CDX2 controls genes involved in the metabolism of 5-fluorouracil and is associated with reduced efficacy of chemotherapy in colorectal cancer
Jean‐Baptiste DelhormeEmilie BersuderChloé TercioloOurania VlamiMarie‐Pierrette ChenardElisabeth MartinS. RohrCécile BrigandIsabelle DulucJean‐Noël FreundIsabelle Groß
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Abstract:
Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ABCC11/DPYD to improve systemic chemotherapy in CRC.Keywords:
CDX2
DPYD
FOLFOX
The gene of the caudal-type homeobox gene -2 ( CDX2), a member of the CDX family, is a principal regulator in the development of embryogenesis and haematogenesis . Recent studies have shown aberrant expression of CDX2 in each subtype of leukemia and its involvement in the genesis, progress and prognosis of leukemia as new gene. CDX2 may be a potential gene maker of leukemia in minimal residual disease detection.Studies also suggested that CDX2 be involved in leukemia by modulating HOX gene. To further investigate the mechanism of CDX2 in leukemia can be of great significance for the prediction of relapse and the individualized and targeted therapy.
Key words:
Caudal-type homeobox gene-2; Leukemia; Homeobox gene; Minimal residual disease
Homeobox A1
CDX2
HNF1B
Homeobox protein Nkx-2.5
DLX5
Minimal Residual Disease
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Background: Homeodomain transcriptional regulatory proteins, which are encoded by Homeobox (HOX) genes, play critical roles in both normal development and carcinogenesis. Previous studies have shown that the expression of HOX genes is deregulated in numerous tumors and this expression is specific to each cancer based on the arising embryonic origin tissue and the site of tumor.
Method: In this in vitro study, the expression levels of HOXA10, CDX1, CDX2, TGIFLX, TGIFLY, and OCT1 genes were compared across 10 different human colorectal cancer cell lines with different differentiation stages. Subsequently, the effect of TGIFLX siRNA-mediated knockdown on the expression levels of CDX1, CDX2, and OCT1 genes was analyzed in SW948 cell line.
Results: The obtained results revealed that these homeobox genes were differentially expressed in different colorectal cancer cell lines. Furthermore, the siRNA-mediated knockdown of TGIFLX led to higher levels of CDX1, CDX2, and OCT1 expression.
Conclusion: Our data suggested that TGIFLX plays an important role in the upstream regulation of CDX1, CDX2, and OCT1 genes.
CDX2
Homeobox A1
HNF1B
Homeobox protein Nkx-2.5
EMX2
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FOLFOX
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This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m2 administered over 90 min, followed by LV, 200 mg m2 administered over 2 h plus 5-FU 400 mg m2 as a bolus and 600 mg m2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3–4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.
FOLFOX
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Homeodomain proteins are encoded by homeobox genes and regulate development and differentiation in many neuronal systems. The mouse vomeronasal organ (VNO) generates in situ mature chemosensory neurons from stem cells. The roles of homeodomain proteins in neuronal differentiation in the VNO are poorly understood. Here we have characterized the expression patterns of 28 homeobox genes in the VNO of C57BL/6 mice at postnatal stages using multicolor fluorescent in situ hybridization. We identified 11 homeobox genes (Dlx3, Dlx4, Emx2, Lhx2, Meis1, Pbx3, Pknox2, Pou6f1, Tshz2, Zhx1, Zhx3) that were expressed exclusively in neurons; 4 homeobox genes (Pax6, Six1, Tgif1, Zfhx3) that were expressed in all non-neuronal cell populations, with Pax6, Six1 and Tgif1 also expressed in some neuronal progenitors and precursors; 12 homeobox genes (Adnp, Cux1, Dlx5, Dlx6, Meis2, Pbx2, Pknox1, Pou2f1, Satb1, Tshz1, Tshz3, Zhx2) with expression in both neuronal and non-neuronal cell populations; and one homeobox gene (Hopx) that was exclusively expressed in the non-sensory epithelium. We studied further in detail the expression of Emx2, Lhx2, Meis1, and Meis2. We found that expression of Emx2 and Lhx2 initiated between neuronal progenitor and neuronal precursor stages. As far as the sensory neurons of the VNO are concerned, Meis1 and Meis2 were only expressed in the apical layer, together with Gnai2, but not in the basal layer.
Homeobox A1
CDX2
EMX2
DLX5
HNF1B
PAX6
Homeobox protein Nkx-2.5
Vomeronasal organ
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The caudal-type homeobox gene is a member of homeobox gene—Para-HOX family,including CDX1,CDX2 and CDX4.As a transcriptional factor,CDX plays an important role in embryo development,hematopoietic system formation,intestinal epithelium tissue development and so forth.The abnormal expression of CDX is usually closely related with tumorigenesis.Researching the relationship between CDX and tumors will contribute to tumor diagnosis and treatment.
Key words:
Genes, homeobox ; Neoplasms
Homeobox A1
CDX2
HNF1B
Homeobox protein Nkx-2.5
EMX2
DLX5
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The past years have witnessed an increasing number of reports relative to homeobox genes in endoderm-derived tissues. In this review, we focus on the caudal-related Cdx-1 and Cdx-2 homeobox genes to give an overview of the in vivo, in vitro, and ex vivo approaches that emphasize their primary role in intestinal development and in the control of intestinal cell proliferation, differentiation, and identity. The participation of these genes in colon tumorigenesis and their identification as important actors of the oncogenic process are also discussed.Key words: caudal, epithelial cell proliferation and differentiation, cancer.
Homeobox A1
CDX2
HNF1B
Homeobox protein Nkx-2.5
DLX5
EMX2
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Homeobox genes, including HOX and non-HOX genes, have been identified to be expressed aberrantly in solid tumors.In gastrointestinal (GI) cancers, most studies have focused on the function of non-HOX genes including caudal-related homeobox transcription factor 1 (CDX1) and CDX2.CDX2 is a crucial factor in the development of pre-cancerous lesions such as Barrett's esophagus or intestinal metaplasia in the stomach, and its tumor suppressive role has been investigated in colorectal cancers.Recently, several HOX genes were reported to have specific roles in GI cancers; for example, HOXA13 in esophageal squamous cell cancer and HOXB7 in stomach and colorectal cancers.HOXD10 is upregulated in colorectal cancer while it is silenced epigenetically in gastric cancer.Thus, it is essential to examine the differential expression pattern of various homeobox genes in specific tumor types or cell lineages, and understand their underlying mechanisms.In this review, we summarize the available research on homeobox genes and present their potential value for the prediction of prognosis in GI cancers.
CDX2
Homeobox A1
Homeobox protein Nkx-2.5
HNF1B
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CDX2
Homeobox A1
HNF1B
Homeobox protein Nkx-2.5
EMX2
DLX5
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CDX2 is a Drosophila caudal-related homeobox transcription factor which is a new found specific nuclear factor(NF) belonging to the family of drosophila caudal-related homeobox gene.It not only controls the development and differentiation of embryonic cell,but also plays an important role in regulating the differentiation and proliferation of adult tissue.Recent studies found that CDX2 gene had expression in many tissues,such as digestive tract,genitourinary tracts,,head and neck.and so on.This article reviews the progress of CDX2 gene.
CDX2
Homeobox A1
HNF1B
EMX2
Homeobox protein Nkx-2.5
DLX5
PAX6
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