STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation

Yuet Mei Hazel Tye, Catherine Lydia Kennedy, Meri Najdovska, Louise McLeod, William McCormack, Norman R Hughes, Anouk Tara Dev, William Sievert, Chia Huey Ooi, T Ishikawa, Hiroko Oshima, Prithi S Bhathal, Andrew E Parker, Masanobu Oshima, Patrick Tan, Brendan John Jenkins

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Abstract

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.
Original languageEnglish
Pages (from-to)466 - 478
Number of pages13
JournalCancer Cell
Volume22
Issue number4
DOIs
Publication statusPublished - 2012

Cite this

Tye, Y. M. H., Kennedy, C. L., Najdovska, M., McLeod, L., McCormack, W., Hughes, N. R., ... Jenkins, B. J. (2012). STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell, 22(4), 466 - 478. https://doi.org/10.1016/j.ccr.2012.08.010
Tye, Yuet Mei Hazel ; Kennedy, Catherine Lydia ; Najdovska, Meri ; McLeod, Louise ; McCormack, William ; Hughes, Norman R ; Dev, Anouk Tara ; Sievert, William ; Ooi, Chia Huey ; Ishikawa, T ; Oshima, Hiroko ; Bhathal, Prithi S ; Parker, Andrew E ; Oshima, Masanobu ; Tan, Patrick ; Jenkins, Brendan John. / STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. In: Cancer Cell. 2012 ; Vol. 22, No. 4. pp. 466 - 478.
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title = "STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation",
abstract = "Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.",
author = "Tye, {Yuet Mei Hazel} and Kennedy, {Catherine Lydia} and Meri Najdovska and Louise McLeod and William McCormack and Hughes, {Norman R} and Dev, {Anouk Tara} and William Sievert and Ooi, {Chia Huey} and T Ishikawa and Hiroko Oshima and Bhathal, {Prithi S} and Parker, {Andrew E} and Masanobu Oshima and Patrick Tan and Jenkins, {Brendan John}",
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Tye, YMH, Kennedy, CL, Najdovska, M, McLeod, L, McCormack, W, Hughes, NR, Dev, AT, Sievert, W, Ooi, CH, Ishikawa, T, Oshima, H, Bhathal, PS, Parker, AE, Oshima, M, Tan, P & Jenkins, BJ 2012, 'STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation', Cancer Cell, vol. 22, no. 4, pp. 466 - 478. https://doi.org/10.1016/j.ccr.2012.08.010

STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. / Tye, Yuet Mei Hazel; Kennedy, Catherine Lydia; Najdovska, Meri; McLeod, Louise; McCormack, William; Hughes, Norman R; Dev, Anouk Tara; Sievert, William; Ooi, Chia Huey; Ishikawa, T; Oshima, Hiroko; Bhathal, Prithi S; Parker, Andrew E; Oshima, Masanobu; Tan, Patrick; Jenkins, Brendan John.

In: Cancer Cell, Vol. 22, No. 4, 2012, p. 466 - 478.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation

AU - Tye, Yuet Mei Hazel

AU - Kennedy, Catherine Lydia

AU - Najdovska, Meri

AU - McLeod, Louise

AU - McCormack, William

AU - Hughes, Norman R

AU - Dev, Anouk Tara

AU - Sievert, William

AU - Ooi, Chia Huey

AU - Ishikawa, T

AU - Oshima, Hiroko

AU - Bhathal, Prithi S

AU - Parker, Andrew E

AU - Oshima, Masanobu

AU - Tan, Patrick

AU - Jenkins, Brendan John

PY - 2012

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N2 - Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.

AB - Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.

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Tye YMH, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes NR et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell. 2012;22(4):466 - 478. https://doi.org/10.1016/j.ccr.2012.08.010