like growth factor-II (IGF-II) is overexpressed in hepatocellular carcinoma (HCC). The present study aimed to analyze the dynamic alteration of IGF-II CpG site methylation status and its molecular mechanism in HCC progression. MethodsIGF-II alterations were observed in rat hepatocarcinogenesis models induced by 2-acetylaminofluorene. Liver IGF-II expression was compared by immunohistochemistry or tissue IGF-II specific concentration (nmol/mg protein). Status of human IGF-II promoter 3 (P3) or rat IGF-II P2 CpG site methylation was amplified by methylation-specific polymerase chain reaction (MSP). Serum IGF-II levels were quantitatively detected by an enzyme-linked immunosorbent assay. ResultsThe levels of hepatic IGF-II expression were significantly elevated in the HCC group (P < 0.001). The unmethylation rate of IGF-II P3 CpG sites was 100% in the HCC-, 52.5% in the paracancerous-, and none (0%) in the distal noncancerous-tissues. Abnormal IGF-II expression was related to differentiation degree, tumor invasion, and positive HBV-DNA (all P < 0.001), with a negative correlation between P3 methylation degree and IGF-II expression. There was a positive correlation between liver IGF-II specific concentration and circulating IGF-II level (r = 0.97, P < 0.001). Significantly negative correlation was found between IGF-II P2 CpG site methylation and circulating IGF-II (rs = −0.89, P < 0.001) or liver IGF-II level (rs = −0.84, P < 0.001). ConclusionsThe increase of serum IGF-II and the alteration of oncogenic gene IGF-II methylation may be biomarkers for HCC diagnosis and DNA methylation may be the therapeutic target of HCC.

The expression and clinical analysis of insulin-like growth factor 2 in bladder cancer

Objective To investigate the expression and clinical significance of IGF2 and its role in the development of bladder cancer. Methods The overall-survival time of patients with different expression level of IGF2 was analyzed by the cancer gene information database(The Cancer Genome Atlas, TCGA) .The expression level of IGF2 in 63 cases of bladder urothelial carcinoma and 17 cases of normal tissue were derected by the immunohistochemical staining.The relationship between IGF2 expression level and clinical factors was analyzed. Results The overall-survival time of patients with high-expression IGF2 was significantly lower than that of low-expression IGF2 patients(P=0.049). The expression level of IGF2 in bladder cancer tissues was significantly higher than that in the normal tissues (P<0.01). In the muscle invasive bladder cancer(T2-T4), the expression level of IGF2 was significantly higher than the non-muscle invasive bladder cancer(Ta-T1). Besides, the expression level of IGF2 in high-grade bladder cancer was also significantly higher than that of low-grade bladder cancer, there was statistically significant(P<0.05). Conclusions The expression level of IGF2 in bladder cancer is negatively related to the overall-survival time, and it's closely associated with the progression of bladder cancer, IGF2 may be an important protein molecule for the target therapy and prognosis of bladder cancer. Key words: Urinary Bladder Neoplasms; Insulin-Like Growth Factor II

Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity.

Intratumour heterogeneity (ITH), referring to the coexistence of different cell subpopulations in a single tumour, has been a major puzzle in cancer research for almost half a century. The lack of understanding of the underlying mechanism of ITH hinders progress in developing effective therapies for cancers. Based on the findings in a recent quantitative experiment on pancreatic cancer, we developed a general evolutionary model for one type of cancer, accounting for interactions between different cell populations through paracrine or juxtacrine factors. We show that the emergence of a stable heterogeneous state in a tumour requires an unequal allocation of paracrine growth factors (public goods) between cells that produce them and those that merely consume them. Our model provides a quantitative explanation of recent in vitro experimental studies in pancreatic cancer in which insulin-like growth factor II (IGF-II) plays the role of public goods. The calculated phase diagrams as a function of exogenous resources and fraction of growth factor producing cells show ITH persists only in a narrow range of concentration of exogenous IGF-II. Remarkably, maintenance of ITH requires cooperation among tumour cell subpopulations in harsh conditions, specified by lack of exogenous IGF-II, whereas surplus exogenous IGF-II elicits competition. Our theory also quantitatively accounts for measured in vivo tumour growth in glioblastoma multiforme (GBM). The predictions for GBM tumour growth as a function of the fraction of tumour cells are amenable to experimental tests. The mechanism for ITH also provides hints for devising efficacious therapies.

Insulin-like growth factor-II in adipocyte regulation: depot-specific actions suggest a potential role limiting excess visceral adiposity.

The IGF system has an important role in growth and development. IGF-II is a recognized fetal growth promoter. However, its physiological postnatal role remains uncertain, although it is maintained in the circulation at a substantially high level throughout life. IGF-II has been strongly linked to obesity in genetic studies, and more recent evidence suggests a metabolic role. We examined fat depot differences in IGF-II's action on differentiation and metabolism. We speculate a specific effect on visceral adipocytes in relation to the differential distribution of insulin receptors between visceral and subcutaneous fat depots. We used a previously established adipocyte, cell culture system of matched pairs of visceral and subcutaneous fat biopsies from 20 normal weight children undergoing routine surgery for nonmalignant, nonseptic conditions. Preadipocytes were differentiated for 14 days in the presence or absence of IGF-II. Oil Red O staining, Western blotting, and reverse transcription polymerase chain reaction techniques were employed to assess levels of adipogenesis markers and levels of the insulin receptor and insulin receptor isoforms. Our data indicate that IGF-II promotes preadipocyte differentiation in subcutaneous preadipocytes but showed a protective, opposing effect restricting visceral preadipocyte differentiation, confirmed by reductions in the differentiation markers peroxisome proliferator-activated receptor gamma and adiponectin and in triglyceride staining. Additionally, IGF-II reduced mRNA expression of the insulin receptor in adipocytes and downregulated insulin receptor isoform A and glucose transporter 4 abundance and corresponding glucose uptake in visceral adipocytes. In conclusion, IGF-II is a regulator of preadipocyte differentiation and metabolism by acting as a differential modulator of fat accumulation favoring less visceral fat deposition in children.

Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women.

Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women. A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception (n = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone-binding globulin, prolactin). Testosterone (n = 330) and sex hormone-binding globulin (n = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels. Estradiol at age 21.5 and sex hormone-binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%-7%) and 3% (1%-5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%-4%) and 4% (1%-7%), respectively]. The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women. The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.

Development of a Parallel Reaction Monitoring-MS Method To Quantify IGF Proteins in Dogs and a Case of Nonislet Cell Tumor Hypoglycemia

Nonislet-cell tumor hypoglycemia (NICTH) is a rare paraneoplastic phenomenon well described in dogs and humans. Tumors associated with NICTH secrete incompletely processed forms of insulin-like growth factor-II (IGF-II), commonly named big IGF-II. These forms have increased bioavailability and interact with the insulin and IGF-I receptor causing hypoglycemia and growth-promoting effects. Immunoassays designed for human samples have been used to measure canine IGF-I and -II, but they possess some limitations. In addition, there are no validated methods for measurement of big IGF-II in dogs. In the present study, a targeted parallel reaction monitoring MS-based method previously developed for cats has been optimized and applied to simultaneously quantify the serum levels of IGF-I, IGF-II, and IGFBP-3, and for the first time, the levels of big IGF-II in dogs. This method allows the absolute quantification of IGF proteins using a mixture of QPrEST proteins previously designed for humans. The method possesses good linearity and repeatability and has been used to evaluate the IGF-system in a dog with NICTH syndrome. In this dog, the levels of big IGF-II decreased by 80% and the levels of IGF-I and IGFBP-3 increased approximately 20- and 4-times, respectively, after removal of the tumor.

DOEGE-POTTER SYNDROME: EXPANDING THE DIFFERENTIAL DIAGNOSIS OF HYPOGLYCEMIA

SESSION TITLE: Disorders of the Pleura 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Hypoglycemia due to solitary fibrous tumor of pleura (SFTPs) is known as Doege-Potter syndrome (DPS). SFTPs are rare mesenchymal tumors that are asymptomatic or demonstrate nonspecific symptoms. They can ectopically secrete insulin-like growth factor II (IGF-II) causing hypoglycemia. DPS occurs in less than 5% of SFTP cases with less than 80 cases reported.1 CASE PRESENTATION: Herein, we report a case of recurrent malignant solitary fibrous tumor in a 54-year-old woman who had her first tumor resected 8 years prior without recurrence for 5 years on surveillance imaging. She presented with confusion, severe hypoglycemia, weight loss and digital clubbing. Computed tomography of the chest revealed recurrence of the mass measuring 13.8x9.6x13.6cm. Insulin, proinsulin, and C-peptide levels were undetectable. IGF-II was elevated at 690mg/ml. She was successfully managed with steroids.She subsequently underwent repeat thoracotomy with excision of the mass including visceral pleural, rib section, and pericardium. Histology was consistent with recurrence of malignant solitary fibrous tumor. IGF-II level dropped to 248ng/ml. Her hypoglycemia completely resolved after excision and prednisone taper. DISCUSSION: SFTPs are generally benign tumors but there is a risk of malignant transformation and recurrence. Definitive treatment and amelioration of associated hypoglycemia is achieved by local control of the mass with surgical resection. Prior to resection, hypoglycemia can be managed with glucocorticoids often requiring more than 20mg/day of prednisolone.1 There is no consensus on the use of adjunctive chemoradiation, however it has been utilized in malignant SFTP treatment. 1,2 Prognosis for malignant SFTP is favorable with surgical resection, with reported 5-year survival of 81%.2 CONCLUSIONS: Our case emphasizes the importance of expanding the differential diagnosis for hypoglycemia. Tumor-induced hypoglycemia should be investigated after ruling out common etiologies. SFTs have a good clinical outcome if complete resection is performed with resolution of DPS. Recurrence is not uncommon, therefore life-long surveillance with imaging may be beneficial. Reference #1: Han G, Zhang Z, Shen X, Wang K, Zhao Y, He J, Gao Y, Shan X, Xin G, Li C, Liu X. Doege–Potter syndrome: A review of the literature including a new case report. Medicine. 2017 Jul;96(27). Reference #2: Lococo F, Cesario A, Cardillo G et al: Malignant solitary fibrous tumors of the pleura: retrospective review of a multicenter series. J Thorac Oncol, 2012; 7: 1698–706 DISCLOSURES: No relevant relationships by Rayan Ihle, source=Web Response No relevant relationships by Muhammad Farhan Khaliq, source=Web Response

A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network

Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans. However, the molecular underpinnings of the LOI phenotype are not clear. Surprisingly, in LOI cells, we find a reversal of the relative activities of two canonical signaling pathways triggered by IGF2, causing further rebalancing between pro- and anti-apoptotic signaling. A predictive mathematical model shows that this network rebalancing quantitatively accounts for the effect of receptor tyrosine kinase inhibition in both WT and LOI cells. This mechanism also quantitatively explains both the stable LOI phenotype and the therapeutic window for selective killing of LOI cells, and thus prevention of epigenetically controlled cancers. These findings suggest a framework for understanding epigenetically modified cell signaling.

IGF-II restores rapamycin-induced suppression of β-cell differentiation and expansion of adult pancreas stem cells

Objective To investigate the mechanism of rapamycin inhibiting the differentiation and proliferation of newborn porcine pancreatic adult stem cells, and to explore the therapeutic methods that may effectively reduce the side effects of rapamycin. Method Porcine NPCCs were treated with rapamycin alone or in combination with IGF-Ⅱ, and the caspase-3 and [3H]-thymidine uptake assays were performed to detect apoptosis and proliferation. The expression of insulin, PDX-1, NeuroD/Beta2, and Foxo1, a downstream transcription factor of IGF-Ⅱ, were analyzed by RT-PCR and Western blot to evaluate the differentiation ability of pancreatic adult stem cells. Results The NPCCs treated with rapamycin inhibited the proliferation of β-cells, increased apoptosis, reduced insulin secretion, inhibited the expression of PDX-1 and NeuroD/Beta2, and decreased the expression of IGF-Ⅱ. Foxo1 expression and induction of Foxo1 from the cytoplasm to the nucleus of the ectopic. The combined treatment of rapamycin and IGF-Ⅱ can reduce the side effects of rapamycin, inhibit the decrease of β-cell number and insulin content, repair the expression of insulin, PDX-1, NeuroD/Beta2, inhibit Foxo1 expression and intracellular ectopic. Conclusion Aberrant expression of IGF-Ⅱ and Foxol genes is the key inducing factor of rapamycin inhibiting the proliferation and differentiation of NPCCs, and IGF-Ⅱ treatment can effectively reduce the side effects of rapamycin on NPCCs differentiation. (Chin J Endocrinol Metab, 2018, 34: 678-683) Key words: Porcine neonatal pancreas cell clusters; Rapamycin; Insulin-like growth factor-Ⅱ; β-cell; Adultpancreas stem cells

Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse.

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2-/-), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2-/- mice are born with hepatic steatosis. Gene expression analysis in Igf2-/- newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2-/- newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

Differential Sensitivity of Human Hepatocellular Carcinoma Xenografts to an IGF-II Neutralizing Antibody May Involve Activated STAT3

Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II–targeted therapy in HCC.

IMP3 promotes TNBC stem cell property through miRNA-34a regulation.

To explore the expression and function of insulin-like growth factor II (IGFII) mRNA binding protein (IMP3) in the Triple Negative Breast Cancer (TNBC). According to previously reported gene expression array, we found that IMP3 had significantly higher expression in the CD44+CD24-ESA+ cell cluster, tumor initiating cell or cancer stem cell (CSCs), compared to other tumor cells. Based on the GEO database (GEO accession No. GSE6883), we detected the mRNA levels of IMP 1,2 and 3 by quantitative polymerase chain reaction (q-PCR) in CD44+CD24-ESA+ cell cluster and other breast tumor cell clusters. Besides, we measured IMP3 expression in microsphere of breast cancer, which exerted more significant tumor stem cell properties. The effects of IMP3 on breast cancer cell stem cell properties were studied by RNA interference and overexpression approaches in vitro. Furthermore, we predicted and identified microRNA, which could target and regulate IMP3 from bioinformatics analysis, and verified the interaction by luciferase assays and rescue experiments. Previously reported data showed that IMP3 expression was significantly upregulated in CD44+CD24-ESA+ cell cluster from breast cancer tissues. Besides, we found IMP3 had higher expression in mesenchymal cells rather than epithelial cells, which was also significantly elevated in SUM159 and T49D cell lines cultured as microsphere rather than adherent cells or differentiated cells. CD44+CD24-ESA+ cell cluster proportion was significantly decreased after silencing IMP3 in SUM1315, and its ability to develop into microsphere was significantly inhibited. By re-expressing IMP3 in SUM315, we restored the self-renewal capacity and tumorigenesis potential of SUM315. Through relative predicting website, we found several miRNAs which could regulate IMP3. miR-34a with highest score was chosen for further analysis. Mimicking miR-34a significantly downregulated IMP3 expression and inhibited its ability to develop into microsphere, while overexpressing IMP3 could rescue this process. IMP3 plays a vital role in maintaining stem cell properties of breast cancer cells, which could be regulated by mir-34a.

IMP3 Immunohistochemical Expression Remains Consistent Among All Grades of Gastrointestinal Neuroendocrine Tumors.

Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3), is an oncofetal protein whose aberrant expression has previously been detected in multiple malignant neoplasms. Pulmonary neuroendocrine carcinomas demonstrate increased expression compared with pulmonary carcinoid tumors, but this relationship has not been studied in gastrointestinal neuroendocrine tumors (GINETs). This study examined IMP3 expression in GINETs, with a focus on correlation with established grading criteria. Fifty-four GINETs were immunohistochemically studied using a monoclonal antibody against IMP3. Using established World Health Organization criteria, the cases were stratified by grade and included 31 grade 1 neuroendocrine tumors (G1 GINETs), 15 grade 2 neuroendocrine tumors (G2 GINETs), and 8 neuroendocrine carcinomas (GINECs). The majority (51/54, 94.4%) of GINETs demonstrated IMP3 staining. Thirty cases (55.6%) showed IMP3 cytoplasmic/membranous staining in 60% or greater of tumor cells, with moderate to strong staining in nearly all of these cases (29/30; 96.7%). Of the remaining 24 cases, 3 cases showed no staining, whereas 17 (81%) demonstrated weak staining. When stratified by grade, there was no statistically significant difference in IMP3 staining among the 3 grades of GINETs; of the G1 GINETs, 14 (45.2%) demonstrated staining in at least 60% of tumor cells, compared with 10 (66.7%) G2 GINETs and 6 (75%) GINECs. Hindgut neoplasms of any grade were the most likely to show significant IMP3 staining. Unlike what has been demonstrated in neuroendocrine neoplasms in the lungs, GINETs appear to have a consistent IMP3 expression profile among all tumors grades, which may be reflective of their unique tumor biology.