Epstein-Barr virus latent membrane protein 2A suppresses the expression of HER2 via a pathway involving TWIST and YB-1 in Epstein-Barr virus-associated gastric carcinomas.
To explore HER2 expression in Epstein-Barr virus-associated gastric carcinoma (EBVaGC) and the possible mechanisms causing down-regulation of HER2 expression in EBVaGC, we first evaluated HER2 and LMP2A expression on a clinicopathological-features matched cohort including 78 EBVaGC and 216 EBV-negative gastric carcinoma (EBVnGC) cases by immunohistochemistry. Cases with high HER2 expression in EBVaGC were significantly less than in EBVnGC (5.1% versus 23.7%; p<0.001), and none of the 34 LMP2A+ EBVaGC showed high HER2 expression. Further, overexpressing LMP2A in EBV-negative SGC7901 cells significantly decreased HER2, TWIST and YB-1 mRNA by 36.1%±8.1%, 87.6%±14.0% and 83.8%±5.7%, and protein by 44%, 57% and 49%, respectively. Additionally, the nucleus/cytoplasm ratios of TWIST and YB-1 were also decreased by 85% and 80%, respectively. Silencing LMP2A by siRNA in EBV-positive SNU719 cells for 48 h significantly increased HER2, TWIST and YB-1 mRNA to 276.7%±14.6%, 1284.8%±38.2% and 332.0%±15.5% and protein to 212%, 457% and 232%, respectively. The nucleus/cytoplasm ratios of TWIST and YB-1 were up-regulated by 4.00- and 3.57-fold, respectively, following LMP2A down-regulation. Moreover, LMP2A+/HER2low EBVaGC cases presented the best overall survival compared with LMP2A-/HER2low and LMP2A-/HER2high cases (p=0.003, log-rank test). These results suggest that LMP2A may suppress the HER2 expression through the TWIST/YB-1 axis in EBVaGC.
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Yi-wang
YW
Zhang
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Xiao-xiao
XX
Zhao
Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Cui
C
Tan
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Zhi-gang
ZG
Zhang
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Ye
Y
Jiang
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Jian-ning
JN
Chen
Department of Gastrointestinal Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Hong-bo
HB
Wei
Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan Guangzhou, Guangdong Province, China.
Ling
L
Xue
Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Hai-gang
HG
Li
Department of Pathology, Guangzhou First Municipal People's Hospital, Guangzhou, Guangdong Province, China.
Hong
H
Du
Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Chun-kui
CK
Shao
D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000378:metabolism* / Q000821:virology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D004854:Herpesvirus 4, Human; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000821:virology; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051879:Twist-Related Protein 1; D014763:Viral Matrix Proteins; D051840:Y-Box-Binding Protein 1; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C103173:TWIST1 protein, human; C070856:YBX1 protein, human; C508053:ERBB2 protein, human