PMID- 23728346
OWN - NLM
STAT- MEDLINE
DCOM- 20140620
LR  - 20220129
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 19
DP  - 2014 May 8
TI  - Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis.
PG  - 2540-6
LID - 10.1038/onc.2013.205 [doi]
AB  - Signalling by the toll-like receptor (TLR) family of pathogen recognition 
      receptors has emerged as a key molecular component in the pathogenesis of an 
      increasing number of inflammatory-related cancers, among which gastric cancer 
      rates as the second most lethal cancer world-wide. The myeloid differentiation 
      factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune 
      signalling by members of the TLR and interleukin (IL)-1 families, and has been 
      associated with either pro- or antitumourigenic responses in various cancer 
      models. However, little is known about the in vivo role of MyD88 adapter-like 
      (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to 
      facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate 
      immune signalling components in gastric tumourigenesis, here we have employed the 
      spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the 
      growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice 
      suppressed tumourigenesis and was associated with increased apoptosis and reduced 
      proliferation in the gastric tumour epithelium, comparable to that observed 
      previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour 
      burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) 
      littermates. At the molecular level, suppressed tumourigenesis in 
      gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of 
      TLR2-regulated protumourigenic genes and signalling pathways, respectively. 
      Consistent with the previously defined non-essential role for TLR2 in gastric 
      tumour inflammation, the extent of inflammatory cell infiltrates in gastric 
      tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained 
      unaltered compared with gp130(F/F) mice. Collectively, our data reveal a 
      differential, but inflammation-independent, requirement for Mal and MyD88 during 
      TLR2-promoted gastric tumourigenesis.
FAU - Kennedy, C L
AU  - Kennedy CL
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
FAU - Najdovska, M
AU  - Najdovska M
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
FAU - Tye, H
AU  - Tye H
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
FAU - McLeod, L
AU  - McLeod L
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
FAU - Yu, L
AU  - Yu L
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
FAU - Jarnicki, A
AU  - Jarnicki A
AD  - Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, 
      Victoria, Australia.
FAU - Bhathal, P S
AU  - Bhathal PS
AD  - Department of Pathology, The University of Melbourne, Melbourne, Victoria, 
      Australia.
FAU - Putoczki, T
AU  - Putoczki T
AD  - Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, 
      Victoria, Australia.
FAU - Ernst, M
AU  - Ernst M
AD  - Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, 
      Victoria, Australia.
FAU - Jenkins, B J
AU  - Jenkins BJ
AD  - Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical 
      Research, Monash University, Clayton, Victoria, Australia.
LA  - eng
GR  - 08-0644/AICR_/Worldwide Cancer Research/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130603
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (TIRAP protein, mouse)
RN  - 0 (Tlr2 protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
SB  - IM
MH  - Animals
MH  - Cell Transformation, Neoplastic/immunology/*metabolism
MH  - Disease Models, Animal
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Membrane Glycoproteins/immunology/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88/immunology/*metabolism
MH  - Receptors, Interleukin-1/immunology/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/physiology
MH  - Stomach Neoplasms/immunology/*metabolism/pathology
MH  - Toll-Like Receptor 2/immunology/*metabolism
EDAT- 2013/06/04 06:00
MHDA- 2014/06/21 06:00
CRDT- 2013/06/04 06:00
PHST- 2012/12/03 00:00 [received]
PHST- 2013/04/08 00:00 [revised]
PHST- 2013/04/29 00:00 [accepted]
PHST- 2013/06/04 06:00 [entrez]
PHST- 2013/06/04 06:00 [pubmed]
PHST- 2014/06/21 06:00 [medline]
AID - onc2013205 [pii]
AID - 10.1038/onc.2013.205 [doi]
PST - ppublish
SO  - Oncogene. 2014 May 8;33(19):2540-6. doi: 10.1038/onc.2013.205. Epub 2013 Jun 3.