TGM2: a cell surface marker in esophageal adenocarcinomas.
BACKGROUND
Esophageal adenocarcinomas (EAC) are aggressive cancers that are increasing in incidence and associated with a poor prognosis. The identification of highly expressed genes in EAC relative to metaplastic Barrett's esophagus (BE) may provide new targets for novel early cancer detection strategies using endoscopically administered, fluorescently labeled peptides.


METHODS
Gene expression analysis of BE and EACs were used to identify the cell surface marker transglutaminase 2 (TGM2) as overexpressed in cancer. The expression of two major isoforms of TGM2 was determined by qRT-polymerase chain reaction in an independent cohort of 128 EACs. Protein expression was confirmed by tissue microarrays and immunoblot analysis of EAC cell lines. TGM2 DNA copy number was assessed using single nucleotide polymorphism microarrays and confirmed by qPCR. TGM2 expression in neoadjuvantly treated EACs and following small interfering RNA-mediated knockdown in cisplatin-treated EAC cells was used to determine its possible role in chemoresistance.


RESULTS
TGM2 is overexpressed in 15 EACs relative to 26 BE samples. Overexpression of both TGM2 isoforms was confirmed in 128 EACs and associated with higher tumor stage, poor differentiation, and increased inflammatory and desmoplastic response. Tissue microarrays and immunohistochemistry confirmed elevated TGM2 protein expression in EAC. Single nucleotide polymorphism and qPCR analysis revealed increased TGM2 gene copy number as one mechanism underlying elevated TGM2 expression. TGM2 was highly expressed in resistant EAC after patient treatment with neoadjuvant chemotherapy/radiation suggesting a role for TGM2 in chemoresistance.


CONCLUSIONS
TGM2 may be a useful cell surface biomarker for early detection of EAC.
*Thoracic Surgery, Department of Surgery; †Department Radiation Oncology; ‡Department of Biomedical Engineering; §Department of Mechanical Engineering; ‖Division of Gastroenterology in Department of Internal Medicine; and ¶Department of Pathology, University of Michigan, Ann Arbor, MI.
Deborah T
DT
Leicht
Tasneem
T
Kausar
Zhuwen
Z
Wang
Daysha
D
Ferrer-Torres
Thomas D
TD
Wang
Dafydd G
DG
Thomas
Jules
J
Lin
Andrew C
AC
Chang
Lin
L
Lin
David G
DG
Beer
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D059186:Chemoradiotherapy, Adjuvant; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000628:therapy; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000032:analysis*; D015996:Survival Rate; D046888:Tissue Array Analysis; D011503:Transglutaminases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D012333:RNA, Messenger; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins