TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Abstract

Introduction 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. Conclusion TGM2 may be a useful cell surface biomarker for early detection of EAC.

Genomic similarity between gastroesophageal junction and esophageal Barrett's adenocarcinomas

“…In addition, we recently showed TGM2 is overexpressed on the surface of EAC cells [26]. In the current study, we chose to validate CDH11, ICAM1 and CLDN3 as examples of potential cell surface markers common to subsets of both GEJAC and tEAC.…”

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

“…In the pathway analysis (Fig 5), we observed that FAM86HP has an indirect interaction with TGM2 (Transglutaminase 2), a stress-response gene [50] involved in mRNA metabolism [51] which has been reported to be upregulated during in ammation [50]. It is interesting to note that TGM2 was over expressed in individuals receiving chemo & radiation therapy, suggesting its involvement in sensitivity to radiation [52,53]. Both, TGM2 and NUPR1 ( Fig 5) have been reported to be implicated in in ammation driven primarily via the JAK/Stat and IL-17A signaling pathway [54].…”

Identification of 17 mRNAs and a miRNA as an integrated prognostic signature for lung squamous cell carcinoma

“…Moreover, TRIB3 might be a prognostic biomarker of acute myeloid leukemia, RHOF was overexpressed in malignant lymphomas and PAQR5 was related to ovarian cancer . In addition, in two other studies, it was indicated that TGM2 was a diagnostic signature for not only esophageal adenocarcinomas, but also for lung cancer . Furthermore, STC2 was considered to be a diagnostic gene of lung cancer, as well as a promising prognostic gene of high‐grade serous ovarian cancer .…”

“…54 In addition, in two other studies, it was indicated that TGM2 was a diagnostic signature for not only esophageal adenocarcinomas, but also for lung cancer. 55,56 Furthermore, STC2 was considered to be a diagnostic gene of lung cancer, as well as a promising prognostic gene of high-grade serous ovarian cancer. 57,58 RPH3AL may be related to the diagnosis of colorectal cancer 59 and, in another study, it was determined that…”