Abstract
Receptor for advanced glycation end products (RAGE) and its ligands are overexpressed in multiple cancers. RAGE has been implicated in tumorigenesis and metastasis, but little is known of the mechanisms involved. In this study, we define a specific functional role for an alternate splice variant termed RAGE splice variant 1 (RAGEv1), which encodes a soluble endogenous form of the receptor that inhibits tumorigenesis. RAGEv1 was downregulated in lung, prostate, and brain tumors relative to control matched tissues. Overexpressing RAGEv1 in tumor cells altered RAGE ligand stimulation of several novel classes of genes that are critical in tumorigenesis and metastasis. Additionally, RAGEv1 inhibited tumor formation, cell invasion, and angiogenesis induced by RAGE ligand signaling. Analysis of signal transduction pathways underlying these effects revealed marked suppression of c-jun-NH2-kinase (JNK) pathway signaling, and JNK inhibition suppressed signaling through the RAGE pathway. Tumors expressing RAGEv1 were significantly smaller than wild-type tumors and displayed prominently reduced activation of JNK. Our results identify RAGEv1 as a novel suppressor, the study of which may offer new cancer therapeutic directions.
| Original language | English |
|---|---|
| Pages (from-to) | 5628-5638 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 70 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jul 1 2010 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Alternatively sliced RAGEv1 inhibits tumorigenesis through suppression of JNK signaling. / Kalea, Anastasia Z.; See, Fiona; Harja, Evis; Arriero, Maria; Schmidt, Ann Marie; Hudson, Barry.
In: Cancer Research, Vol. 70, No. 13, 01.07.2010, p. 5628-5638.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alternatively sliced RAGEv1 inhibits tumorigenesis through suppression of JNK signaling
AU - Kalea, Anastasia Z.
AU - See, Fiona
AU - Harja, Evis
AU - Arriero, Maria
AU - Schmidt, Ann Marie
AU - Hudson, Barry
PY - 2010/7/1
Y1 - 2010/7/1
N2 - Receptor for advanced glycation end products (RAGE) and its ligands are overexpressed in multiple cancers. RAGE has been implicated in tumorigenesis and metastasis, but little is known of the mechanisms involved. In this study, we define a specific functional role for an alternate splice variant termed RAGE splice variant 1 (RAGEv1), which encodes a soluble endogenous form of the receptor that inhibits tumorigenesis. RAGEv1 was downregulated in lung, prostate, and brain tumors relative to control matched tissues. Overexpressing RAGEv1 in tumor cells altered RAGE ligand stimulation of several novel classes of genes that are critical in tumorigenesis and metastasis. Additionally, RAGEv1 inhibited tumor formation, cell invasion, and angiogenesis induced by RAGE ligand signaling. Analysis of signal transduction pathways underlying these effects revealed marked suppression of c-jun-NH2-kinase (JNK) pathway signaling, and JNK inhibition suppressed signaling through the RAGE pathway. Tumors expressing RAGEv1 were significantly smaller than wild-type tumors and displayed prominently reduced activation of JNK. Our results identify RAGEv1 as a novel suppressor, the study of which may offer new cancer therapeutic directions.
AB - Receptor for advanced glycation end products (RAGE) and its ligands are overexpressed in multiple cancers. RAGE has been implicated in tumorigenesis and metastasis, but little is known of the mechanisms involved. In this study, we define a specific functional role for an alternate splice variant termed RAGE splice variant 1 (RAGEv1), which encodes a soluble endogenous form of the receptor that inhibits tumorigenesis. RAGEv1 was downregulated in lung, prostate, and brain tumors relative to control matched tissues. Overexpressing RAGEv1 in tumor cells altered RAGE ligand stimulation of several novel classes of genes that are critical in tumorigenesis and metastasis. Additionally, RAGEv1 inhibited tumor formation, cell invasion, and angiogenesis induced by RAGE ligand signaling. Analysis of signal transduction pathways underlying these effects revealed marked suppression of c-jun-NH2-kinase (JNK) pathway signaling, and JNK inhibition suppressed signaling through the RAGE pathway. Tumors expressing RAGEv1 were significantly smaller than wild-type tumors and displayed prominently reduced activation of JNK. Our results identify RAGEv1 as a novel suppressor, the study of which may offer new cancer therapeutic directions.
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UR - http://www.scopus.com/inward/citedby.url?scp=77954350266&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-0595
DO - 10.1158/0008-5472.CAN-10-0595
M3 - Article
C2 - 20570900
AN - SCOPUS:77954350266
VL - 70
SP - 5628
EP - 5638
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 13
ER -