ABSTRACT
Previously we have demonstrated a reciprocal deregulation of various homeobox genes (HOXB6, B8, C8 and C9 vs Cdx-1) in human colorectal cancer (CRC). In the present study, using RT-PCR, we have investigated the expression pattern of these homeobox genes in various human colon cell lines, representing various stages of colon cancer progression and differentiation. Thus, we have tested polyposis coli Pc/AA adenoma cells, Caco-2, HT-29 and LS174T adenocarcinoma cell lines. All cell lines, except LS174T, demonstrated a pattern of deregulated homeobox gene expression which resembled that of CRC. In contrast, the pattern of expression of these genes in the highly oncogenic LS174T cells, as well as in Caco-2 cells transfected with activated Ha-ras or Polyoma middle T oncogene, resembled that of the normal mucosa. The reciprocal deregulation of HOX and Cdx-1 genes in CRC and in CRC-derived cell lines suggests a possible role in human CRC development.
Subject(s)
Colonic Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Genes, Homeobox/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenomatous Polyposis Coli/metabolism , Adenomatous Polyposis Coli/pathology , Butyric Acid/pharmacology , Cell Count , Cell Differentiation/drug effects , Colonic Neoplasms/pathology , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Homeodomain Proteins/genetics , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transfection , Tumor Cells, CulturedABSTRACT
In the present study, the possible involvement of homeobox-containing genes in colorectal cancer (CRC) development was investigated. Using a stepwise screening approach and RT-PCR, we have demonstrated that the human HOXB6, B8, C8 and C9 are overexpressed at various stages of CRC. In contrast, all CRC cases exhibited a marked decrease in the homeodomain-containing Cdx1 gene expression. Recent data which suggest a regulatory link between HOXB8 and several tumor suppressor genes, such as DCC, APC, and TGF beta, sustain a possible implication of homeobox genes in colon carcinogenesis. Moreover, our data showing a decrease in Cdx1 expression are consistent with the notion that genes functioning in the establishment and maintenance of the intestinal epithelium might, upon deregulation, disturb the normal control of cellular proliferation, differentiation, and death, thus leading to cancer development.
Subject(s)
Colorectal Neoplasms/etiology , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Genes, Homeobox , Base Sequence , DNA Primers/genetics , DNA, Complementary/genetics , Genes, Tumor Suppressor , Homeodomain Proteins/genetics , Humans , Polymerase Chain ReactionABSTRACT
Colorectal cancer (CRC) is one of the most frequent cancers in humans. It develops via a multistage process involving alterations of both protooncogenes and tumor suppressor genes. In the present report we determined the level of expression of several Wnt genes in CRC by RT-PCR and direct sequencing. While Wnt-1 was not detectably expressed in any colonic tissues, Wnt-5a gene was efficiently expressed both in nontumorous as well as in colonic tumor tissues. In contrast, the Wnt-2 gene, which was expressed at low levels in normal colon, exhibited overexpression in all tumor tissue samples at the different Dukes' stages of CRC progression, including premalignant polyps and liver metastases. Overexpression of the Wnt-2 gene occurred also in other digestive neoplasms such as gastric and esophageal carcinomas, as well as in diverticulitis associated with stenosis or pseudo-tumor.
