A transcriptional repressor of osteopontin expression in the 4T1 murine breast cancer cell line.
Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of approximately 298 amino acids which is an important mediator of tumor metastatic behavior. We have previously demonstrated that endotoxin-dependent OPN gene transcription is regulated by a constitutive transcriptional repressor protein, heterogeneous nuclear ribonucleoprotein A/B (hnRNP-A/B). However, in the context of cancer, the role of hnRNP-A/B in the transcriptional regulation of OPN and its metastasis-promoting functions has not been previously studied. We examined hnRNP-A/B in the 4T1 murine mammary epithelial tumor cell line, a thioguanine resistant subline which closely mimics stage IV breast cancer in humans. Our data indicate that hnRNP-A/B p37 binds to the OPN promoter, significantly decreases OPN promoter activity and mRNA levels, ablates OPN protein expression, and inhibits OPN dependent in vitro correlates of metastatic behavior, motility, and invasion. These results are unique and may suggest new therapies to re-establish loco-regional control of cancers.
Gao
Chengjiang
C
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Mi
Zhiyong
Z
Guo
Hongtao
H
Wei
Junping
J
Wai
Philip Y
PY
Kuo
Paul C
PC
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000235:genetics*; D014162:Transfection
D004273:DNA, Neoplasm; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin