Short DNA sequences and bacterial DNA induce esophageal, gastric, and colorectal cancer cell invasion.
Toll-like receptor 9 (TLR9) recognizes both bacterial and self-DNA and it is abundantly expressed in the gastrointestinal tract. In this study, we investigated the influences of both bacterial DNA and specific short DNA sequences on TLR9-mediated gastrointestinal cancer cell invasion. We assessed the effect of various DNA ligands on cellular invasion and on TLR9 and matrix metalloproteinase expression of three gastrointestinal cancer cell lines. DNA-ligands described in this study include CpG-ODN M362, 9-mer (hairpin), human telomeric sequence h-Tel22 G-quadruplex, and bacterial DNAs from Escherichia coli and Helicobacter pylori. All of the DNAs studied were demonstrated to induce invasion in the studied cells. The DNA-induced invasion was inhibited with a broad-spectrum MMP inhibitor and partly also with chloroquine suggesting that it could be mediated via MMP activation, endosomal signaling, and TLR9. Interestingly, H. pylori DNA was shown to induce a more pronounced invasion in a gastric cancer cell line than in the other cell lines. Our results suggest that bacterial DNA as well as deoxynucleotides having stable secondary structures (i.e. hairpins or G-quadruplex structures) may serve as endogenous, invasion-inducing TLR9-ligands and promote local progression and metastasis of cancers in the alimentary tract.
Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland. joonas.kauppila@oulu.fi
Joonas H
JH
Kauppila
Tuomo J
TJ
Karttunen
Juha
J
Saarnio
Pia
P
Nyberg
Tuula
T
Salo
David E
DE
Graves
Petri P
PP
Lehenkari
Katri S
KS
Selander
D001483:Base Sequence; D018938:Caco-2 Cells; D002738:Chloroquine / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004269:DNA, Bacterial / Q000009:adverse effects*; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D004926:Escherichia coli / Q000235:genetics; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics; D006801:Humans; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C408982:CPG-oligonucleotide; D004269:DNA, Bacterial; D004151:Dipeptides; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D002738:Chloroquine; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9