Overexpression of the retinoic acid-responsive gene Stra6 in human cancers and its synergistic induction by Wnt-1 and retinoic acid.
Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse C57MG cells to isolate mRNAs induced by Wnt-1 and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor-gamma-responsive genes in human cancers.
Szeto
W
W
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jiang
W
W
Tice
D A
DA
Rubinfeld
B
B
Hollingshead
P G
PG
Fong
S E
SE
Dugger
D L
DL
Pham
T
T
Yansura
D G
DG
Wong
T A
TA
Grimaldi
J C
JC
Corpuz
R T
RT
Singh
J S
JS
Frantz
G D
GD
Devaux
B
B
Crowley
C W
CW
Schwall
R H
RH
Eberhard
D A
DA
Rastelli
L
L
Polakis
P
P
Pennica
D
D
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002884:Chromosomes, Human, Pair 15; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C108001:Stra6 protein, mouse; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D014212:Tretinoin