Role of insulin-like growth factors family in endometrial cancer / 国际肿瘤学杂志

The expression and activity of insulin-like growth factors (IGFs) are increased in endometrial cancer (EC).IGFs not only mediate the positive impact of estrogen on EC,but also increase the risk for development of EC in patients with metabolic disorder.In addition,IGFs play a key role in the invasion,metastasis and drug resistance of EC.Thus,drugs that target IGFs may be the novel treatment of EC.

The role of microRNA-133b in proliferation of vascular smooth muscle cells induced by endothelial cells under low shear stress / 医用生物力学

Objective To investigate the role of microRNAs (miRs) in the proliferation of vascular smooth muscle cells （VSMCs）induced by endothelial insulin-like growth factor-1 (IGF-1) under low shear stress (LowSS). Methods Endothelial cells (ECs) and VSMCs were co-cultured and exposed to normal shear stress (NSS, 1.5 Pa) and LowSS (0.5 Pa) for 12 h with parallel plate flow chamber system, respectively. Real-time PCR was used to examine the expression levels of miRs. The target genes of miR-133b were predicted by multiple algorithms. The expression of polypyrimidine tract binding protein 1 (Ptbp1) and N-myc downstream regulated 1 (Ndrg1) in VSMCs was detected by Western blotting. The VSMC proliferation was detected by EdU flow cytometry assay. Results After treated with recombinant IGF-1, the expression of both miR-133b and miR-378a in VSMCs was increased. Compared with NSS, LowSS significantly induced the expression of miR-133b in the co-cultured VSMCs, but had no obvious effect on miR-378a. In VSMCs, the protein and mRNA levels of Ptbp1 and Ndrg1 were down-regulated by miR-133b mimics. miR-133b inhibitor up-regulated the mRNA levels of Ptbp1 and Ndrg1. miR-133b overexpression promoted the proliferation of VSMCs significantly. Conclusions IGF-1 secreted by ECs in response to LowSS can upregulate the expression of miR-133b in the co-cultured VSMCs, which subsequently depresses the expression of Ptbp1 and Ndrg1, and induces the proliferation of VSMCs eventually. The research findings provide a potential new target for cardiovascular disease therapy.

Non-islet Cell Tumour Hypoglycaemia (NICTH) in Malignant Mesothelioma: Case Report

Non-islet cell tumour hypoglycaemia (NICTH) is an uncommon but important clinical condition. It can occur in a setting of known malignancy. Here, we report the case of a 56-year-old, non-diabetic, female patient with unresectable malignant pleural mesothelioma who presented with unexplained recurrent hypoglycaemia. Surreptitious use of insulin or other hypoglycaemic agents were ruled out. Investigations revealed markedly suppressed insulin-like growth factor-I, normal insulin-like growth factor-II and elevated “big”-insulin-like growth factor-II, supporting the diagnosis of NICTH. Plasma growth hormone concentration was low. Initial treatments using prednisone alone, as well as the subsequent addition of diazoxide, were unsuccessful in maintaining euglycaemia. A combination of dexamethasone and recombinant human growth hormone was used successfully to ameliorate the hypoglycaemic episodes. We herein describe an uncommon clinical manifestation of malignant mesothelioma and provide an overview of the pathophysiology of this syndrome, as well as explore a different treatment regimen as reported in the literature.

Insulin Signaling Network in Cancer.

The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer.

The progress on cell signaling pathways related lung cancer / 实用肿瘤学杂志

Lung cancer is one of the most common malignant tumors in the world .However,its pathogen-esis is still unclear .With the deep research of related signal pathways underlying the development ,progression and prognosis of lung cancer , we find that the mTOR signaling pathway , JAK-STAT pathway , Notch signaling and IGF have been identified to play a major role in the growth ,proliferation,differentiation,apoptosis and invasion of tumor cells.Therefore this paper is to review the effects of the above several pathways ,which may prove a new ba-sis for the pathogenesis and therapy of lung cancer .

The levels of insulin-like growth factors in children with acute leukemia / 临床儿科杂志

Objective To detect the levels of insulin-like growth factors in children with acute leukemia (AL). Methods A total of 50 previously untreated AL patients were selected, meanwhile 30 healthy children were selected as normal controls. AL children were given regular chemotherapy. All cases were not given the brain radiotherapy. The levels of insulin-like growth factor-1 (IGF-1), free insulin-like growth factor-1 (fIGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) in AL patients before treatment and 6 months after complete remission were measured by enzyme-linked immunosorbent assay (ELISA), and were compared with those in normal controls. Results Before treatment, compared with normal controls, the serum levels of IGF-1, IGFBP-3 in AL patients were lower while the level of fIGF-1 was higher, and the differences were signiifcant (P<0.01). At six months after complete remission, the levels of IGF-1 and fIGF-1 in AL patients were similar to those before treatment, but were signiifcantly different from those in control group (P<0.05);the level of IGFBP-3 was signiifcantly higher than that before treatment (P<0.01), but was similar to that in control group. Before treatment, the level of IGFBP-3 in AL patients was positively correlated with the level of IGF-1 (r=0.777, P<0.01), and negatively correlated with the level of fIGF-1 (r=-0.714, P<0.01). Conclusion Insuline-like growth factors were involved in the pathophysiological process in children with AL.

Pay more attention to the study of the relationship between diabetes mellitus and cancer / 中华内分泌代谢杂志

Diabetic patients are at increased risk of some cancers,mainly pancreatic cancer,liver cancer,colorectal cancer,breast cancer,endometrial cancer,etc.,and these cancers often result in higher mortalities than that in nondiabetics.The exact mechanism of this relationship is still unclear.The most suggested factor are hyperinsulinemia and insulin-like growth factors with their growth promoting and mitogenic effects.Recently,some insulin analogues are suspected to have these carcinogenic effects,but no firmly proven data are available yet.Metformin may have a protective effect in this regard.

Influence of Gender on Serum Growth Hormone, Insulin-Like Growth Factor-I and Its Binding Protein-3 during Aging

PURPOSE: The serum concentrations of insulin-like growth factors-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and growth hormone (GH) are related to body composition, function and metabolism, and are influenced by the aging process. This study was to investigate the influence of gender on serum concentrations of IGF-I, IGFBP-3 and GH in middle and old age subjects. MATERIALS AND METHODS: Sixty healthy volunteers (male 35, female 25, 36-70 years) were divided into 50 years groups, based on gender. Women > 50 years were post-menopause. IGF-I, IGFBP-3, and GH were determined by immunoradiometric assay. RESULTS: IGF-I was shown to be negatively correlated with age (women r = -0.62, p 50 years showed a significant reduction in IGF-I values than women 50 years showed smaller IGF-I/IGFBP-3 molar ratios (0.177998 +/- 0.039404) than men of same age group (0.228326 +/- 0.050979, p < 0.01) and women < or = 50 years (0.247667 +/- 0.069411, p < 0.01). Age was shown to positively correlate with GH/IGF-I (r = 0.49, p < 0.05) and GH/IGFBP-3 ratios (r = 0.40, p < 0.05) in women. CONCLUSIONS: The influence of aging on serum concentrations of IGF-I is more remarkable in women than in men. Menopause causes reduction of IGF-I/IGFBP-3 molar ratio. Women have the trend of progressive hypoactivity of GH to stimulate IGF-I and IGFBP-3 secretions with age.

A preliminary study on the relationship of insulin-like growth factor-Ⅰ receptor and the carcinogenesis of gastde cancer / 中华消化杂志

Objective To study the relationship of insulin-like growth factor-Ⅰ receptor(IGF-ⅠR)and carcinogenesis of gastric cancer.Methods The expression of IGF-ⅠR was detected in 40 cases of resected gastric cancer tissues and adjacent normal gastric mucosa by immunohistochemistry.The expression of IGF-ⅠR in gastric cancer cell lines(MGC803 and SGC7901)was detected by Western Blot.siRNAs targeted to IGF-ⅠR were designed,synthesized and transfected into MGC803 cells,the changes of IGF-IR protein level were detected by Western Blot at 48 h after transfection,the cell proliferation was examined by MTT,and then the growth curve was obtained.Results The positive rate of IGF-IR expression in gastric cancer tissues was 75.5%,significantly higher than that of adjacent normal tissues (25%,P＜0.01).The expression level of IGF-IR was related with TNM stage,lymphnode metastasis (P＜0.05),but not related with sex,age,histological differentiation,invasion depth of gastric cancer (P＞0.05).Intense expression of IGF-ⅠR was showed in gastric cancer cell lines.The inhibition ratio of IGF-ⅠR expression in sigNAl group were 89.80%±4.10%,the cell proliferation decreased to mininlunl level at the fifth day aftertransfection(by 29.0%±4.0%of mock-treated group),the cell number decreased by 21.15%±1.10%of mock treated group at the same time.Conclusions IGF-ⅠR is over-expressed in gastric cancer cells and can be effectively silenced by RNA interferes,therefore the growth of tmnor cell Was inhibited.Thus,it indicates that IGF-ⅠR may be a promising target for gene therapy of gastric cancer.

pSUPER-siRNA-IGF1R protein enhances sensitivity of human liver cancer cells to mitomycin in vitro / 肿瘤

Objective: To investigate whether the plasmid of short hairpin RNA targeting human insulin like growth factor receptor 1 (pSUPER-siRNA-IGF1R) can enhance mitomycin-induced apoptosis of human liver cancer SMMC7721 cells and the corresponding mechanism. Methods: The siRNA targeting IGF1R was designed and the pSUPER-siRNA-IGFI R plasmid was constructed and transfected into SMMC7721 cells. The stable cell lines were screened by G418. The growth curve of every group was detected by CCK8 method. After mitomycin treatment, the sensitivity of hepatoma cells to chemotherapy was monitored by CCK8 method. The apoptotic index (AI) was examined by flow cytometry. The expression of apoptosis-related proteins p53, Bax, bcl-2 was determined by Western blotting. The empty control group and positive control were set up. Results: The apoptosis induced by mitomycin were significantly enhanced in stable cell line and the AI was significantly elevated compared with other groups (P < 0.05). The expression of wild type p53 and Bax protein was significantly up-regulated but the expression of bcl-2 protein was significantly down-regulated (P < 0.05). Conclusion: The constructed pSUPER-siRNA-IGF1R plasmid silences RNA transcription and enhances the apoptosis of tumor cells induced by mitomycin.

El dilema de la obesidad en ambos sexos / Dilemma of obesity in both sexes

En la obesidad glúteo-femoral, las consecuencias metabólicas son comparativamente escasas y los efectos endocrinos resultan directamente ligados al exceso de tejido adiposo. En la obesidad abdominal -en cambio- la actividad hormonal es muy importante: resistencia a la insulina e hiperinsulinemia, aumento de la actividad de los factores de crecimiento insulin-análogos (IGFs), aumento de la producción de testosterona (T), dihidrotestosterona (DHT) y estradiol (E2) "biodisponibles", por disminución de la proteína ligadora de andrógenos y estradiol (GLAE). Estas condiciones sugieren una posible asociación con el cáncer mamario y/o endometrial. La secreción de la hormona de crecimiento (HC) se reduce significativamente en la obesidad, junto con los factores hipotalámicos, hipofisarios y periféricos que contribuyen a la secreción anormal de la HC, jugando así un importante papel en la conformación corporal y en el balance de energía. La leptina circulante, producto que se expresa en los adipocitos con el gen ob, ejerce un efecto estimulante sobre la HC. Finalmente, una serie de pacientes seleccionados por su obesidad han sido identificados con importantes aumentos en los factores de crecimiento con valores descendidos de las proteínas portadoras de los IGFs. La obesidad abdominal se caracteriza también por la hiperinsulinemia de ayuno y una exagerada liberación de la insulina después de la carga de glucosa.

In the gluteo-femoral obesity, the metabolic consequences are comparative scarce and the endocrine effects are directly linked to the excess of adipose tissue. In abdominal obesity the endocrine effects are very important: insulin resistance and hyperinsulinemia, increase of IGF-I activity, increase of active androgen production by ovarian estroma, important reduction of sex-hormone-binding-globulin (SHBG) and increasing "bioavailable" estradiol (E2), testosterone (T) and dihidrotestosterone (DHT). In short, obesity and abnormal endocrinology appear to be associated with the development of endometrium and breast cancer in women. Growth hormone (GH) secretion is markedly reduced in obesity, and hypothalamic, pituitary and peripheral factors may contribute to the abnormal GH secretion. GH plays a critical rol in the regulation of body composition and energy balance. The circulating leptin is a product of specific adipocyte ob-gene that exerts stimulating effect on GH release. Furthermore, selected series of obese patients have shown that high free insulin like growth factor (IGF-I) and low IGF-binding proteins generally increased in overweight subjects. Obesity is also characterized by fasting hyperinsulinemia and exaggerated insulin release after a glucose load. Recently it has also demonstrated that leptine plays an important role in the reproductive system at all levels of the hypothalamus-pituitary-gonadal axis.

Study on the Action Mechanism of Insulin-Like Growth Factors and HBV-DNA Integration During Hepatocarcinogenesis / 中国医师杂志

Objective To observe the expressions of insulin-like growth factors(IGFs) and proliferating cell nuclear antigen(PCNA) in various kinds of liver tissues,we discussd the relationship among IGFs,PCNA and HBV-DNA integration in the process of hepatocarcinogenesis,provide some theoretical basis for the mechanism of hepatocarcinogenesis and clinical diagnosis and therapy of HCC.Methods 32 cases of HCC,32 cases of paracancerous liver tissues(PLT),12 cases of chronic active hepatitis(CAH),10 cases of fetal liver tissues(FLT) and 8 cases of normal adult liver tissues(NALT) were collected.Southern hybridization was used to detect HBV-DNA integration in various kinds of liver tissues.Then a colloid gold immunoelectron microscopic technique was used to make a systematic study on the expression and ultrastructural location of IGFs and PCNA in different liver tissues.Results The HBV-DNA integration was positively existed in 81 3%(26/32) of HCC and PLT,and 83 3%(10/12) in CAH,but the integration in NALT and FLT was no existed.PCNA was expressed by 87 5%(28/32) of HCC and 84 4%(27/32) of PLT,respectively.The postive rates of IGF-Ⅰ and IGF-ⅠR expressed by HCC were 40 6%(13/32) and 56 3%(18/32),those of IGF-Ⅰand IGF-ⅠR expressed by PLT were 50 0%(16/32) and 65 6%(21/32),respectively.The positive rates of IGF-Ⅱ and IGF-Ⅱ receptor(IGF-ⅡR) expressed by HCC were both 78 1%(25/32),and those expressed by PLT were both 81 3%(26/32).In the integration group of HBV-DNA had higher positive rates of IGF-Ⅱ and IGF-ⅡR,which were expressed by the HCC and PLT groups,than that of non-integration group of HBV-DNA(P

Serum Insulin-like Growth Factors and their Binding Proteins in the Women With Polycystic Ovary / 대한산부인과학회잡지

OBJECTIVE: The involvement of IGF system in hyperandrogenism and abnormal follicular development is controversial. This study is to assess whether IGF system contribute to it in the women with polycystic ovary(PCO). METHODS: Baseline serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), testosterone (T), androstenedione (ADD), prolactin, thyroid stimulating hormone (TSH), free insulin-like growth factor(IGF)-I, free IGF-II, insulin-like growth factor binding protein(IGFBP)-1, and IGFBP-3 were measured in twelve healthy regularly cycling volunteers and forty-two women with PCO then, the changes of baseline serum levels were evaluated after laparoscopic ovarian electrocauterization in nine PCO patients. In addition, the expression pattern of IGF-I and IGF-II was examined in the ovary of control and PCO group. RESULTS: Baseline levels of LH, ADD, free IGF-II, and IGFBP-3 were significantly higher in PCO group. However, there were no significant differences in the levels of free IGF-I and IGFBP-1, although free IGF-I showed decreasing tendency in PCO group. And there was a significant positive correlation between the LH and free IGF-II level in the PCO(P=0.011, r2=0.3899), but not in the control. After ovarian electrocauterization, LH, T, and ADD levels decreased, and free IGF-I and IGFBP-3 level increased. While free IGF-II and IGFBP-1 level showed no significant changes. In the ovary, expression of both IGFs showed similar pattern in normal and PCO ovaries. CONCLUSIONS: The elevated IGFBP-3 level may alter the bioavailability of IGF(s) in the PCO. The change in IGF-I level and resumption of ovulation after electrocauterization, suggest a possible role of IGF system in the impairment of follicular development in the PCO.

Biological roles of insulin-like growth factor binding proteins (IGFBPs)

The insulin-like growth factor binding protein (IGFBP) family is a critical component of the insulin-like growth factor (IGF) system which regulate the biological actions of the IGFs and may also be capable of IGF-independent actions. To date, seven distinct IGFBPs have been described. Among these IGFBPs, IGFBPs-1-6 bind IGFs with high affinity, while only IGFBP-7 binds with low affinity. Recently, we have demonstrated that connective tissue growth factor (CTGF) also binds IGFs with low affinity, suggesting that a family of low-affinity IGFBPs, distinct from the high-affinity members, may exist, and together these constitute an IGFBP superfamily. IGFBPs have various biological roles. IGFBPs act not only as a carrier proteins, but also as a modulators of IGF actions by involving in IGF ligand-receptor interactions through influences on both the bioavailability and distribution of IGFs in the extracellular environment. In addition, some IGFBPs (IGFBPs-1, -3, and -5) appears to have intrinsic activity independent of IGFs. This review will focus on recent studies on the biological roles of IGFBPs in IGF-dependent and IGF-independent modes.

A comparison of bioresorbable membranes alone or in combination with platelet-derived growth factors and insulin-like growth factors on the periodontal healing of the dehiscence defects in dogs / 대한치주과학회지

The purpose of present study is to compare the effect of treatment using Guidor(R) as a barrier membrane in conjunction with platelet-derived growth factor and insulin like growth factors on experimental dehiscence defects. Following the resection of premolar crowns, roots were submerged. After 12 weeks of healing period, experimental dehiscence defects of 4mm in height and 4mm in width were surgically created on the mid-facial aspect of the lower premolar roots in each of 4 adult dogs. After root planning and demineralization of the root surface with citric acid, the control groups received 4% methylcellulose gel only, the test group I received 4% methylcellulose gel and were covered by Guidor(R) and the test group II were treated with PDGF and IGF and 4% methylcellulose gel with Guidor(R) coverage. Histological and histomorphometric analysis following 8 weeks of healing revealed the following results. 1. The new bone formation showed no statistically significant difference in all groups with 0.59+/-0.82mm(14.03+/-19.60%) for control, 0.70+/-0.39mm(16.30+/-9.01%) for group I, 0.87+/-0.76mm(18.74+/-16.03%) for group II. 2. The new cementum formation showed no statistically significant difference in all groups with 0.54+/-0.48mm(16.38+/-14.57%) for control, 0.95+/-0.38mm(23.43+/-9.30%) for group I, 1.01+/-0.75mm(22.10+/-16.11%) for gorup II. 3. The root resorption showed statistically significant differences betweenthe control group and all test groups(p<0.05) with 2.11+/-0.53mm(52.93+/-12.32%) for control, 0.63+/-0.27mm(15.32+/-7.05%) for group I, 0.89+/-0.33mm (19.26+/-7.11%) for group II. On the bases of these results, there were no statistically difference between treatment using resorbable membrane and resorbable membrane in conjunction with PDGF and IGF in the dehiscence defects, where it was difficult to maintain space. The use of membrane seemed to be more effective in the inhibition of root resorption.

Expression of Insulin-Like Growth Factor-Binding Protein-5 in Full-Term Rats with Hyperoxia-Induced Chronic Lung Diseases and Its Machanism / 实用儿科临床杂志

Objective To investigate the expression of insulin-like growth factor-binding protein-5( IGFBP-5) in full-term rats with hyperoxia-induced chronic lung diseases(CLD) and its mechanism.Methods Ninety-six full-term rats were randomly exposed to hyperoxia (hyperoxia group)and room air(room air group).CLD was induced by hyperoxia exposure.RT-PCR and immunohistochemical metho -ds were used to detect the expression of IGFBP-5 at 1,3,7,10 ,14 and 21 days after exposure.Results The expression of IGFBP -5 was dynamic, the expression of IGFBP-5 increased significantly in hyperoxia group compared with room air group at 3 d to 10 d after hyperoxia exposure (P