Porcine Circular RNA Insulin-like Growth Factor 1 Receptor Promotes Adipocyte Differentiation / 中国生物化学与分子生物学报

Circular RNA (circRNA), as a competitive endogenous RNA (ceRNA), plays an importantrole in the regulation of cell differentiation. The purpose of this study was to identify and analyze porcinecircular RNA insulin-like growth factor 1 receptor (circIGF1R), explore its expression patterns, construct a ceRNA regulatory network related to circIGF1R, and explore the regulation of its ectopicexpression on adipogenic differentiation of mouse mesenchymal stem cells (C3H10T1 / 2) effect. Forwardand reverse PCR, Sanger sequencing, RNase R enzyme digestion tests, and qRT-PCR were used toverify that circIGF1R is a circRNA formed by the second exon of insulin-like growth factor 1 receptor(IGF1R). It was expressed in all tissues of pigs, and its expression level increased with age in adiposetissues. miRDB, TargetScan and miRWalk online software were used to predict circIGF1R target genes. RNAhybrid software was used for binding site prediction. DAVID bioinformatics functional analysissoftware was used to perform GO and KEGG enrichment analysis on candidate target genes. Cytoscapesoftware was used to construct the ceRNA network diagram. Based on the gene expression correlation andpredicted target relationship, the GO and KEGG enrichment analysis was drawn and the ceRNA networkwas constructed; the dual luciferase reporter gene test was used, and we found that circIGF1R andFABP4 can bind to ssc (Sus scrofa chromosome) -miR-133a-5p. The circIGF1R overexpression vectorwas successfully constructed and expressed in C3H10T1/ 2 cells. It was found that after overexpression ofcircIGF1R, the expression of key adipogenic regulatory factors CEBPa, CEBPß, FABP4 and PPAR? increased significantly(P<0. 01), and the number of lipid droplets increased significantly. The results ofthis study show that circIGF1R exists in pig adipose tissues, and may positively regulate the adipogenicdifferentiation of C3H10T1/ 2 cells through the ceRNA mechanism, which lays a theoretical foundation forfurther research on circIGF1R regulating the adipogenic differentiation of pig precursor intramuscularadipocytes.

Effects of miRNA-628-3p on proliferation, apoptosis and invasion of non-small cell lung cancer H1299 cells and its targeting relationship with insulin-like growth factor 1 receptor / 肿瘤研究与临床

Objective:To investigate the effects of miRNA-628-3p (miR-628-3p) on the proliferation, apoptosis and invasion of non-small cell lung cancer H1299 cells and its targeting relationship with insulin-like growth factor 1 receptor (IGF-1R).Methods:The blank control group (untreated H1299 cells), miR-NC group (H1299 cells transfected with empty plasmid), miR-628-3p-M group (H1299 cells transfected with miR-628-3p mimic sequence plasmid) and miR-628-3p-I group (H1299 cells transfected with miR-628-3p inhibitory sequence plasmid) were established. The cells in each group were cultured for 72 h, and the cell proliferation ability was detected by methyl thiazol tetrazolium (MTT) method, the number of cell monoclonal formation was determined by crystal violet staining, the level of cell apoptosis was determined by flow cytometry, and the cell invasion ability was determined by Transwell method. The mRNA levels of miR-628-3p and IGF-1R in cells were determined by real-time fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the protein level of IGF-1R in cells was determined by Western blotting.Results:Compared with the blank control group and miR-NC group, the cell survival rate [(42±7)% vs. (78±6)%, (76±7)%], the number of monoclonal formation [235±35 vs. 614±89, 618±75], the number of invasive cells [(265±85) cells vs. (693±185) cells, (703±119) cells], relative expression of IGF-1R mRNA (2.17±0.14 vs. 3.38±0.15, 3.37±0.13) and relative expression of IGF-1R protein (0.34±0.13 vs. 0.89±0.19, 0.88±0.18) in the miR-628-3p-M group were lower (all P < 0.05), but the apoptosis rate [(9.30±3.51)% vs. (3.30±1.54)%, (3.10±1.94)%] and relative expression of miR-628-3p (6.93±0.17 vs. 3.29±0.15, 3.30±0.16) were higher (all P < 0.05); the cell survival rate [(90±6)%], the number of monoclonal formation (1 063±102), the number of invasive cells [(1 985±426) cells], relative expression of IGF-1R mRNA (4.30±0.18) and relative expression of IGF-1R protein (1.47±0.17) in the miR-628-3p-I group were higher (all P < 0.05), but the apoptosis rate [(0.90±0.20)%] and the relative expression of miR-628-3p (1.93±0.18) were lower (both P < 0.05). Compared with the miR-628-3p-M group, the miR-628-3p-I group had higher cell survival rate, the number of monoclonal formation, the number of invasive cells, and the relative expressions of IGF-1R mRNA and protein (all P < 0.05), but the apoptosis rate and relative expression of miR-628-3p were lower (both P < 0.05). Conclusions:After regulation of miR-628-3p level, the proliferation, migration and invasion of H1299 cells are affected. miR-628-3p may have a targeting relationship with IGF-1R.

Insulin-like growth factor-1 receptor inhibitor alleviates diabetic kidney disease mouse tubulopathy / 中华肾脏病杂志

Objective@#To investigate the effects of insulin-like growth factor 1 receptor (IGF-1R) inhibitor on tubulopathy in diabetic kidney disease (DKD) mice.@*Methods@#C57BL/6J male mice were randomly divided into normal control group (n=10) and DKD model group (n=30), by giving a single intraperitoneal injection of STZ 150 mg/kg to establish a DKD model. After established successfully, the mice in DKD model group were randomly divided into DKD group (n=10), benazepril group (n=10) and IGF-1R inhibitor group (n=10). IGF-1R inhibitor group was given intraperitoneal injection of IGF-1R inhibitor (30 mg·kg-1·d-1) and benazepril group was given intraperitoneal injection of benazepril (30 mg·kg-1·d-1). Normal control group and DKD group were given an equal amount of normal saline. After 8 weeks of feeding, mice were euthanatized. Body weight and kidney weight were recorded. Blood, urine and kidney samples were collected. Biochemical tests such as blood glucose and urine albumin were measured by automatic biochemical instruments and albumin excretion rate was calculated. Pathological changes of mice were observed by hematoxylin-eosin staining (HE) and periodic acid-schiff staining (PAS). Phosph (p) IGF-1R expression level was determined by immunohistochemistry and Western blotting.@*Results@#Compared with the normal control group, blood glucose, kidney weight/body weight and urinary albumin excretion rate were significantly higher in DKD group (all P<0.01). In DKD mice, glomerular expansion, tubular stenosis, tubular swelling and tubular atrophy were significantly detected. Meanwhile, the number of proximal tubular epithelial (PTE) cells was decreased, and the renal tubular injury scores, the average glomerular volume, and pIGF-1R protein expression were increased (all P<0.05). Compared with the DKD group, albumin excretion rate was significantly reduced (P<0.01), the above pathological changes were alleviated and the effect of IGF-1R inhibitor was more significant. Compared with the DKD group, the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P<0.05). Compared with the benazepril group, the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P<0.05).@*Conclusion@#IGF-1R inhibitor has better effect than benazepril on alleviating the tubulopathy of DKD mice.

Insulin-like growth factor-1 receptor inhibitor alleviates diabetic kidney disease mouse tubulopathy / 中华肾脏病杂志

Objective To investigate the effects of insulin-like growth factor 1 receptor (IGF-1R) inhibitor on tubulopathy in diabetic kidney disease (DKD) mice.Methods C57BL/6J male mice were randomly divided into normal control group (n=10) and DKD model group (n=30),by giving a single intraperitoneal injection of STZ 150 mg/kg to establish a DKD model.After established successfully,the mice in DKD model group were randomly divided into DKD group (n=10),benazepril group (n=10) and IGF-1R inhibitor group (n=10).IGF-1R inhibitor group was given intraperitoneal injection of IGF-1R inhibitor (30 mg· kg-1· d-1) and benazepril group was given intraperitoneal injection of benazepril (30 mg· kg-1· d-1).Normal control group and DKD group were given an equal amount of normal saline.After 8 weeks of feeding,mice were euthanatized.Body weight and kidney weight were recorded.Blood,urine and kidney samples were collected.Biochemical tests such as blood glucose and urine albumin were measured by automatic biochemical instruments and albumin excretion rate was calculated.Pathological changes of mice were observed by hematoxylin-eosin staining (HE) and periodic acid-schiff staining (PAS).Phosph (p) IGF-1R expression level was determined by immunohistochemistry and Western blotting.Results Compared with the normal control group,blood glucose,kidney weight/body weight and urinary albumin excretion rate were significantly higher in DKD group (all P ＜ 0.01).In DKD mice,glomerular expansion,tubular stenosis,tubular swelling and tubular atrophy were significantly detected.Meanwhile,the number of proximal tubular epithelial (PTE) cells was decreased,and the renal tubular injury scores,the average glomerular volume,and plGF-1R protein expression were increased (all P ＜ 0.05).Compared with the DKD group,albumin excretion rate was significantly reduced (P ＜ 0.01),the above pathological changes were alleviated and the effect of IGF-1R inhibitor was more significant.Compared with the DKD group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P ＜ 0.05).Compared with the benazepril group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P ＜ 0.05).Conclusion IGF-1R inhibitor has better effect than benazepril on alleviating the tubulopathy of DKD mice.

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.

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.

IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Insulin-like growth factor-1 receptor (IGF-1R) is involved in both glucose and bone metabolism. IGF-1R signaling regulates the canonical Wnt/β-catenin signaling pathway. In this study, we investigated whether the IGF-1R/ β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis (DOP). Serum from patients with or without DOP was collected to measure the IGF-1R level using enzyme-linked immunosorbent assay (ELISA). Rats were given streptozotocin following a four-week high-fat diet induction (DOP group), or received vehicle after the same period of a normal diet (control group). Dual energy X-ray absorption, a biomechanics test, and hematoxylin-eosin (HE) staining were performed to evaluate bone mass, bone strength, and histomorphology, respectively, in vertebrae. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to measure the total and phosphorylation levels of IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin. The serum IGF-1R level was much higher in patients with DOP than in controls. DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group. HE staining showed that the histomorphology of DOP vertebrae was seriously impaired, which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae. PCR analysis demonstrated that IGF-1R mRNA expression was significantly up-regulated, and western blotting detection showed that phosphorylation levels of IGF-1R, GSK-3β, and β-catenin were enhanced in DOP rat vertebrae. Our results suggest that the IGF-1R/β-catenin signaling axis plays a role in the pathogenesis of DOP. This may contribute to development of the underlying therapeutic target for DOP.

The effect of levonorgestrel-releasing intrauterine system on IGF-Ⅰ and IGF-IR expression after transcervical resection of polyp / 中国医师杂志

Objective To evaluate the effect of levonorgestrel-releasing intrauterine system (LNG-IUS) on insulin-like growth factor-Ⅰ (IGF-Ⅰ) and insulin-like growth factor-Ⅰ receptor (IGF-IR) expression after transcervical resection of polyp (TCRP).Methods 100 cases of endometrial polyps were selected.The control group (n =50) was treated with TCRP only,while the observation group (n =50) was treated with LNG-IUS after TCRP.The scores of pictorial blood loss assessment chart (PBCA),endometrial thickness,recurrence rate,mRNA expression of IGF-Ⅰ and IGF-IR in endometrial tissue were compared between the two groups.Results At 1,3,6,12 months follow-up,the PBAC score and endometrial thickness of observation group were significantly lower than control group (P ≤ 0.05).At 12 months after operation,the mRNA expression levels of IGF-Ⅰ and IGF-IR in the endometrium of the observation group were significantly lower than those of the control group (P ≤ 0.05).After 12 months of follow-up,the recurrence rates of the control group and the observation group were 16.0％ (8/50) and 4.0％ (2/50),respectively.The recurrence rate of the observation group was significantly lower than that of the control group (P ≤ 0.05).Conclusions TCRP combined with LNG-IUS treatment can significantly reduce EP recurrence,and down-regulation of the mRNA expression of IGF-Ⅰ and IGF-IR maybe its possible mechanism.

IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Insulin-like growth factor-1 receptor (IGF-1R) is involved in both glucose and bone metabolism. IGF-1R signaling regulates the canonical Wnt/β-catenin signaling pathway. In this study, we investigated whether the IGF-1R/ β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis (DOP). Serum from patients with or without DOP was collected to measure the IGF-1R level using enzyme-linked immunosorbent assay (ELISA). Rats were given streptozotocin following a four-week high-fat diet induction (DOP group), or received vehicle after the same period of a normal diet (control group). Dual energy X-ray absorption, a biomechanics test, and hematoxylin-eosin (HE) staining were performed to evaluate bone mass, bone strength, and histomorphology, respectively, in vertebrae. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to measure the total and phosphorylation levels of IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin. The serum IGF-1R level was much higher in patients with DOP than in controls. DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group. HE staining showed that the histo-morphology of DOP vertebrae was seriously impaired, which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae. PCR analysis demonstrated that IGF-1R mRNA expression was significantly up-regulated, and western blotting detection showed that phosphorylation levels of IGF-1R, GSK-3β, and β-catenin were enhanced in DOP rat vertebrae. Our results suggest that the IGF-1R/β-catenin signaling axis plays a role in the pathogenesis of DOP. This may contribute to development of the underlying therapeutic target for DOP.

Expressions and Clinical Significance of Insulin-like Growth Factor-1 and its Receptor in Patients With Type 2 Diabetes Mellitus and Gastric Cancer / 胃肠病学

Insulin-like growth factor-1 (IGF-1) is an important mitogenic factor, which has an intense role in promoting proliferation and anti-apoptosis, and is abnormally expressed in many malignant tumors. Aims: To investigate the expressions and clinical significance of IGF-1 and its receptor (IGF-1R) in patients with type 2 diabetes mellitus (T2DM) and gastric cancer (GC). Methods: A total of 338 patients with GC received surgery from Jan. 2010 to Jan. 2013 were enrolled, and were divided into GC group and GC-T2DM group. The expressions of IGF-1 and IGF-1R were detected by immunohistochemistry, and their relationship with clinicopathological parameters were analyzed. The effect of expressions of IGF-1 and IGF-1R on survival of patients was evaluated. Results: Compared with GC group, the positivity rates of IGF-1 (81.3% vs. 42.3%; χ2=31.427, P0.05). Conclusions: Compared with GC patients, the positivity rates of IGF-1 and IGF-1R in GC-T2DM patients are significantly increased, and have certain negative effects on the clinicopathological parameters of the patients, suggesting that the two may promote the development and progression of GC through some mechanism.

Effects of electroacupuncture at "Zhongliao" (BL 33) and "Tianshu" (ST 25) on ovarian function in rats with premature ovarian insufficiency / 中国针灸

<p><b>OBJECTIVE</b>To explore the effects of electroacupuncture (EA) at "Zhongliao" (BL 33) and "Tianshu" (ST 25) on ovarian function in rats with premature ovarian insufficiency (POI).</p><p><b>METHODS</b>A total of 48 SD female rats with regular estrus were divided into a blank group (=8), a model group (=10), an EA group (=10), a binding group (=10) and a tamoxifen (TAM) group (=10). The rats in the model group, EA group, binding group and TAM group were all treated with intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg) for 15 consecutive days to establish the model of POI; the rats in the blank group were treated with normal diet. After the model was established successfully, the rats in the EA group were treated with EA at "Zhongliao" (BL 33) and "Tianshu" (ST 25) with continuous wave (1 to 3 Hz, 0.1 to 1 mA) for 20 minutes, once a day (five times a week) for the first two weeks and once every other day (three times a week) for the following two weeks. The rats in the TAM group were treated with subcutaneous injection of tamoxifen (1mg/kg), once a day (five times a week) for the first two weeks and once every other day (three times a week) for the following two weeks. The rats in the binding group were bound by a small sack as the EA group. The rats in the blank group and the model group were treated with normal diet. After four weeks, the sexual gland weight and index were tested in each group; the ELISA method was applied to test the level of anti-mllerian hormone (AMH) and inhibin B; the morphology of ovary was observed; the number of primordial follicles, primary follicle, antral follicle and atretic follicle was counted; the expression of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1 receptor (IGF-1R) were measured.</p><p><b>RESULTS</b>(1) Compared with the blank group, the ovary weight, ovary index, uterus weight and uterus index were significantly decreased after treatment in the model group, EA group, binding group and TAM group (all <0.01); but the differences between the model group and the EA group, binding group, TAM group were not significant (all >0.05). (2) Compared with the blank group, the levels of serum AMH, inhibin B and E were significantly reduced; the levels of FSH and LH were significantly increased in the model group; EA group, binding group and TAM group (all <0.01). Compared with the model group, the levels of serum AMH, inhibin B and E were significantly increased, the level of FSH and LH were significantly reduced in the EA group and TAM group (all <0.01). (3) Compared with the blank group, in the model group, EA group, binding group and TAM group the ovary was dark red and pale, surrounded by particle or not; the morphology was small and atrophic; the primordial follicles was reduced even vanished; the structure of primary follicle was damaged and loosely arranged; the mature follicle was few; the atretic follicle and interstitial gland were increased. (4) Compared with the blank group, the expressions of IGF-1 mRNA and IGF-1R mRNA were increased in the model group (all <0.01); compared with the blank group, the expression of IGF-1 mRNA was increased in the binding group (<0.05), but that of IGF-1R mRNA was not significantly different (>0.05); compared with the model group, the expression of IGF-1 mRNA was not significantly different in the EA group, binding group and TAM group (all >0.05), but that of IGF-1R mRNA was reduced (<0.05, <0.01).</p><p><b>CONCLUSION</b>EA at "Zhongliao" (BL 33) and "Tianshu" (ST 25) has improvement effect on ovarian function in rats with VCD-induced POI, which is likely to be related to regulating the IGF-1R mRNA expression to improve the IGF-1/ IGF-1R axis.</p>

miR-126-mediated activation of IGF2/IGF1R/IRS1 signaling promotes the Herceptin resistance in ErbB2 positive breast cancer cells / 中国医师杂志

Objective To explore the role of insulin-like growth factor-2/insulin-like growth factor1 receptor/insulin receptor substrate-1 (IGF2/IGF1R/IRS1) signal pathway inducing the chemoresistance of epidermal growth factor receptor 2 (ErbB2) positive breast cancer cells to Herceptin.Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay were used to determine the expression levels of IGF2,IGF1 R,and IRS1.The direct targets of miR-126 were validated by dual-luciferase reporter gene assay.In SKBR3/pool2 cells,IGF1 R activity was reduced by an inhibitor of IGF1 R,and IRS1 was knocked-down by shRNAs.Furthermore,3-(4,5-dimenthylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was performed to evaluate the sensitivity of these treated cells to Herceptin.Results IGF2,IGF1 R,and IRS1 were significantly higher expressed in SKBR3/pool2 cell compared to that in SKBR3 cell.Western blot assay showed that IGF2/IGF1R/IRS1 was activated in SKBR3/pool2 cells.Bioinformatics analysis combined with luciferase activity suggested that miR-126 directly targeted IRS1.MTS results demonstrated that the chemosensitivity to Herceptin of SKBR3/ pool2 cells with inhibitor of IGF1R or shRNAs targeting IRS1 or overexpressing miR-126 was significantly reduced.Conclusions IGF2/IGF1R/IRS1 signal pathway confers to the chemoresistance of ErbB2 positive breast cancer cells to Herceptin.

The function and mechanism of ErbB3 and IGF1R in breast cancer with Herceptin resistance / 中国医师杂志

Objective To investigate the role of epidermal growth factor receptor 3 (ErbB3) and insulin-like growth factor-1 receptor (IGF1R) in enhancing the resistance of Herceptin in human breast cancer.Methods HRG (Heregulin,the ligand of ErbB3) or IGF2 (insulin-like growth factor2,the ligand of IGF1R) was correspondingly added into breast cancer cells SKBR3 and BT474,and then 3-(4,5-dimenthylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and were performed in these cells to evaluate the sensitivity of these cells to Herceptin.Furthermore,we used HRG or IGF2 antibodies to inhibit their joint receptors in Herceptin-resistant breast cancer cells SKBR3/POOL2 and BT474/HR20.Finally,the sensitivity of these treated cells to Herceptin was detected via MTS assay.HRG or IGF2 was added into breast cancer cell BT474,and co-IP assay was used to detect the expressions of ErbB3 and IGF1R which combined with ErbB2.Results The treatment groups used HRG or IGF2 enhanced the resistance of Herceptin in Herceptin-sensitive breast cancer cells.On the other hand,we used antibodies of HRG and IGF2 to block their combining with their receptors in Herceptin-resistant breast cancer cells,the cells became more sensitive to Herceptin.BT474 cell was treated with HRG or IGF2.The expressions of ErbB3 and IGF1R which combined with ErbB2 were increased.Conclusions The formation of heterodimers ErbB2/ErbB3 and ErbB2/IGF1R might enhance the resistance of Herceptin in ErbB2-overexpression human breast cancers.

Research advances in insulin-like growth factor 1 receptor and its pathway in diagnosis and treatment of primary liver cancer / 临床肝胆病杂志

The main biological functions of insulin-like growth factor 1 receptor (IGF-1 R) include formation and maintenance of transformed cell phenotype,involvement in cell proliferation and differentiation,and inhibition of cell apoptosis.In addition,IGF-1R regulates cell cycle and works with epidermal growth factor and platelet-derived growth factor to mediate cells to enter S phase from G1 phase.Overexpressed IGF-1R has become one of the target proteins for diagnostic imaging and localization therapy for primary liver cancer.Inhibition of the expression or function of IGF-1R can effectively control the growth and metastasis of tumor cells and enhance their sensitivity to chemotherapy and radiotherapy.This article reviews the role and significance of IGF-1R and its pathway in the diagnosis and treatment of primary liver cancer.

Research advances in insulin-like growth factor-1 receptor in pancreatic cancer / 临床肝胆病杂志

Insulin-like growth factor-1 receptor (IGF-1 R) widely exists in the surface of various types of cells and is closely associated with the formation and development of tumor cells.It also provides a new direction for the targeted therapy for tumors.This article reviews the expression,development,and progression of IGF-1R in pancreatic cancer and research advances in IGF-1R as a target for tumor treatment.

Clinicopathological and prognostic analysis of insulin like growth factor 1 receptor protein expression in primary gastrointestinal stromal tumors / 中华普通外科杂志

Objective To investigate the clinicopathological significance of expression of insulin like growth factor 1 receptor (IGF1R) protein in primary gastrointestinal stromal tumors (GIST) and their impacts on prognosis.Methods Between January,2005 and January,2011,84 primary GIST patients underwent surgery.Immunohistochemical analysis was performed based on tissue microarray to estimate expression pattern of IGF1R in tumor cells and nomal controls.Association of IGF1R expression with clinicopathological features and relapse-free survival (RFS) were also analyzed.Results The negative,weakly positive,positive,and strong positive expression rates of IGF1 R protein in GIST group were 20％,14％,48％ and 18％,respectively;while in the control group were 32％,40％,20％ and 8％,respectively (x2 =30.663,P ＜ 0.001).The 5-year overall survival (OS) rate was 93％.1-year,3-year and 5-year RFS rate were 99％,76％ and 60％,respectively.As shown by univariate analysis the following factors were poor prognostic indicators for RFS,non-gastric tumor location (P =0.017),large tumor size (P =0.022),high mitotic index (P ＜ 0.001),high cellularity (P =0.012),tumor rupture (P =0.013),absent or low expression of IGF1R (P =0.022).Tumor size (HR5.1-10 ≤5 cm =1.86,95％ CI:0.67-5.15;HR＞10 ≤5cm =6.71,95％ CI:0.67-5.15,overall P =0.023),and mitotic index (HR5.1-10/50HPFsvs.≤5/50HPFs =5.72,95％ CI:2.09-15.64;HR＞10/50HPF ≤5/50HPFs =3.44,95％ CI:1.13-10.45,overall P =0.002) were negative independent risk predictors by multivariate analysis.Conclusions High expression of IGF1R may be involved in the occurrence,development and poor prognostic of primary GIST.Expression of IGF1 R is correlated with high risk potential and may predict early recurrence.

Bioinformatics analysis of sequence and structure of insulin-like growth factor-I receptor / 生物工程学报

The length of IGF1R 3'UTR is greater than 7 kb. The structure of IGF1R 3'UTR is complex, with multiple binding sites of miRNAs. IGF1R is involved in the regulation of MAPK and PI3K/AKT signaling pathways and theformation and development of tumors. Bioinformatics analysis can reveal the structure features of IGF1R, which provides ideas for further research. The analysis shows that the binding sites between IGF1R and miRNAs have the highest mutation rate in Neuroblastoma. We analyzed the structure of 3'UTR, miRNAs binding sites, physical and chemical properties, hydrophilic-hydrophobic property, glycosylation and phosphorylation sites, secondary structure and tertiary structure modeling of IGF1R. The locations and names of amino acids interacting in IGF1R and IGF1 were obtained by molecular docking. Therefore, if IGF1R 3'UTR is mutated, the capacity of IGF1R combined with miRNAs will reduce and the IGF1R expression will be up-regulated, and the function of miRNAs will be repressed. We can change the sites of IGF1R to combine with IGF1 to repress the function of IGF1R and IGF1. Then the function of IGF1R will be repressed.

Relation between cervical squamous cancer lesion among Uighur and Han ethnic women in Xinjiang with expression of PI3K,ERK,IGF-1R and ER protein / 重庆医学

Objective To observe the expression levels of PI3K ,ERK ,IGF‐1R and ER in cervicitis and cervical squamous cancer tissues among Uighur and Han ethnic patients and their correlation .Methods The 90 paraffin embedding samples of cervici‐tis tissue( 46 cases for Han and 44 cases for Uighur) and 224 paraffin embedding samples of cervical squamous cancer tissue (36 ca‐ses for Han and 188 cases for Uighur) were collected and detected the protein expression levels by using immunohistochemistry .Re‐sults The positive expression rates of IGF‐1R and PI3K in cervical squamous cancer were 58 .04% and 92 .41% respectively ,which were higher than 13 .33% and 57 .78% in cervicitis tissue ,the positive expression rates of ER and ERK in cervical squamous cancer were 22 .32% and 68 .30% respectively ,which were lower than 63 .33% and 95 .56% in cervicitis tissue ;the positive expression rate of IGF‐1R and PI3K of cervical squamous cancer in Han and Uighur were 69 .44% ,88 .89% and 55 .85% ,93 .09% respective‐ly ,which were higher than 15 .22% ,54 .35% and 11 .36% ,61 .36% of cervicitis tissue ;the positive expression rate of ER and ERK of cervical squamous cancer in Han and Uighur were 13 .89% ,83 .33% and 23 .94% ,65 .43% respectively ,which were lower than 65 .22% ,93 .48% and 61 .36% ,97 .73% of cervicitis tissue respectively ;the expression of ERK in Uighur cervical squamous carci‐noma tissue was 65 .43% ,which was lower than 83 .33% in Han ,the difference was statistically significant (P<0 .01) .Conclusion PI3K ,ERK ,IGF‐1R and ER protein expression positive or deficiency is closely related to the occurrence of cervical cancer ,which may serve as the important biological indicators for detecting cervical cancer ,and the ethnic difference of ERK protein expression exists in cervical cancer .

Expressions of IGF-1R and IGFBP-3 in colon cancer metastasis and their correlations with lymphatic metastasis / 国际肿瘤学杂志

Objective To investigate the expressions of insulin-like growth factor receptor-1 (IGF-1R) and insulin-like growth factor binding protein-3 (1GFBP-3) and their correlations with clinicopathological parameters in the primary colon cancer,as well as their roles in lymph node metastasis of colon cancer.Methods The expressions of IGF-1R and IGFBP-3 in 78 cases of colon cancer tissues and 78 cases of normal colon mucosa tissues were detected by SP immunohistochemical technology and the correlations between the expressions and the clinical pathological parameters of colon cancer were analyzed.Results The positive rate of IGF-1R in colon cancer (66.7％,52/78) was significantly higher than that in control group (24.4％,19/78),x2 =28.150,P =0.000.The positive rate of IGFBP-3 in colon cancer (73.1％,57/78) was significantly lower than that in control group (89.7％,70/78),x2 =7.158,P =0.007.IGF-1R expression in colon cancer was significantly correlated with the invasion (x2 =5.804,P =0.016),TNM stage (x2 =5.246,P =0.022) and lymph node metastasis (x2 =12.955,P =0.000).IGFBP-3 expression in colon cancer was signi-ficantly correlated with the TNM stage (x2 =7.096,P=0.008),lymph node metastasis (x2 =5.893,P =0.015) and distant metastasis (P =0.003).Both with other factors had no significant correlation (P ＞ 0.05).1GF-1R expression and IGFBP-3 expression showed a negative correlation (r =-0.245,P =0.03).Conclusion The over expression of IGF-1R and low expression of IGFBP-3 are associated with TNM stage and lymph node metastasis in colon cancer.IGF-1R and IGFBP-3 may become new targets of the treatment of colon cancer.