HMMR通过MEK/ERK信号通路促进肝细胞癌侵袭转移

李逊; 严娇; 蔡顺礼; 陈华剑

doi:10.16016/j.2097-0927.202203004

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HMMR通过MEK/ERK信号通路促进肝细胞癌侵袭转移

基础医学 | 更新时间：2026-01-09

- HMMR通过MEK/ERK信号通路促进肝细胞癌侵袭转移
- HMMR promotes invasion and metastasis of hepatocellular carcinoma via activating MEK/ERK signaling pathway
- 陆军军医大学学报 2022年44卷第17期页码：1720-1727
- 作者机构：
  
  1.400016 重庆，重庆市急救医疗中心：检验科
  2.400016 重庆，重庆市急救医疗中心：肝胆外科
- 作者简介：
  
  [ 陈华剑，E-mail: chenhuajian2205@126.com CHEN Huajian, E-mail: chenhuajian2205@126.com
- 基金信息：
- DOI：10.16016/j.2097-0927.202203004
  中图分类号： R394.3;R73-37;R735.7
- 收稿：2022-03-01，
  
  修回：2022-05-09，
  
  纸质出版：2022-09-15
- 稿件说明：
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李逊, 严娇, 蔡顺礼, 等. HMMR通过MEK/ERK信号通路促进肝细胞癌侵袭转移[J]. 陆军军医大学学报, 2022,44(17):1720-1727.

Xun LI, Jiao YAN, Shunli CAI, et al. HMMR promotes invasion and metastasis of hepatocellular carcinoma via activating MEK/ERK signaling pathway[J]. Journal of Army Medical University, 2022, 44(17): 1720-1727.
李逊, 严娇, 蔡顺礼, 等. HMMR通过MEK/ERK信号通路促进肝细胞癌侵袭转移[J]. 陆军军医大学学报, 2022,44(17):1720-1727. DOI： 10.16016/j.2097-0927.202203004.

Xun LI, Jiao YAN, Shunli CAI, et al. HMMR promotes invasion and metastasis of hepatocellular carcinoma via activating MEK/ERK signaling pathway[J]. Journal of Army Medical University, 2022, 44(17): 1720-1727. DOI： 10.16016/j.2097-0927.202203004.

摘要

目的

探讨透明质酸介导的细胞游走受体(hyaluronan-mediated motility receptor，HMMR)对肝细胞癌侵袭转移的影响及潜在机制。

方法

采用qRT-PCR和Western blot法检测肝癌细胞系和肝癌组织，以及免疫组化检测肝癌组织中HMMR的表达；通过划痕实验、Transwell小室观察沉默/过表达HMMR对肝癌细胞迁移和侵袭能力的影响；通过小鼠肝癌肺转移模型观察沉默HMMR对肝癌肺转移的影响；采用Western blot检测HMMR对E-cadherin、N-cadherin、Vimentin、p-MEK、p-ERK等蛋白水平的影响。

结果

肝癌细胞系中HMMR呈高表达。肝癌组织中HMMR的表达水平显著高于癌旁组织(

0.05)，并且转移组癌组织中HMMR的水平明显高于非转移组(

0.05)。沉默HMMR后细胞的迁移侵袭能力明显低于对照组(

0.01)，并且E-cadherin表达上调，N-cadherin、Vimentin表达下调(

0.01)；而过表达HMMR后细胞迁移侵袭能力显著增强(

0.01)，并且N-cadherin、Vimentin表达上调，E-cadherin表达下调(

0.01)。体内实验结果显示基因敲减HMMR的肝癌细胞导致的肺转移病灶数显著低于对照组(

0.05)；过表达HMMR后p-MEK和p-ERK表达上调(

0.01)，而MEK、EKR无明显变化(

0.05)。MEK抑制剂削弱了过表达HMMR介导的细胞的迁移侵袭(

0.01)。

结论

HMMR在肝癌中高表达并且可能通过调控MEK/ERK信号通路从而促进肝细胞癌侵袭转移。

Abstract

Objective

To investigate the effect of hyaluronan-mediated motility receptor (HMMR) on the invasion and metastasis of hepatocellular carcinoma (HCC) cells.

Methods

The expression levels of HMMR in HCC cell lines and tissues were detected by qRT-PCR

Western blotting and immunohistochemical assay. The effects of silencing/overexpression of HMMR on the migration and invasion of HCC cells were observed by wound healing test and Transwell assay. Control HMMR cells and shRNA targeting HMMR cells were respectively injected into nude mice

via

tail vein to construct a mouse model of lung metastasis. Western blotting was used to detect the effect of HMMR expression on the protein levels of E-cadherin

N-cadherin

Vimentin

p-MEK and p-ERK.

Results

HMMR was highly expressed in liver cancer cell lines

and was generally up-regulated in HCC tissues than adjacent normal tissues (

0.05)

and the mRNA and protein levels of HMMR were significantly higher in the metastatic HCC tissues than the non-metastatic HCC tissues (

0.05). Silencing HMMR weakened the migration and invasion abilities of cells (

0.01)

down-regulated E-cadherin protein level and up-regulated N-cadherin and Vimentin levels (

0.01). While overexpression of HMMR promoted the motility and migration and invasion abilities of HCC cells (

0.01)

enhanced the expression of N-cadherin and Vimentin

and down-regulated the level of E-cadherin (

0.01).

In vivo

study showed that knockdown of HMMR resulted in significantly less lung metastases than the control group (

0.05)

while

overexpression of HMMR enhanced the levels of p-MEK and p-ERK (

0.01)

but had no effect on MEK and ERK levels (

0.05). Furthermore

MEK inhibitor U1026 significantly reduced the migration and invasion abilities of HMMR-overexpressed Huh7 cells (

0.01).

Conclusion

HMMR is highly expressed in HCC cells

and may promote the migration and invasion of HCC cells

via

MEK/ERK signaling pathway.

关键词

Keywords

references

SUNG H, FERLAY J, SIEGEL R L, et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J ] . CA Cancer J Clin, 2021, 71(3): 209-249. DOI:10.3322/caac.21660.

LI J Y, JI X J, WANG H D. Targeting long noncoding RNA HMMR-AS1 suppresses and radiosensitizes glioblastoma[J]. Neoplasia, 2018, 20(5): 456-466. DOI:10.1016/j.neo.2018.02.010.

LU X Q, ZHANG J Q, ZHANG S X, et al . Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis[J ] . BMC Cancer, 2021, 21(1): 697. DOI:10.1186/s12885-021-08358-7.

KANG H G, KIM W J, KANG H G, et al . Galectin-3 interacts with C/EBPβ and upregulates hyaluronan-mediated motility receptor expression in gastric cancer[J ] . Mol Cancer Res, 2020, 18(3): 403-413. DOI:10.1158/1541-7786.MCR-19-0811.

CHEN W G, GAO C, LIU Y, et al . Bioinformatics analysis of prognostic miRNA signature and potential critical genes in colon cancer[J ] . Front Genet, 2020, 11: 478. DOI:10.3389/fgene.2020.00478.

YANG D, MA Y, ZHAO P C, et al . Systematic screening of protein-coding gene expression identified HMMR as a potential independent indicator of unfavorable survival in patients with papillary muscle-invasive bladder cancer[J ] . Biomed Pharmacother, 2019, 120: 109433. DOI:10.1016/j.biopha.2019.109433.

SHEN S, KONG J J, QIU Y W, et al . Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis[J ] . J Cell Biochem, 2019, 120(6): 10069-10081. DOI:10.1002/jcb.28290.

DAI Q H, LIU T, GAO Y C, et al . Six genes involved in prognosis of hepatocellular carcinoma identified by Cox hazard regression[J ] . BMC Bioinformatics, 2021, 22(1): 167. DOI:10.1186/s12859-021-04095-7.

ZHANG S, CHANG M C, ZYLKA D, et al . The hyaluronan receptor RHAMM regulates extracellular-regulated kinase[J ] . J Biol Chem, 1998, 273(18): 11342-11348. DOI:10.1074/jbc.273.18.11342.

HE Z C, MEI L, CONNELL M, et al . Hyaluronan mediated motility receptor (HMMR) encodes an evolutionarily conserved homeostasis, mitosis, and meiosis regulator rather than a hyaluronan recepto r[J ] . Cells, 2020, 9(4): E819. DOI:10.3390/cells9040819.

王敏, 陈泽峰, 韩志伟, 等. 基于TCGA数据库分析肝细胞肝癌组织中HMMR表达与患者临床特征及预后的相关性[J]. 现代肿瘤医学, 2021, 29(7): 1173-1178. DOI: 10.3969/j.issn.1672-4992.2021.07.015.

WANG M, CHEN Z F, HAN Z W, et al . The correlation between the expression of HMMR and clinical characteristics and prognosis of hepatocellular carcinoma based on TCGA database[J ] . J Mod Oncol, 2021, 29(7): 1173-1178. DOI: 10.3969/j.issn.1672-4992.2021.07.015.

黄晨阳, 李强, 程斌. HMMR促进原发性肝癌细胞增殖且与不良预后的相关性[J]. 国际检验医学杂志, 2020, 41(7): 861-866. DOI:10.3969/j.issn.1673-4130.2020.07.021.

HUANG C Y, LI Q, CHENG B. Clinical significance of HMMR expressionin liver cancer patients and its influence on proliferation of liver cancer cell[J]. Int J Lab Med, 2020, 41(7): 861-866. DOI:10.3969/j.issn.1673-4130.2020.07.021.

YE S, LIU Y, FULLER A M, et al . TGFβ and hippo pathways cooperate to enhance sarcomagenesis and metastasis through the hyaluronan-mediated motility receptor (HMMR)[J ] . Mol Cancer Res, 2020, 18(4): 560-573. DOI:10.1158/1541-7786.MCR-19-0877.

ZHANG H Z, REN L L, DING Y, et al . Hyaluronan-mediated motility receptor confers resistance to chemoth erapy via TGFβ/Smad2-induced epithelial-mesenchymal transition in gastric cancer[J ] . FASEB J, 2019, 33(5): 6365-6377. DOI:10.1096/fj.201802186R.

LU T Z, ZHENG Y H, GONG X C, et al . High expression of hyaluronan-mediated motility receptor predicts adverse outcomes: a potential therapeutic target for head and neck squamous cell carcinoma[J ] . Front Oncol, 2021, 11: 608842. DOI:10.3389/fonc.2021.608842.

YANG C X, SHENG Y M, SHI X X, et al . CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor[J ] . Cell Death Dis, 2020, 11(10): 831. DOI:10.1038/s41419-020-03037-0.

GOMEZ K E, WU F L, KEYSAR S B, et al . Cancer cell CD44 mediates macrophage/monocyte-driven regulation of head and neck cancer stem cells[J ] . Cancer Res, 2020, 80(19): 4185-4198. DOI:10.1158/0008-5472.CAN-20-1079.

ASSMANN V, JENKINSON D, MARSHALL J F, et al . The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments[J ] . J Cell Sci, 1999, 112(Pt 22): 3943-3954. DOI:10.1242/jcs.112.22.3943.

MISSINATO M A, TOBITA K, ROMANO N, et al . Extracellular component hyaluronic acid and its receptor Hmmr are required for epicardial EMT during heart regeneration[J ] . Cardiovasc Res, 2015, 107(4): 487-498. DOI:10.1093/cvr/cvv190.

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