Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer

AC West, K Tang, H. Tye, L Yu, N. Deng, M Najdovska, S. J. Lin, JJ Balic, E. Okochi-Takada, P. McGuirk, B. Keogh, W. McCormack, P. S. Bhathal, M. Reilly, M. Oshima, T. Ushijima, P. Tan, B. J. Jenkins

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Abstract

Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130 F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130 F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

Original languageEnglish
Pages (from-to)5134-5144
Number of pages11
JournalOncogene
Volume36
Issue number36
DOIs
Publication statusPublished - 7 Sep 2017

Cite this

West, AC ; Tang, K ; Tye, H. ; Yu, L ; Deng, N. ; Najdovska, M ; Lin, S. J. ; Balic, JJ ; Okochi-Takada, E. ; McGuirk, P. ; Keogh, B. ; McCormack, W. ; Bhathal, P. S. ; Reilly, M. ; Oshima, M. ; Ushijima, T. ; Tan, P. ; Jenkins, B. J. / Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. In: Oncogene. 2017 ; Vol. 36, No. 36. pp. 5134-5144.
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title = "Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer",
abstract = "Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50{\%} of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130 F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130 F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.",
author = "AC West and K Tang and H. Tye and L Yu and N. Deng and M Najdovska and Lin, {S. J.} and JJ Balic and E. Okochi-Takada and P. McGuirk and B. Keogh and W. McCormack and Bhathal, {P. S.} and M. Reilly and M. Oshima and T. Ushijima and P. Tan and Jenkins, {B. J.}",
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West, AC, Tang, K, Tye, H, Yu, L, Deng, N, Najdovska, M, Lin, SJ, Balic, JJ, Okochi-Takada, E, McGuirk, P, Keogh, B, McCormack, W, Bhathal, PS, Reilly, M, Oshima, M, Ushijima, T, Tan, P & Jenkins, BJ 2017, 'Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer', Oncogene, vol. 36, no. 36, pp. 5134-5144. https://doi.org/10.1038/onc.2017.121

Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. / West, AC; Tang, K; Tye, H.; Yu, L; Deng, N.; Najdovska, M; Lin, S. J.; Balic, JJ; Okochi-Takada, E.; McGuirk, P.; Keogh, B.; McCormack, W.; Bhathal, P. S.; Reilly, M.; Oshima, M.; Ushijima, T.; Tan, P.; Jenkins, B. J.

In: Oncogene, Vol. 36, No. 36, 07.09.2017, p. 5134-5144.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer

AU - West, AC

AU - Tang, K

AU - Tye, H.

AU - Yu, L

AU - Deng, N.

AU - Najdovska, M

AU - Lin, S. J.

AU - Balic, JJ

AU - Okochi-Takada, E.

AU - McGuirk, P.

AU - Keogh, B.

AU - McCormack, W.

AU - Bhathal, P. S.

AU - Reilly, M.

AU - Oshima, M.

AU - Ushijima, T.

AU - Tan, P.

AU - Jenkins, B. J.

PY - 2017/9/7

Y1 - 2017/9/7

N2 - Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130 F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130 F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

AB - Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130 F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130 F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

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U2 - 10.1038/onc.2017.121

DO - 10.1038/onc.2017.121

M3 - Article

VL - 36

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EP - 5144

JO - Oncogene

JF - Oncogene

SN - 0950-9232

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