Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma(HCC).Especially the over- expression of the fetal growth factor IGF-Ⅱ,IGF-Ⅰ receptor(IGF-IR),and cytoplasmic downstream effectors such as insulin-receptor substrates(IRS)contribute to proliferation,anti-apoptosis,and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱsignaling during HCC development and progression.Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies,various experimental strategies have been developed,including neutralizing antibodies and selective receptor kinase inhibitors,with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.

Influence of baicalin on the expression of receptor activator of nuclear factor-κB ligand and osteoprotegerin in human periodontal ligament cells

Objective To study the effect of baicalin on the expression of receptor activator of nuclear factor-κB ligand(RANKL)and osteoprotegerin(OPG)in cultured human periodontal ligament(HPDL)cells.Methods Small interfering RNA(siRNA)eukaryotic expression vector targeted transforming growth factor βⅡ receptor(TGF-β RⅡ)was constructed and transfected into T cells.HPDL cells with T cells transfected with siRNA or not were placed in the culture medium that had been added with lipopolysaccharide(LPS)and baicalin.The obtained solution was divided into six groups according to the components(group Ⅰ:HPDL cells+LPS+T cells transfected with siRNA1+baicalin;group Ⅱ:HPDL cells+LPS+T cells transfected with siRNA1;group Ⅲ:HPDL cells+LPS+T cells+baicalin;group Ⅳ:HPDL cells+LPS+T cells;group Ⅴ:HPDL cells+baicalin;group Ⅵ:HPDL cells)and was cultured for 48 hours.RT-PCR was used to observe the effect of baicalin on the expression of OPG-RANKL in HPDL cells.Results The ratio of RANKL/OPG in group Ⅰ was lower than that in group Ⅱ(P<0.01)and higher than that in group Ⅲ(P<0.01);The ratio of RANKL/OPG in group Ⅲ was lower than that in group Ⅳ(P<0.01);the ratio of RANKL/OPG in group Ⅳ was higher than that in group Ⅵ(P<0.01);the ratio of RANKL/OPG in group Ⅴ was lower than that in group Ⅵ(P<0.05).Conclusion ① Baicalin could decrease the ratio of RANKL/OPG in HPDL cells.② The TGF-β signaling transduction plays an important role in the effect of baicalin on the RANKL/OPG ratio in HPDL cells.③ Baicalin acts not only through TGF-β to regulate RANKL/OPG in HPDL cells,but also through other pathways.

Effects of insulin, insulin-like growth factor-I and -II on proliferation and intracellular signaling in endometrial carcinoma cells with different expression levels of insulin receptor isoform A

Background Hyperinsulinemia, insulin-like growth factor （IGF）-I and -Ⅱ （IGF-Ⅱ） are associated with increased risk of endometrial carcinoma. Insulin receptor isoform A （IR-A） is more frequently expressed in endombtrial carcinoma than in normal endometrial tissues. To better understand their roles in endometrial carcinoma, we investigated the effects of insulin, IGF-I, and IGF-II in endometrial carcinomas cells with different IR-A expression levels. Methods To explore the role of IR-A in mediating the activity of IGF-I, IGF-II, and insulin, we investigate the cellular proliferation of endometrial carcinoma cell lines RL95-2 and RL95-2-1R-A by MTS assays. Then we examined the protein kinase Akt phosphorylation and extracellular signal-regulated kinase （ERK） 1/2 phosphorylation in both cell lines by Western blotting. The effect of IGF-II and AG1024 on cell cycle progression and apoptosis was assessed by fiowcytometry. To examine whether the effects of IGFs were mediated by IR-A, we blocked IGF-I receptor （IGF-IR） in both cell lines using AG1024, an IGF-IR-specific inhibitor. Results IGF-I and IGF-II significantly enhanced proliferation of both cell lines （P 〈0.05）. By contrast, insulin significantly increased proliferation of RL95-2-1R-A cells only （P 〈0.05）. IGF-I and IGF-II significantly increased pAkt levels in RL95-2 cells and pERK1/2 levels in RL95-2-1R-A cells （all, P 〈0.05）. Insulin increased pERK1/2 levels in RL95-2-1R-A cells only （P 〈0.05）. LY294002 and PD98059 inhibited the specific signaling activities and cellular proliferation. After AG1024 pretreatment, neither IGF-I nor IGF-II affected pAkt levels in RL95-2 cells. IGF-II, but not IGF-I, increased pERK1/2 levels in RL95-2-1R-A cells. After AG1024 pretreatment, the proliferation rate and DNA content corresponding to the S phase increased and apoptosis decreased significantly in IGF-II-treated RL95-2-1R-A cells only （P 〈0.05）. Conclusions The proliferation effect of insulin is mediated by IR-A. When IR-A dominates in a cell line, IGF-II activated cell proliferation mainly through the ERKI/2 pathway. On the other hand, IGF-II activated cell proliferation mainly through the Akt pathway. IR-A can at least partly mediate the proliferative and anti-apoptotic effects of IGF-II through the ERKI/2 pathway.

人类表皮生长因子受体2阳性乳腺癌患者中胰岛素样生长因子Ⅱ受体的表达和意义

目的探讨胰岛素样生长因子Ⅱ受体(IGF-ⅡR)在人类表皮生长因子受体2(HER-2)阳性乳腺癌患者中的表达和价值。方法回顾性分析2007年1月至2009年12月间在内蒙古自治区人民医院接受规范性治疗的400例非Ⅳ期乳腺癌患者的临床资料。根据HER-2检测状态将患者分成观察组(HER-2阳性)96例和对照组(HER-2阴性)304例,再进一步检测患者的IGF-ⅡR表达,将观察组分成观察A组(IGF-ⅡR阳性组,52例)和观察B组(IGF-ⅡR阴性组,44例)。而后实施4.5年的中位数随访期,比较各组患者的生存情况。结果观察A组的无病生存率和总生存率均明显低于观察B组和对照组,差异均有统计学意义(均P<0.05)。观察B组患者的无病生存率和总生存率与对照组比较,差异无统计学意义(P>0.05)。各组患者的肿瘤复发和转移率比较,差异无统计学意义(P>0.05)。观察A组的死亡率为23.1%,观察B组为6.8%,对照组为5.9%,差异有统计学意义(P<0.05)。结论 IGF-ⅡR过表达对HER-2阳性乳腺癌患者的预后具有较大影响,监测IGF-ⅡR的表达可避免患者的过度治疗,值得临床重视。