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中华肝脏外科手术学电子杂志 ›› 2019, Vol. 08 ›› Issue (04) : 370 -374. doi: 10.3877/cma.j.issn.2095-3232.2019.04.021

所属专题: 文献

基础研究

肝星状细胞通过影响Ang-1/Tie2轴促进肝癌血管新生
林洋1, 曹彦龙1, 邱红1, 林楠2, 吴建华1,()   
  1. 1. 844000 新疆维吾尔自治区喀什地区第一医院肝胆外科
    2. 510630 广州,中山大学附属第三医院肝胆外科
  • 收稿日期:2019-05-10 出版日期:2019-08-10
  • 通信作者: 吴建华
  • 基金资助:
    新疆维吾尔自治区自然科学基金(2016D01C019)

Hepatic stellate cells promote angiogenesis of hepatocellular carcinoma by affecting Ang-1/Tie2 axis

Yang Lin1, Yanlong Cao1, Hong Qiu1, Nan Lin2, Jianhua Wu1,()   

  1. 1. Department of Hepatobiliary Surgery, the First People’s Hospital of Kashgar Area, Xinjiang Uygur Autonomous Region, Kashgar 844000, China
    2. Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
  • Received:2019-05-10 Published:2019-08-10
  • Corresponding author: Jianhua Wu
  • About author:
    Corresponding author: Wu Jianhua, Email:
引用本文:

林洋, 曹彦龙, 邱红, 林楠, 吴建华. 肝星状细胞通过影响Ang-1/Tie2轴促进肝癌血管新生[J/OL]. 中华肝脏外科手术学电子杂志, 2019, 08(04): 370-374.

Yang Lin, Yanlong Cao, Hong Qiu, Nan Lin, Jianhua Wu. Hepatic stellate cells promote angiogenesis of hepatocellular carcinoma by affecting Ang-1/Tie2 axis[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2019, 08(04): 370-374.

目的

探讨肝星状细胞(HSC)对肝癌细胞血管新生的影响及相关机制。

方法

胶原酶灌注法成功获取人原代肝癌细胞(HC)、人HSC和人肝窦血管内皮细胞(HVEC)。RT-PCR检测3组细胞内血管新生相关基因表达情况。RT-PCR法和ELISA检测HSC在不同浓度TGF-β激活条件下血管生成素(Ang-1)表达情况。RT-PCR及Western Blot检测HVEC与HSC共培养后Tie2基因和蛋白的表达情况。多组Ang-1和Tie2 mRNA比较采用单因素方差分析和LSD-t检验。

结果

HC、HSC和HVEC中Ang-1 mRNA的相对表达量分别为1.6±0.4、7.6±1.6、0.4±0.1,HSC表达量最高(F=94.6,P<0.05);Tie2 mRNA的相对表达量分别为0.1、1.3、14.4±2.2,HVEC表达量最高(F=239.4,P<0.05)。随着TGF-β刺激浓度的增大,HSC内α-SMA表达量增高,细胞内的Ang-1 mRNA表达增加;细胞培养液上清具有同样的增加趋势。随着HSC活化程度增加,共培养体系内的HVEC表达Tie2 mRNA能力越强,且HSC诱导Tie2蛋白的表达亦增强。

结论

肝癌微环境中活化态HSC是Ang-1的主要来源,HSC可能通过Ang-1/Tie2轴有效促进肝癌血管新生。

Objective

To investigate the effect and its mechanism of hepatic stellate cells (HSC) on the angiogenesis of liver cancer cells.

Methods

Primary human hepatocellular carcinoma cells (HC), human hematopoietic stem cells (HSC) and human vascular endothelial cells (HVEC) were successfully obtained with collagenase perfusion. The expression levels of angiogenesis-related genes in 3 groups were measured by RT-PCR. The expression levels of angiopoietin-1 (Ang-1) in HSCs activated under different concentrations of TGF-β were measured by RT-PCR and ELISA. The expression levels of Tie2 gene and protein in coculture of HVECs and HSCs were detected by RT-PCR and Western blot. The expression levels of Ang-1 and Tie2 mRNA among different groups were statistically compared by univariate ANOVA and LSD-t test.

Results

The relative expression levels of Ang-1 mRNA in HCs, HSCs and HVECs were 1.6±0.4, 7.6±1.6 and 0.4±0.1, respectively, the expression level in HSCs was the highest (F=94.6, P<0.05). The relative expression levels of Tie2 mRNA were 0.1, 1.3 and 14.4±2.2, respectively, with the highest level in HVECs (F=239.4, P<0.05). With the increasing concentration of TGF-β, the expression of α-SMA and Ang-1 mRNA in HSCs was up-regulated. The same increasing trend was observed in the supernatant of cell culture solution. With the increase of HSC activation, the ability of expressing Tie2 mRNA of HVECs in the co-culture system enhanced, and the ability of inducing Tie2 protein expression of HSCs enhanced, too.

Conclusions

Activated HSC is the main source of Ang-1 in the microenvironment of liver cancer. HSC can effectively promote the angiogenesis of liver cancer probably through the Ang-1/Tie2 axis.

图1 HC、HSC、HVEC细胞中Ang-1、Tie2 mRNA表达情况
图2 不同浓度TGF-β激活HSC后Ang-1 mRNA和蛋白分泌情况
图3 RT-PCR和Western blot检测HSC和HVEC共培养后HVEC中Tie2变化
[1]
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2):87-108.
[2]
Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer[J]. Nat Rev Cancer, 2015, 15(11):653-667.
[3]
Coulon S, Heindryckx F, Geerts A, et al. Angiogenesis in chronic liver disease and its complications[J]. Liver Int, 2011, 31(2):146-162.
[4]
Hawighost H, Knapstein PG, Knopp MV, et al. Uterine cervical carcinoma: comparison of standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival[J]. Cancer Res, 1998, 58(16):3598-3602.
[5]
Lin N, Chen Z, Lu Y, et al. Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma[J]. Hepatol Res, 2015, 45(3):326-336.
[6]
唐亚军,潘楚芝,卢逸,等.活化态肝星状细胞促进肝癌血管新生的机制[J/CD].中华肝脏外科手术学电子杂志,2016, 5(5):323-327.
[7]
El-Serag HB. Hepatocellular carcinoma[J]. N Engl J Med, 2011, 365(12):1118-1127.
[8]
Ju MJ, Qiu SJ, Fan J, et al. Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection[J]. Am J Clin Pathol, 2009, 131(4):498-510.
[9]
Song J, Ge Z, Yang X, et al. Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin[J]. Cancer Lett, 2015, 356(2 Pt B):713-720.
[10]
Eveno C, Hainaud P, Rampanou A, et al. Proof of prometastatic niche induction by hepatic stellate cells[J]. J Surg Res, 2015, 194(2):496-504.
[11]
Kalluri R, Zeisberg M. Fibroblasts in cancer[J]. Nat Rev Cancer, 2006, 6(5):392-401.
[12]
Zhao W, Zhang L, Yin Z, et al. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice[J]. Int J Cancer, 2011, 129(11):2651-2661.
[13]
Zhu B, Lin N, Zhang M, et al. Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma[J]. J Transl Med, 2015(13):365.
[14]
Lund EL, Høg A, Olsen MW, et al. Differential regulation of VEGF, HIF1alpha, and angiopoietin-1, -2, and-4 by hypoxia and ionizing radiation in human glioblastoma[J]. Int J Cancer, 2004, 108(6):833-838.
[15]
Malsonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural agonist for Tie2 that disrupts in vivo angiogenesis[J]. Science, 1997, 277(5322):55-60.
[16]
Huang J, Inoue M, Hasegawa M, et al. Sendai viral vector mediated angiopoietin-1 gene transfer for experimental ischemic limb disease[J]. Angiogenesis, 2009, 12(3):243-249.
[17]
Scharpfenecker M, Fiedler U, Reiss Y, et al. The Tie2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism[J]. J Cell Sci, 2005, 118(Pt 4):771-780.
[18]
Lee SW, Kim WJ, Jun HO, et al. Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2[J]. Int J Mol Med, 2009, 23(2):279-284.
[19]
Reiss Y, Knedla A, Tal AO, et al. Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2[J]. J Pathol, 2009, 217(4):571-580.
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