Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence.
Animals
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
Disease Models, Animal
Gene Expression
Humans
Immunohistochemistry
Liver Neoplasms
/ genetics
Male
Neoplasm Grading
Neoplasm Recurrence, Local
Neoplasm Staging
Postoperative Period
Prognosis
RNA, Messenger
/ genetics
Rats
Receptor, ErbB-2
/ genetics
Smad3 Protein
/ metabolism
Trastuzumab
epithelial-to-mesenchymal transition
hepatocellular carcinoma
human epidermal growth factor receptor 2
tumor recurrence
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
26
11
2018
revised:
01
01
2019
accepted:
11
01
2019
pubmed:
5
2
2019
medline:
17
4
2020
entrez:
5
2
2019
Statut:
ppublish
Résumé
The ERBB2 oncogene hypothesis is challenged in hepatocellular carcinoma (HCC) with the conflicting evidences of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 could be a new target as a treatment option for HCC as well as tumor recurrence after surgery. HER2 in HCC biology needs further explorations. Clinical and mRNA data of HCC patients were obtained from TCGA HCC cohort, GSE89377 and GSE115018. Western Blotting and immunohistochemistry were employed to test expression of HER2, E-cadherin, and Vimentin. In HepG2, JM1, HER2-transfected McA cells, and TGF-β cocultured JM1 cells, HCC biology, including cell survival, proliferation, and epithelial-to-mesenchymal transition (EMT) phenotypes were evaluated. ERBB2 mRNA amplification was found in HCC datasets, and its expression was downregulated in high grade HCC with a worse overall survival. HER2 overexpression was identified in H4IIE, HepG2, JM1 cells, and 82% (14/17) HCC samples, and tumor stage was correlated with expression of HER2, E-cadherin, and Vimentin (P < 0.05). Trastuzumab with the high concentrations suppressed proliferation of HER2-positive hepatoma cells (P < 0.05); in the coculture model to induce EMT of JM1 cells, HER2 expression increased with downregulated E-cadherin and upregulated Vimentin. Trastuzumab intravenous injection inhibited in vivo tumor size and metastases (P < 0.05). Signal analysis revealed that HER2 functioned through upregulation of β-catenin and inhibition of SMAD3. HER2 expression pattern is linked with tumor stage and overall survival; the transforming function of HER2 is found more relevant through β-catenin and SMAD3. HER2-targeted treatment is recommended to suppress the HER2-mediated tumor growth during postoperative liver regeneration.
Sections du résumé
BACKGROUND
The ERBB2 oncogene hypothesis is challenged in hepatocellular carcinoma (HCC) with the conflicting evidences of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 could be a new target as a treatment option for HCC as well as tumor recurrence after surgery. HER2 in HCC biology needs further explorations.
METHODS
Clinical and mRNA data of HCC patients were obtained from TCGA HCC cohort, GSE89377 and GSE115018. Western Blotting and immunohistochemistry were employed to test expression of HER2, E-cadherin, and Vimentin. In HepG2, JM1, HER2-transfected McA cells, and TGF-β cocultured JM1 cells, HCC biology, including cell survival, proliferation, and epithelial-to-mesenchymal transition (EMT) phenotypes were evaluated.
RESULTS
ERBB2 mRNA amplification was found in HCC datasets, and its expression was downregulated in high grade HCC with a worse overall survival. HER2 overexpression was identified in H4IIE, HepG2, JM1 cells, and 82% (14/17) HCC samples, and tumor stage was correlated with expression of HER2, E-cadherin, and Vimentin (P < 0.05). Trastuzumab with the high concentrations suppressed proliferation of HER2-positive hepatoma cells (P < 0.05); in the coculture model to induce EMT of JM1 cells, HER2 expression increased with downregulated E-cadherin and upregulated Vimentin. Trastuzumab intravenous injection inhibited in vivo tumor size and metastases (P < 0.05). Signal analysis revealed that HER2 functioned through upregulation of β-catenin and inhibition of SMAD3.
CONCLUSION
HER2 expression pattern is linked with tumor stage and overall survival; the transforming function of HER2 is found more relevant through β-catenin and SMAD3. HER2-targeted treatment is recommended to suppress the HER2-mediated tumor growth during postoperative liver regeneration.
Identifiants
pubmed: 30714677
doi: 10.1002/cam4.2006
pmc: PMC6434216
doi:
Substances chimiques
RNA, Messenger
0
SMAD3 protein, human
0
Smad3 Protein
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1269-1278Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Références
Science. 1987 Jan 9;235(4785):177-82
pubmed: 3798106
Int J Cancer. 2015 Mar 1;136(5):E359-86
pubmed: 25220842
Oncogene. 2007 Oct 4;26(45):6469-87
pubmed: 17471238
Cancer Med. 2019 Mar;8(3):1269-1278
pubmed: 30714677
Cancer Res. 2004 Nov 1;64(21):7954-61
pubmed: 15520202
J Biol Chem. 2012 Mar 2;287(10):7026-38
pubmed: 22241478
Mol Biol Cell. 2002 Jun;13(6):1929-39
pubmed: 12058060
Anticancer Res. 1999 Jul-Aug;19(4A):2501-3
pubmed: 10470182
Lancet. 2017 Jan 7;389(10064):56-66
pubmed: 27932229
Lancet Oncol. 2014 Jan;15(1):23-34
pubmed: 24314615
Bioorg Med Chem Lett. 2016 Jan 15;26(2):677-683
pubmed: 26652482
Scand J Gastroenterol. 2014 Jan;49(1):99-108
pubmed: 24188385
Biochem Biophys Res Commun. 1994 Nov 30;205(1):73-8
pubmed: 7999105
N Engl J Med. 2008 Jul 24;359(4):378-90
pubmed: 18650514
J Clin Pathol. 2005 May;58(5):500-3
pubmed: 15858121
EMBO J. 2000 Jul 3;19(13):3159-67
pubmed: 10880430
J Gastroenterol. 1994 Oct;29(5):616-20
pubmed: 7528080
Future Oncol. 2015;11(21):2923-36
pubmed: 26414336
Semin Liver Dis. 1999;19(3):329-38
pubmed: 10518312
Gastroenterology. 2002 Dec;123(6):2017-27
pubmed: 12454858
Med Oncol. 2017 Jun;34(6):101
pubmed: 28432618
Science. 1989 May 12;244(4905):707-12
pubmed: 2470152
Anticancer Res. 2003 May-Jun;23(3B):2671-4
pubmed: 12894556
Oncol Rep. 2001 Jul-Aug;8(4):727-30
pubmed: 11410773
Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L199-207
pubmed: 25326580
BJS Open. 2017 Oct 24;1(3):84-96
pubmed: 29951610
Hepatology. 2018 Feb;67(2):600-611
pubmed: 28859220
Dig Liver Dis. 2003 May;35(5):332-8
pubmed: 12846405
Endocr Relat Cancer. 2018 Oct;25(10):837-852
pubmed: 29875136
J Surg Oncol. 2013 Mar;107(4):393-401
pubmed: 22927239
Cell Mol Life Sci. 2004 Dec;61(23):2965-78
pubmed: 15583858
Hepatology. 2004 Apr;39(4):944-53
pubmed: 15057898
Histol Histopathol. 1994 Oct;9(4):677-82
pubmed: 7894139
Oncogene. 2008 Oct 16;27(47):6120-30
pubmed: 18591932