Homeobox genes: Potential candidates for the transcriptional control of the transformed and invasive phenotype

Abstract

Abstract--The transformation of a cell and the acquisition of the invasive and metastatic phenotype result from the activation of a group of complex cellular processes rather than from the effect of a single gene product. It is likely that the coordination of the multiple genes involved in malignancy is under the control of a few genes that act as master genes or orchestrator genes. The latter probably code for transcription factors that control the genetic program for tumor invasion and metastasis. Homeobox genes are a family of transcription factors that contain a 183 bp highly conserved nucleotide sequence coding for a 61 amino acid domain that binds specifically to DNA. First discovered in Drosphila as genes controlling segmentation and segment identity, homeobox genes have since been identified in many other species including nematodes, frog, mouse and human. There is strong support for the suggestion that homeobox genes play a key role in development and differentiation. In humans, there are 38 homeobox genes organized in four clusters that are localized on chromosomes 2, 7, 12 and 17. The specific functions of each of these genes are generally unknown. Alterations in expression of several homeobox genes have been reported in a variety of malignant lesions, suggesting that they could play a role in the development of cancer. Using reverse transcriptase reaction coupled with polymerase chain reaction and degenerate oligonucleotides corresponding to the 5' and 3' ends of the highly conserved homeodomain, we amplified 130 bp cDNA fragments from the human breast cancer cell line MCF7 that were subsequently cloned into pBluescript vector. Sequencing of the clones, resulted in the identification of the homeodomains of four different human homeobox genes: HOXB6, HOXA1, HOXA10 and HOXC6. Further studies should determine the specific role of these four homeobox genes in the development and progression of human breast cancer and potentially determine if they might be good targets for gene therapy.

Loss of HOXC6 expression induces apoptosis in prostate cancer cells

“…There are two alternatively spliced HOXC6 mRNA species: HOXC6-1, a 1.8 kb transcript (clone 211; NM_004503) that encodes a 27 kDa protein (Chariot et al, 1996), and HOXC6-2, a 2.2 kb transcript (clone 173; NM_153653) that encodes an 18 kDa protein. HOXC6 is also expressed in the human breast cancer cell line MCF7 (Castronovo et al, 1994), in the HeLa cervical cancer line (our unpublished data), and we show here that HOXC6 is expressed in the LnCaP, C4-2, DU145, and PC3 PCa lines. Expression of HOXC6 is hormonally regulated, and is repressed specifically in mammary stroma in response to estrogen and progesterone (Garcia-Gasca and Spyropoulos, 2000).…”

Transcriptional regulation of the HOX4C gene by basic fibroblast growth factor on rheumatoid synovial fibroblasts

“…A number of HOX genes are expressed in certain neoplasms and involved in abnormal cellular proliferation (43)(44)(45). For example, Jurkat T cells transfected with the HOX HB24 gene form tumors in the nude mouse (46).…”

Relationship between DNA methylation and gene expression of the HOXB gene cluster in small cell lung cancers

“…It may reflect the particular regulatory functions of the HOX gene network whose expression pattern can be considered to be tissue-specific in adults [12][13][14][15][16][17][18][19][20][21]. Like imprinted genes, homeobox-containing genes behave unusually as regards DNA methylation during development: sites in non-island regions escape global de novo methylation during the pregastrula stage and became methylated late in development [32 34].…”

“…After embryogenesis, HOX genes may continue to be transcribed according to a tissue-specific pattern of expression. In cancer, alterations of this pattern, as compared to the corresponding normal mature tissues, have been described [12][13][14][15][16][17][18][19][20][21]. However, few data are presently available on HOX gene regulation in adult tissues or on the mechanisms responsible for the changes observed in cancer cells.…”