Transglutaminase 2 as an independent prognostic marker for survival of patients with non-adenocarcinoma subtype of non-small cell lung cancer

Choi, Chang; Jang, Se Jin; Park, Seong Yeol; Choi, Yong; Jeong, Jae-Heon; Kim, Dae Seok; Kim, Mi Kyeong; Park, Kang Seo; Nam, Byung Ho; Kim, Hyeong Ryul; Kim, Soo Youl; Hong, Kyung Taek

doi:10.1186/1476-4598-10-119

Cited by 25 publications

(16 citation statements)

References 20 publications

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“…In ccRCC, TGase 2 specifically interacts with p53 to promote oncogenesis. Although the roles of TGase 2 in cancer are well studied, the subgroup of TGase 2-positive patients in specific cancer types is small [63]. Therefore, from a therapeutic point of view, TGase 2 is commonly considered a chemo-sensitizing target instead of an anti-cancer therapeutic target [42].…”

Section: Tgase 2 In Cancer Tissuementioning

confidence: 99%

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α) in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field.

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Section: Tgase 2 In Cancer Tissuementioning

confidence: 99%

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim

Keillor

2020

IJMS

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“…11 Increased expression of TGM2 is reported to be a negative prognostic marker in multiple cancers. 19–22,43 Although a relationship to patient outcome was not found in our analyses, increased TGM2 was associated with higher tumor stage and poor differentiation indicating tumors overexpressing TGM2 may be more proliferative or aggressive. We observed higher TGM2 in EAC showing inflammatory and desmoplastic response (Table 1) and thus may be influenced by these processes.…”

Section: Discussionmentioning

confidence: 53%

“…In breast cancer and in non–small-cell lung cancers, TGM2 promoter hypermethylation seem to influence TGM2 expression and chemosensitivity. 19,38 In neuroblastoma cells, treatment with a histone deacetylase inhibitor increased expression of both the short and long isoforms of TGM2 , rendering them more resistant to chemotherapy treatment. 39 We therefore treated OE19 and OE33 EAC cell lines with the methylation and histone deacetylase inhibitors, 5-aza-2-deoxycytidine and trichostatin A, respectively, and examined their effect on TGM2 mRNA expression using qRT-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…15 In other epithelial cancers cell lines, expression of TGM2 has been linked to cisplatin and doxorubicin drug resistance with knockdown of TGM2 causing increased chemosensitivity. 16–18 TGM2 is also overexpressed in various primary tumors including lung, 19 colon, 20 ovarian, 21 breast, 6 and glioblastoma. 22 The role of TGM2 and its various isoforms in these cancers may differ as to whether it induces apoptosis, 23 cell proliferation, 24 or chemoresistance, 25–27 and the exact mechanisms of TGM2 regulation is an area of intense investigation.…”

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confidence: 99%

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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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“…In adenocarcinoma, unlike in squamous cell lung cancer, various kinds of driver mutations have been studied and various treatment options exist. In a previous study, TG2 was revealed to be a significant prognostic factor in squamous lung cancer (30). It is therefore necessary to study TG2 in the setting of squamous NSCLC.…”

Section: Discussionmentioning

confidence: 95%

Transglutaminase 2 Expression Predicts Progression Free Survival in Non-Small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

et al. 2013

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Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and in the constitutive activation of nuclear factor kappa B (NF-κB). We investigated the association of non-small cell lung cancer (NSCLC) treatment efficacy with TG2 and NF-κB expression in 120 patients: 102 with adenocarcinoma and 18 with other histologic types. All patients underwent surgery; 88 received adjuvant chemotherapy, with 28 receiving platinum-based doublet chemotherapy as first-line treatment and 29 receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients' TG2 and NF-κB expression values were calculated semiquantitatively. The median TG2 value was 50 (range, 0-300) and the median NF-κB value was 20 (range, 0-240). Disease-free survival did not differ between the low- and high-TG2 groups. Among patients who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was longer in the low-TG2 group than in the high-TG2 group (11.0 vs. 7.0 months; P=0.330). Among those who received EGFR-TKI therapy, PFS was also longer in the low-TG2 group than in the high-TG 2 group (11.0 vs. 2.0 months; P=0.013). Similarly, in EGFR wild-type patients treated with EGFR-TKI, PFS was longer in patients with low TG2 expression (9.0 vs. 2.0 months; P=0.013). TG2 expression levels can predict PFS in patients with NSCLC treated with EGFR-TKI.

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Transglutaminase 2 as an independent prognostic marker for survival of patients with non-adenocarcinoma subtype of non-small cell lung cancer

Cited by 25 publications

References 20 publications

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

Transglutaminase 2 Expression Predicts Progression Free Survival in Non-Small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

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