Interaction between insulin-like growth factor binding protein-related protein 1 and transforming growth factor beta 1 in primary hepatic stellate cells

BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.

Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic ?brosis via the regulation of MMPs/TIMPs in mice

Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation

BACKGROUND Atrial fibrillation(AF)is one of the most common persistent arrhythmias among adult cardiovascular diseases.It is important to identify potential risk factors for AF.Members of the insulin-like growth factor(IGF)family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.assess genetic relationships between IGF family members and AF.METHODS MR was performed based on genome-wide association study(GWAS)datasets,and concentration levels of 14 IGF family members were retrieved.An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations.A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects.Two-sample MR packages were used to perform MR analysis in R.MR-Egger,weighted median(WM),and inverse va-riance weighted(IVW)methods were used.RESULTS Core Tip:Due to the high prevalence of atrial fibrillation(AF),and adverse outcomes related to it,it is important to identify risk factors associated with development of the condition.Insulin-like growth factor(IGF)family members exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.The results of the current study provide novel insights on the pathogenesis of AF,and implic-ations of serum IGF family member concentrations when assessing the risk of AF.The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF.Further observational and experimental studies are critically needed.

Circulating insulin-like growth factor-binding protein 3 as prognostic biomarker in liver cirrhosis

AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.

Effects of insulin-like growth factor binding protein-related protein 1 in mice with hepatic fibrosis induced by thioacetamide

Background Insulin-like growth factor binding protein-related protein 1 （IGFBPrP1） can activate hepatic stellate cells and increase extracellular matrix （ECM） in vitro. However, the effects of IGFBPrP1 in mice with hepatic fibrosis, and the mechanisms of these effects, are currently unknown. We aim to address these issues in this study. Methods Intraperitoneal injection of thioacetamide （TAA） is a classic method for establishing a mouse model of hepatic fibrosis. Using this model, we administered anti-IGFBPrP1 antibody, again via intraperitoneal injection. The morphological changes of liver fibrosis were observed with both HE and Masson stainning. The immunohistochemical assays and Western blotting were used to measure changes in IGFBPrP1, a-smooth muscle actin （a-SMA） and ECM in liver tissues, and the expression of transforming growth factor-β1 （TGF-β1） and Smad3. Data were statistically analyzed using one-way analysis of variance （ANOVA）, the SNK-q test for inter-group differences. Results The Masson staining analysis showed that compared with normal control group, content of collagen fiber in TAA5w group was significantly increased （P 〈0.01）, and it was significantly decreased in TAA5w/alGFBPrP1 group compared with in TAA5w group （P 〈0.01）. The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin （FN） was significantly up-regulated in the TAA5w group （P 〈0.01）. Anti-IGFBPrP1 treatment reversed these changes （P 〈0.01）. Conclusions IGFBPrP1 plays an important role in the development of hepatic fibrosis. Anti-IGFBPrP1 prevents fibrosis in mice by suppressing the activation of hepatic stellate cells, inhibiting the synthesis of major components of the ECM （namely, collagen I and FN）. The mechanism for this suppression of fibrosis is associated with the TGF-β1/Smad3 signaling pathways.

Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21

Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.

Effects of insulin-like growth factor binding protein 7 on cell cycle and proliferation of gastric cancer in vitro and in vivo

Objective To investigate the effects of insulin-like growth factor binding protein 7(IGFBP7)on the proliferation,cell cycle of gastric cancer cell and the expression of cynlin D1,cyclin-dependent kinase(CDK)4,and to observe the effects of IGFBP7 on the growth of gastric tumor xenografts in nude mice.Methods The MKN-28cell line was interfered by small interfere ribonucleic acid(siRNA)(interfered group),and blank control group,

妊高征患者胰岛素样生长因子水平及对胎儿生长发育的影响

目的 :探讨妊娠高血压综合征 (妊高征 )患者血清胰岛素样生长因子 (IGF 1)和胰岛素样生长因子结合蛋白 3 (IGFBP 3 )水平与疾病程度及新生儿出生体重之间的关系。方法 :用放射免疫方法测定 3 3例妊高征和 3 2例正常血压妊娠妇女的血清IGF 1、IGFBP 3的水平。结果 :重度妊高征组IGF 1显著低于正常组 ,IGFBP 3在各组间的水平浓度差异均无显著性 ,但IGF 1与IGFBP 3之间呈正相关。新生儿出生体重随妊高征严重程度的加剧而降低 ,各组间比较差异有显著性 (F =5 .45 3 ,P =0 .0 0 2 )。结论 :妊高征患者的发病及严重程度与IGF 1有明显的关系 ,IGF

冠心病患者血清miR-335、LTBP-2水平变化及临床意义

目的研究冠状动脉粥样硬化性心脏病(冠心病)患者血清微小核糖核酸(miR)-335、潜在转化生长因子结合蛋白2(LTBP-2)水平变化及临床意义。方法选择2016年3月至2018年3月于解放军第153医院收治的冠心病患者120例作为研究对象,记为研究组,另取同期于我院接受体检的健康人员50例为对照组。分别采用实时荧光定量聚合酶链式反应检测两组人员血清mi R-335表达情况,采用酶联免疫吸附法检测血清LTBP-2表达情况。并根据Gensini积分的不同将研究组患者分为轻度病变组36例、中度病变组43例、重度病变组41例,对比不同病变程度患者血清miR-335、LTBP-2水平,并作相关性分析。结果研究组血清miR-335水平低于对照组,而LTBP-2水平高于对照组,差异有统计学意义(均P<0.05)。轻度病变组、中度病变组、重度病变组患者的血清miR-335水平呈逐渐降低趋势,而LTBP-2水平呈逐渐升高趋势,且经单因素方差分析,各组间对比差异均有统计学意义(均P<0.05)。经Pearson相关性分析可得:冠心病患者血清miR-335与Gensini积分呈负相关关系(r=-0.683,P<0.05),而LTBP-2呈与Gensini积分正相关关系(r=0.626,P<0.05),且血清mi R-335与LTBP-2水平呈负相关关系(r=-0.711,P<0.05)。结论冠心病患者血清miR-335存在明显低表达,而LTBP-2存在明显高表达,临床工作中可通过联合检测上述两项指标水平,从而有利于冠心病的早期诊断以及病情严重程度评估。

沙颍河铅污染对儿童GH-IGF-1轴和体格发育的影响

目的：探讨沙颍河铅污染现状及其对儿童生长激素-胰岛素样生长因子-1（ GH-IGF-1）轴和体格发育的影响。方法：随机选择淮河沙颍河流域S县两个村庄作为调查点（依距河岸距离远近分别定为对照区和污染区）；原子吸收分光光度法检测河水和调查点饮用水及土壤中的铅含量。整群抽取两村庄小学8～13岁在校学生作为研究对象，伏安极谱法测定儿童血清铅含量；ELISA法检测儿童血清胰岛素样生长因子-1（ IGF-1）、胰岛素样生长因子结合蛋白3（IGFBP3）、生长激素（GH）和生长激素结合蛋白（GHBP）水平；电子体重计、身高坐高计、皮褶厚度计及Gulick卷尺分别测量体重、身高、皮褶厚度和胸围。结果：河水3个采样断面铅浓度均超过国家地表水水质标准Ⅴ级。污染区饮用水及土壤铅含量均高于对照区（ t＝2．663和2．300，P＜0．05）。污染区儿童血清铅含量高于对照区儿童（t＝3．227，P＝0．002）。污染区男孩身高、体重、皮褶厚度、胸围与对照区比较差异均无统计学意义（P均＞0．05）。两区女孩身高、体重和胸围差异均无统计学意义（P均＞0．05），但污染区女孩皮褶厚度高于对照区（t＝3．036，P＝0．003）。结论：沙颍河流域的饮用水中铅含量明显升高，污染区儿童血清GH-IGF-1轴相关因子水平受到影响。

血清胰岛素样生长因子结合蛋白2联合糖链抗原72-4检测对胃癌的诊断价值

目的:探讨血清胰岛素样生长因子结合蛋白2(IGFBP-2)联合糖链抗原72-4(CA72-4)检测对胃癌的诊断价值。方法:62例胃癌患者作为胃癌组,30例良性胃病患者作为良性胃部疾病组,40例正常体检者作为对照组,采用酶联免疫吸附法测定受试者血清IGFBP-2、CA72-4水平,放射免疫法测定受试者血清胰岛素样生长因子-1(IGF-1)、IGF-2水平,Pearson法分析胃癌患者血清IGFBP-2、CA72-4与IGF-1、IGF-2的相关性;应用受试者工作特征(ROC)曲线下面积(AUC)分析IGFBP-2、CA72-4对胃癌诊断的灵敏度和特异度。结果:胃癌组患者血清IGFBP-2、CA72-4、IGF-1及IGF-2水平显著高于良性胃部疾病组和对照组(P<0.05),且血清IGFBP-2水平分别与CA72-4、IGF-1及IGF-2水平呈正相关(r=0.849、0.603、0.711,P<0.05),血清CA72-4水平分别与IGF-1及IGF-2水平呈正相关(r=0.611、0.694,P<0.05);CA72-4早期诊断胃癌的敏感度最高(91.3%),IGFBP-2的特异度最高(92.6%);IGFBP-2截断值(579.74)高于CA72-4(17.83),CA72-4联合IGFBP-2检测胃癌的AUC=0.89,优于单一IGFBP-2(AUC=0.73)或CA72-4(AUC=0.65),单一IGFBP-2又优于CA72-4,差异有统计学意义(P<0.05)。结论:血清IGFBP-2联合CA72-4检测对胃癌的早期诊断优于单一IGFBP-2或CA72-4。

阻塞性腺样体和扁桃体肥大与胰岛素样生长因子系统

阻塞性腺样体和扁桃体肥大可能引起儿童生长发育异常,其病理生理机制尚不明确。本文就血清胰岛素样生长因子-1(insulin-likegrowthfactorI,IGF-1)/胰岛素样生长因子结合蛋白-3(insulin-likegrowthfactor-bindingprotein3,IGFBP-3)概况及其在阻塞性腺样体和扁桃体肥大患儿生长激素分泌异常诊断和疗效判断方面的意义进行综述。

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

AIM:To characterize how insulin-like growth factor 2(IGF2)m RNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol.METHODS:Non-alcoholic steatohepatitis(NASH)was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient(MCD)diet for either two or four weeks.As a control,animals were fed a methionine and choline supplemented diet.Serum triglycerides,cholesterol,glucose,aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques.Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction.Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard.Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis.Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue.Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels.Additionally,nuclear localization of the nuclear factor kappa B(NF-κB)subunit p65 was examined in frozen tissues.RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 m RNA binding protein 2-2(IGF2BP2-2/IMP2-2/p62)induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model.Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals.Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol.Moreover,serum cholesterol was significantly elevated in p62 transgenic mice.Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis.Filipin staining revealed increased free cholesterol in p62 transgenic livers,which were not diet-derived.The m RNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-Co A reductase(HMG-Co A reductase or HMGCR)were not significantly upregulated,potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2(SREBF2)gene expression and increased irondeposition in transgenic animals.CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

N6-methyladenosine methylation regulates the tumor microenvironment of Epstein-Barr virus-associated gastric cancer

BACKGROUND N6-methyladenosine(m6A)methylation modification exists in Epstein-Barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric cancer(EBVaGC)is a distinctive molecular subtype of GC.We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.METHODS First,The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC(EBVnGC).Second,we identified Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment of m6A-related differentially expressed genes.We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment(TME).Finally,cell counting kit-8 cell proliferation test,transwell test,and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1(IGFBP1)in EBVaGC cell lines.RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC.Compared with EBVnGC,the expression levels of m6A methylation regulators Wilms tumor 1-associated protein,RNA binding motif protein 15B,CBL proto-oncogene like 1,leucine rich pentatricopeptide repeat containing,heterogeneous nuclear ribonucleoprotein A2B1,IGFBP1,and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC(P<0.05).The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher(P=0.046).GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC.Compared with EBVnGC,the infiltration of activated CD4+T cells,activated CD8+T cells,monocytes,activated dendritic cells,and plasmacytoid dendritic cells were significantly upregulated in EBVaGC(P<0.001).In EBVaGC,the expression level of proinflammatory factors interleukin(IL)-17,IL-21,and interferon-γ and immunosuppressive factor IL-10 were significantly increased(P<0.05).In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line(SNU719)than in an EBVnGC cell line(AGS)(P<0.05).IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719.Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS.CONCLUSION m6A regulators could remodel the TME of EBVaGC,which is classified as an immune-inflamed phenotype and referred to as a“hot”tumor.Among these regulators,we demonstrated that IGFBP1 affected proliferation,migration,and apoptosis.

Effects of parenteral nutrition with and without GH on the GH/IGF-1 axis after hepatectomy in hepatocellular carcinoma with liver cirrhosis

Postoperative hepatic insulin-like growth factor-1(IGF-1)production may be severely disturbed in patients with liver cirrhosis.Complex alterations in the GH/IGF-1 axis are thought to play an important role in the protein catabolism that complicates major surgical procedures.The aim of this study was to explore the effects of parenteral nutrition(PN)with and without growth hormone(GH)on the GH/IGF-1 axis after hepatectomy for hepatocellular carcinoma(HCC)with cirrhosis and evaluate the potential roles of recombinant human GH(rhGH)therapy.Twenty-four patients with HCC with cirrhosis who underwent hepatectomy were randomly divided into two groups:a PN group(n=12)and an rhGH+PN group(n=12).Liver function,serum GH,IGF-1 and IGFBP-3 were measured before the operation and at postoperative days(POD)1 and 6.Insulin-like growth factor-1 and IGFBP-3 mRNA in the liver tissue was detected by RT-PCR.The liver Ki67 immunohistochemistry staining was studied.At the same time,12 patients with cholelithiasis or liver hemangioma who underwent operation served as normal control group.On POD 6,serum prealbumin,GH,IGF-1,IGFBP-3,hepatic IGF-1 mRNA,IGFBP-3 mRNA and liver Ki67 LI were higher in the rhGH+PN group than in the PN group.There was no significant difference in the 6-and 12-month tumor-free survival rate and the median tumor-free survival time between the PN group and the rhGH+PN group(P>0.05).These data indicate that rhGH+PN could ameliorate the changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of cirrhosis.