Abstract
Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Accessions
GenBank/EMBL/DDBJ
References
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. (2000). Gene ontology: tool for the unification of biology The Gene Ontology Consortium. Nat Genet 25: 25–29.
Ayala G.E, Dai H, Ittmann M, Li R, Powell M, Frolov A et al. (2004). Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res 64: 6082–6090.
Bernal JA, Luna R, Espina A, Lazaro I, Ramos-Morales F, Romero F et al. (2002). Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis. Nat Genet 32: 306–311.
Bobrovnikova-Marjon EV, Marjon PL, Barbash O, Vander Jagt DL, Abcouwer SF . (2004). Expression of angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 is highly responsive to ambient glutamine availability: role of nuclear factor-kappaB and activating protein-1. Cancer Res 64: 4858–4869.
Cavallaro U, Christofori G . (2004). Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4: 118–132.
Dasgupta B, Yi Y, Hegedus B, Weber JD, Gutmann DH . (2005). Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma. Cancer Res 65: 9843–9850.
Eisen MB, Spellman PT, Brown PO, Botstein D . (1998). Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95: 14863–14868.
Fidler IJ . (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3: 453–458.
Gallagher PG, Bao Y, Prorock A, Zigrino P, Nischt R, Politi V et al. (2005). Gene expression profiling reveals cross-talk between melanoma and fibroblasts: implications for host-tumor interactions in metastasis. Cancer Res 65: 4134–4146.
Gentleman RC, Lawless JF, Lindsey JC, Yan P . (1994). Multi-state Markov models for analysing incomplete disease history data with illustrations for HIV disease. Stat Med 13: 805–821.
Glinsky GV, Berezovska O, Glinskii AB . (2005). Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 115: 1503–1521.
Goswami S, Wang W, Wyckoff JB, Condeelis JS . (2004). Breast cancer cells isolated by chemotaxis from primary tumors show increased survival and resistance to chemotherapy. Cancer Res 64: 7664–7667.
Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S . (2000). Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 355: 716–719.
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). Cancer statistics, 2005. CA Cancer J Clin 55: 10–30.
Jordan MA, Wilson L . (2004). Microtubules as a target for anticancer drugs. Nat Rev Cancer 4: 253–265.
Kang Y, Massague J . (2004). Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118: 277–279.
Kim YH, Girard L, Giacomini CP, Wang P, Hernandez-Boussard T, Tibshirani R et al. (2006). Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25: 130–138.
Kozaki K, Miyaishi O, Tsukamoto T, Tatematsu Y, Hida T, Takahashi T . (2000). Establishment and characterization of a human lung cancer cell line NCI-H460-LNM35 with consistent lymphogenous metastasis via both subcutaneous and orthotopic propagation. Cancer Res 60: 2535–2540.
Liu FT, Rabinovich GA . (2005). Galectins as modulators of tumour progression. Nat Rev Cancer 5: 29–41.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al. (2005). Genes that mediate breast cancer metastasis to lung. Nature 436: 518–524.
Miyamoto K, Fukutomi T, Akashi-Tanaka S, Hasegawa T, Asahara T, Sugimura T et al. (2005). Identification of 20 genes aberrantly methylated in human breast cancers. Int J Cancer 116: 407–414.
Morowitz MJ, Barr R, Wang Q, King R, Rhodin N, Pawel B et al. (2005). Methionine aminopeptidase 2 inhibition is an effective treatment strategy for neuroblastoma in preclinical models. Clin Cancer Res 11: 2680–2685.
Nicholson BE, Frierson HF, Conaway MR, Seraj JM, Harding MA, Hampton GM et al. (2004). Profiling the evolution of human metastatic bladder cancer. Cancer Res 64: 7813–7821.
Osada H, Takahashi T . (2002). Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene 21: 7421–7434.
Pantel K, Brakenhoff RH . (2004). Dissecting the metastatic cascade. Nat Rev Cancer 4: 448–456.
Quinn LM, Latham SE, Kalionis B . (1998). A distal-less class homeobox gene, DLX4, is a candidate for regulating epithelial-mesenchymal cell interactions in the human placenta. Placenta 19: 87–93.
Ramaswamy S, Ross KN, Lander ES, Golub TR . (2003). A molecular signature of metastasis in primary solid tumors. Nat Genet 33: 49–54.
Takeuchi T, Tomida S, Yatabe Y, Kosaka T, Osada H, Yanagisawa K et al. (2006). Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J Clin Oncol 24: 1679–1688.
Tomida S, Koshikawa K, Yatabe Y, Harano T, Ogura N, Mitsudomi T et al. (2004). Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients. Oncogene 23: 5360–5370.
Acknowledgements
We thank Keishi Katoh for his helpful discussion on bioinformatic analysis. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grain-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Supplementary information
Rights and permissions
About this article
Cite this article
Tomida, S., Yanagisawa, K., Koshikawa, K. et al. Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach. Oncogene 26, 4600–4608 (2007). https://doi.org/10.1038/sj.onc.1210242
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210242
Keywords
This article is cited by
-
Epithelial-mesenchymal transition process during embryo implantation
Cell and Tissue Research (2022)
-
PSMD1 and PSMD2 regulate HepG2 cell proliferation and apoptosis via modulating cellular lipid droplet metabolism
BMC Molecular Biology (2019)
-
DLX4 hypermethylation is a prognostically adverse indicator in de novo acute myeloid leukemia
Tumor Biology (2016)
-
Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β
Oncogene (2011)
-
The microRNA network and tumor metastasis
Oncogene (2010)