HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins

Yanjun WANG; Gaoxiong WANG; Tiancong HUANG; Xinfeng LI

doi:10.16016/j.1000-5404.201810003

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HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins

Basic Medicine | 更新时间：2026-01-09

- HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins
- Journal of Third Military Medical University Vol. 41, Issue 5, Pages: 430-436(2019)
- 作者机构：
  
  362000 泉州，福建医科大学附属第二医院肝胆外科
- 作者简介：
- 基金信息：
  
  the Project for Young Scholars of Health and Family Planning Commission of Fujian Province(2015-1-56);the Science and Technology Project of Quanzhou City(Z[2014]0118)
- DOI：10.16016/j.1000-5404.201810003
  CLC： R341;R363.21;R735.8
- Received：02 October 2018，
  
  Revised：2018-12-05，
  
  Published：15 March 2019
- 稿件说明：
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Yanjun WANG, Gaoxiong WANG, Tiancong HUANG, et al. HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins[J]. Journal of Third Military Medical University, 2019, 41(5): 430-436.
DOI：

Yanjun WANG, Gaoxiong WANG, Tiancong HUANG, et al. HMGB1 promotes progression of intrahepatic cholangiocarcinoma through regulating Erk1/2, Cyclin D1 and MMP14 proteins[J]. Journal of Third Military Medical University, 2019, 41(5): 430-436. DOI： 10.16016/j.1000-5404.201810003.

摘要

目的

探讨高迁移率族蛋白1(high mobility group box1

HMGB1)在肝内胆管细胞癌(intrahepatic cholangiocarcinoma，ICC)进展中的作用及机制。

方法

运用免疫组化法检测75例ICC癌组织石蜡标本中HMGB1蛋白表达情况，分析其表达水平与临床病理特征关系；在体外，外源性HMGB1处理细胞及siRNA抑制HMGB1表达后运用CCK-8、细胞迁移、侵袭试验研究HMGB1对肝内胆管癌细胞恶性生物学行为的影响；运用western-blot检测细胞内蛋白。

结果

免疫组化检测结果显示54.67%(41/75)的肝内胆管细胞癌组织过表达HMGB1蛋白，HMGB1过表达与肿瘤分化程度(

=0.019)、临床分期(

=0.017)及血管侵犯(

=0.033)有明显正相关性。CCK-8结果显示HMGB1可以促进肝内胆管癌细胞HuCCT-1的增殖(

0.05)。细胞迁移试验显示外源性HMGB1处理后细胞迁移数目增加到空白组的(1.85±0.08)倍(

0.01)；同时，siRNA抑制细胞HMGB1表达后细胞迁移数目减弱到空白组的(0.48±0.04)倍(

0.01)。同样地，细胞侵袭试验结果显示外源性HMGB1处理后的HuCCT-1细胞穿过基质胶的数目增加到空白组的(1.46±0.05)倍(

0.01)；siRNA抑制细胞HMGB1表达后细胞侵袭数目减弱到空白组的(0.67±0.07)倍(

0.01)。Western blot结果显示外源性HMGB1处理HuCCT-1细胞后细胞内Erk1/2、Cyclin D1及MMP14蛋白表达明显增加；siRNA沉默HMGB1表达后细胞内MMP14蛋白表达减弱。

结论

HMGB1在肝内胆管细胞癌的进展中发挥作用，其机制可能与调控Erk1/2、Cyclin D1及MMP14蛋白相关。

Abstract

Objective

To explore the effect and the mechanism of high mobility group box1 (HMGB1) in the progression of intrahepatic cholangiocarcinoma (ICC).

Methods

The expression of HMGB1 in ICC specimens obtained from 75 patients was exa

mined by immunohistochemistry (IHC). The correlation between HMGB1 expression level and clinicopathologic characteristics was analyzed. In

in vitro

study

ICC cells were treated with exogenous HMGB1 and siRNA

then the effect of HMGB1 on ICC cells malignant biological behavior was assessed using CCK-8 assay

cell migration and invasion assay. Western blot analysis was used to detect intracellular proteins.

Results

IHC results showed that overexpression of HMGB1 was found in 54.6% (41/75) ICCs. The overexpression of HMGB1 was significantly correlated with tumor differentiation grade (

=0.019)

TNM stage (

=0.017) and vessel invasion (

=0.033). CCK-8 assay showed that exogenous HMGB1 promoted the proliferation of HuCCT-1 cells (

0.05). Cell migration assay indicated that exogenous HMGB1 treatment promoted cell migration by 1.85±0.28 fold (

0.01)

and siRNA treatment reduced cell migration by 0.48±0.04 fold (

0.01). Similarly

exogenous HMGB1 increased invasion of HuCCT-1 cells by 1.46±0.05 fold (

0.01) through matrigel layer

and siRNA treatment reduced cell invasion by 0.67±0.07 (

0.01). Western blotting indicated that the expression of Erk1/2

Cyclin D1 and MMP14 were up-regulated in the cells treated with exogenous HMGB1. Moreover

Western blot results showed that suppression of HMGB1 by siRNA induced the down-regulation of MMP14.

Conclusion

HMGB1 plays a role in the progression of ICC

and the mechanism may be involved in the regulation of Erk1/2

Cyclin D1 and MMP14 proteins.

关键词

Keywords

references

ZHOU H B. Hepatitis B virus infection and intrahepatic cholangiocarcinoma[J]. World J Gastroenterol, 2014, 20(19): 5721. DOI:10.3748/wjg.v20.i19.5721.

ROTHERMUND K, ROGULSKI K, FERNANDES E, et al . C-Myc-independent restoration of multiple phenotypes by two C-Myc target genes with overlapping functions[J ] . Cancer Res, 2005, 65(6): 2097-2107. DOI:10.1158/0008-5472.CAN-04-2928.

SOLDEVILLA B, DÍAZ R, SILVA J, et al . Prognostic impact of ΔTAp73 isoform levels and their target genes in colon cancer patients[J ] . Clin Cancer Res, 2011, 17(18): 6029-6039. DOI:10.1158/1078-0432.CCR-10-2388.

TANG D, KANG R, ZEH H J 3rd, et al . High-mobility group box 1 and cancer[J ] . Biochim Biophys Acta, 2010, 1799(1-2): 131-140. DOI:10.1016/j.bbagrm.2009.11.014.

陈科济, 范飞, 朱斌, 等.肝癌患者血清高迁移率族蛋白B1的表达及与p53和临床病理的相关性[J].第二军医大学学报, 2012, 33(1): 103-105.

CHEN K J, FAN F, ZHU B, et al : Serum HMGB1 level and its correlation with p53 and clinical pathology in patients with liver cancer. Acad J Sec Mil Med Univ, 2012, 33(1):103-105. DOI: 10.3724/SP.J.1008.2012.00103.

WENG H, DENG Y, XIE Y, et al . Expression and significance of HMGB1, TLR4 and NF-κB p65 in human epidermal tumors[J ] . BMC Cancer, 2013, 13: 311. DOI:10.1186/1471-2407-13-311.

WU D, DING Y, WANG S, et al . Increased expression of high mobility group box 1 (HMGB1) is associated with progression and poor prognosis in human nasopharyngeal carcinoma[J ] . J Pathol, 2008, 216(2): 167-175. DOI:10.1002/path.2391.

VOLP K. Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas[J]. Gut, 2006, 55(2): 234-242. DOI:10.1136/gut.2004.062729.

CHUNG H W, LEE S G, KIM H, et al . Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer[J ] . J Transl Med, 2009, 7: 38. DOI:10.1186/1479-5876-7-38.

CHENG B Q, JIA C Q, LIU C T, et al . Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma[J ] . Dig Liver Dis, 2008, 40(6): 446-452. DOI:10.1016/j.dld.2007.11.024.

XU Y F, GE F J, HAN B, et al . High-mobility group box 1 expression and lymphnode metastasis in intrahepatic cholangiocarcinoma[J ] . World J Gastroenterol, 2015, 21(11): 3256-3265. DOI:10.3748/wjg.v21.i11.3256.

HAYAKAWA K, PHAM L D, KATUSIC Z S, et al . Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery[J ] . Proc Natl Acad Sci USA, 2012, 109(19): 7505-7510. DOI:10.1073/pnas.1121146109.

QIU J, XU J, ZHENG Y, et al . High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia[J ] . Stroke, 2010, 41(9): 2077-2082. DOI:10.1161/STROKEAHA.110.590463.

AMONYINGCHAROEN S, SURIYO T, THIANTANAWAT A, et al . Taurolithocholic acid promotes intrahepatic cholangiocarcinoma cell growth via muscarinic acetylcholine receptor and EGFR/ERK1/2 signaling pathway[J ] . Int J Oncol, 2015, 46(6):2317-2326..

MIYOSHI A, KITAJIMA Y, KIDO S, et al . Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma[J ] . Br J Cancer, 2005, 92(2): 252-258. DOI:10.1038/sj.bjc.6602266.

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