Expression of transglutaminase-2 isoforms in normal human tissues and cancer cell lines: dysregulation of alternative splicing in cancer

Phatak, Vinaya; Croft, S. M.; Setty, Srinath; Scarpellini, Alessandra; Hughes, David C.; Rees, Robert C.; McArdle, Stephanie E.B.; Verderio, Elisabetta

doi:10.1007/s00726-011-1127-4

Cited by 33 publications

(56 citation statements)

References 33 publications

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“…The expression levels of the constitutively spliced full-length TGM2-v1 and of four TGM2 variants ( TGM2-v2, v3, v4A, v4B ), generated by alternative splicing, 32 were evaluated by real-time PCR in mesothelium and MPM derived cell lines.…”

Section: Resultsmentioning

confidence: 99%

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

et al. 2017

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Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to environmental/occupational exposure to asbestos, characterized by the presence of significant areas of hypoxia. In this study, we firstly explored the expression and the role of transglutaminase 2 (TG2) in MPM cell adaptation to hypoxia. We demonstrated that cells derived from biphasic MPM express the full-length TG2 variant at higher levels than cells derived from epithelioid MPM and normal mesothelium. We observed a significant induction of TG2 expression and activity when cells from biphasic MPM were grown as a monolayer in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core was demonstrated. We described that the hypoxic induction of TG2 was HIF-2 dependent. Importantly, TGM2-v1 silencing caused a marked and significant reduction of MPM cell viability in hypoxic conditions when compared with normoxia. Notably, a TG2-selective irreversible inhibitor that reacts with the intracellular active form of TG2, but not a non-cell-permeable inhibitor, significantly compromised cell viability in MPM spheroids. Understanding the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic options for MPM treatment.

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Section: Resultsmentioning

confidence: 99%

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

et al. 2017

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“…37 Previous work suggested that the short TGM2 form lacks the residual GTP-binding and carboxy-terminal portion necessary for recognition and binding to phospholipase C and is proapoptotic, whereas the long TGM2 form correlates more with increased cell survival. 23 Because the expression arrays used do not differentiate between the long and short TGM2 isoforms, we examined the expression of both isoforms in an independent and larger cohort, 128 EAC tumors, which also served as our validation cohort.…”

Section: Resultsmentioning

confidence: 99%

“…Because of the reported influence of TGM2 expression in various cancer cell lines on chemoresistance, 16,37 we examined TGM2 expression in a subset of 21 patients who had received preoperative chemotherapy, concurrent radiation therapy and subsequent esophagectomy, and whose tumors demonstrated minimal to no treatment response. TGM2 mRNA expression of this cohort was examined using qRT-PCR and compared with TGM2 expression from both normal esophagus (negative control) and EAC tumors with known TGM2 amplification (positive control) obtained from patients who had not received any chemotherapy or radiation therapy before operation.…”

Section: Resultsmentioning

confidence: 99%

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Leicht

Kausar

Wang

et al. 2014

Journal of Thoracic Oncology

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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.

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“…Some studies indicated that TG2 with its catalytic activity can incorporate polyamine in HPV18 E7 protein, thus inhibiting its binding to pRb protein in the cytosol and nucleus, thereby protecting the caspases degradation pathway [13,29,30]. In addition, recently, studies have shown that there is an increase in the splicing process of TG2 in dysplastic cells, indicating a relation between these TG2 molecules and the ones with intracellular cancer alterations [31].…”

Section: Discussionmentioning

confidence: 99%

“…These primers amplify E6 and E7 regions of the 38 most common HPV types. Nested PCR reaction was performed specifically with the types 45, 11,16,6,18,42,52,33,58,53,39,54,66,51,31,67,59, 62, 69, 35 e 68. All samples were analyzed by both the first reaction (PCR) and the second reaction (nested PCR).…”

Section: Hpv Typingmentioning

confidence: 99%

Expression analysis of transglutaminase 2 in premalignant lesions of the cervix

et al. 2017

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Background: The medical management of low-grade squamous intraepithelial lesions (LSIL) is variable, thus a biomarker could assist with the clinical conduct. Type 2 transglutaminase (TG2) has been proposed as a cellular-interfering factor in HPV infection and carcinogenesis. Therefore, this study has the objective of evaluating TG2 expression in LSIL and highgrade squamous intraepithelial lesions (HSIL) and of relating it to the different HPV viral types. Methods: This study included 146 patients with suspected LSIL or HSIL detected in routine conventional Papanicolaou tests. The presence of HPV DNA and viral typing was defined by the polymerase chain reaction method (PCR). TG2 Immunohistochemistry (IHC) was conducted according to the manufacturer's instructions; IHC was carried out in an Autosteiner-Link 48 Dako equipment. IHC quantitation was performed by relative expression and by using the software Image J. Qualitative variables, such as frequencies and proportions, were compared by using the χ2 test for independent samples. For comparison of the qualitative to the quantitative data, nonparametric Mann-Whitney test was used.

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Expression of transglutaminase-2 isoforms in normal human tissues and cancer cell lines: dysregulation of alternative splicing in cancer

Cited by 33 publications

References 33 publications

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Expression analysis of transglutaminase 2 in premalignant lesions of the cervix

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