HoxC8 expression in human colorectal cancer: a compensentory response of the cell to counter the transformation process?

Introduction: Homebox genes encode transcription factors that play important roles during early developmental processes. Some are expressed in adulthood and alterations have been linked to carcinogenesis. Both proto-oncogenic and tumor suppressor functions have been described for homeobox genes. Dysregulation of HoxC8 in tumors has been correlated with tumor progression in a limited number of studies. However, evidence for a tumor suppressor function for HoxC8 exists as well. We have investigated the functional consequences of expressing HoxC8 in cell lines and compared HoxC8 expression in patients with colo-rectal cancer (CRC) to clinico-pathological paramenters.

Experimental design: Ecdysone-inducible HoxC8 cell lines were established and applied in diverse functional assays. Putative HoxC8 target genes were identified by cDNA microarray analysis using these cell lines. To evaluate the impact of HoxC8 dysregulation in CRC, the transcription profile of HoxC8 was determined in colorectal cancer cell lines, colorectal mucosa, adenomas, colorectal cancer specimens and hepatic metastases by RT-PCR, respectively.

Results : HoxC8 induction significantly decreased cell growth, colony formation and cell migration, but increased cellular adhesion. Additionally, apoptosis induced by doxorubicin, bleomycin and CD95 increased when HoxC8 was induced. A number of the HoxC8 target genes we identified are regulators of the cell cycle and have tumor suppressor functions. Human colorectal cancer cell lines displayed variable intensities of HoxC8 transcription. In patient samples, no HoxC8 transcription was observed in colon mucosa (0/19) and polyps (0/10), but in 22% (15/69) of colorectal cancers. Interestingly, HoxC8 transcription was significantly associated with smaller tumors and with the absence of lymphatic invasion.

Conclusion: Our results support a potential tumor suppressor function for HoxC8. We propose that upregulation of HoxC8 and its targets in certain contexts may be a compensentory response of the cell to counter transformation processes. Thus, de novo expression of tumor suppressor gene networks regulated by Hox genes may be an important mechanism operating in cells to eliminate or hinder tumor growth.

Keywords: Homebox, HoxC8, carcinogenesis, colorectal cancer, tumor-suppressor gene