ABSTRACT
BACKGROUND: Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk. METHODS: Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2. RESULTS: A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk. CONCLUSION: We found that CDX2 downregulation is associated with MMR deficiency, right-sided tumors, and poor differentiation at both the mRNA and protein level. Whether CDX2 plays an active role in tumor progression in MSI/MMR-deficient tumors remains to be elucidated.
Subject(s)
Brain Neoplasms/genetics , Colonic Neoplasms/genetics , Colorectal Neoplasms/genetics , Homeodomain Proteins/genetics , Neoplastic Syndromes, Hereditary/genetics , Protein Processing, Post-Translational/genetics , Adult , Aged , Aged, 80 and over , CDX2 Transcription Factor , Cell Differentiation , Colonic Neoplasms/pathology , Down-Regulation , Female , Genes, Tumor Suppressor/physiology , Humans , Male , Middle Aged , ProteomicsABSTRACT
INTRODUCTION: Homeobox genes are often deregulated in cancer. They can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. It is implicated in differentiation, proliferation, cell-adhesion, and migration. CDX2 has been proposed as a tumor suppressor in colorectal cancer but its role is still controversial. This systematic review were undertaken in order to clarify CDX2s role in colorectal cancer. METHODS: A literature search was performed in the MEDLINE database from 1966 to February 2014. Only studies in which all or a part of the experimental design were performed on human colorectal cancer tissue were included. Thus, studies solely performed in cell-lines or animal models were excluded. RESULTS: Fifty-two articles of relevance were identified. CDX2 expression was rarely lost in colorectal cancers, however the expression pattern may often be heterogeneous within the tumor and can be selectively down regulated at the invasive front and in tumor buddings. Loss of CDX2 expression is probably correlated to tumor grade, stage, right-sided tumor location, MMR-deficiency, CIMP, and BRAF mutations. The CDX2 gene is rarely mutated but the locus harboring the gene is often amplified and may suggest CDX2 as a linage-survival oncogene. CDX2 might be implicated in cell proliferation and migration through cross-talk with the Wnt-signaling pathway, tumor-stroma proteins, and inflammatory cytokines. CONCLUSION: A clear role for CDX2 expression in colorectal cancer remains to be elucidated, and it might differ in relation to the underlying molecular pathways leading to the cancer formation.
