Identification of LMX1B as a novel oncogene in human ovarian cancer.
Ovarian cancers are thought to result from the accumulation of multiple genetic aberrations that transform ovarian and/or fallopian tube surface epithelial cells, allowing for their abnormal growth, proliferation and metastasis. In the report presented here, we carried out genome-wide copy-number analysis using comparative genomic hybridization on a panel of mouse ovarian cancer (OVCA) cell lines previously established in our laboratory. We identified a recurrent focal amplification on mouse chromosomal region 2qB, which contains the LIM-homeodomain-containing transcription factor 1B (Lmx1b) gene. LMX1B is not expressed in normal human ovary, but is expressed in many human OVCA cell lines and primary tumors. High expression of LMX1B correlates with poor outcome. To clarify the role of LMX1B in ovarian carcinogenesis, we transduced LMX1B into a panel of mouse and human OVCA cell lines and demonstrated that LMX1B strongly promotes migration of cancer cells in culture and promotes xenograft growth in nude mice. Conversely, knockdown of LMX1B in a human cell line with endogenous high expression of LMX1B inhibits cell migration in vitro and tumor growth in vivo. Microarray analysis of cells overexpressing LMX1B identified the nuclear factor (NF)-κB pathway as a potential mediator of tumor progression and subsequent treatment of NFκB inhibitor decreased the migratory capacity of these cells. Thus, our data demonstrate that LMX1B is a novel oncogene in OVCA pathogenesis.
1] Department of Pathology, Massachusetts General Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
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He
Vincent Center for Reproductive Biology, Department of Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
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L
Guo
1] Harvard Medical School, Boston, MA, USA [2] Division of Hematology-Oncology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
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Vathipadiekal
Vincent Center for Reproductive Biology, Department of Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
P A
PA
Sergent
1] Harvard Medical School, Boston, MA, USA [2] Vincent Center for Reproductive Biology, Department of Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
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WB
Growdon
Department of Statistics, Brigham Young University, Provo, UT, USA.
D A
DA
Engler
1] Harvard Medical School, Boston, MA, USA [2] Vincent Center for Reproductive Biology, Department of Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
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BR
Rueda
1] Harvard Medical School, Boston, MA, USA [2] Division of Hematology-Oncology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
M J
MJ
Birrer
Women's Cancer Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Orsulic
1] Department of Pathology, Massachusetts General Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
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Mohapatra
D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D005260:Female; D005784:Gene Amplification; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D047368:Tumor Burden
C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D016328:NF-kappa B; D014157:Transcription Factors