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Caldas ÁMC, Nunes WA, Taboada R, Cesca MG, Germano JN, Riechelmann RP. Loss of CDX2 and high COX2 ( PTGS2) expression in metastatic colorectal cancer. Ecancermedicalscience 2024; 18:1666. [PMID: 38439814 PMCID: PMC10911677 DOI: 10.3332/ecancer.2024.1666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Indexed: 03/06/2024] Open
Abstract
Lack of expression of the tumour suppressor gene caudal-type homeobox 2 (CDX2) associates with poor outcomes in early stage colorectal cancer (CRC). Yet its prognostic value in the context of other prognostic biomarkers in metastatic CRC (mCRC) is unknown. Overexpressed cyclooxygenase-2 (COX2) has been reported in advanced CRC. However, CDX2 and COX2 relationship in mCRC remains undetermined. We aimed to assess their expression in mCRC tumours from a clinically characterised cohort and their influence on overall survival (OS) and progression-free survival (PFS) in first line. Among 720 consecutive mCRC patients, 346 had tumour samples appropriate for tissue microarray assembly and immunohistochemistry analyses. Clinical and survival data were retrospectively assessed. Loss of CDX2 expression was detected in 27 (7.8%) samples, enriched in poorly differentiated tumours (20%; p < 0.01) and in those with the BRAF p.V600E variant (40%; p < 0.01). Most tumours (93.4%) expressed COX2. COX2-negative samples were enriched in poorly differentiated mCRC. In unadjusted analyses, median OS (p < 0.001) and median PFS (p < 0.05) were inferior for patients with CDX2-negative versus CDX2-positive tumours. In conclusion, loss of CDX2 was significantly associated with poorly differentiated mCRC and BRAF p.V600E allele and a prognostic marker of worse OS.
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Affiliation(s)
- Álvaro M C Caldas
- Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Warley A Nunes
- Department of Pathology, AC Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Rodrigo Taboada
- Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Marcelle G Cesca
- Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Janaína N Germano
- Statistic Group at the International Research Center (CIPE), AC Camargo Cancer Center, São Paulo 01509-900, Brazil
| | - Rachel P Riechelmann
- Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo 01509-900, Brazil
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Wang Y, Li Z, Li W, Liu S, Han B. Methylation of CDX2 gene promoter in the prediction of treatment efficacy in colorectal cancer. Oncol Lett 2018; 16:195-198. [PMID: 29928401 PMCID: PMC6006183 DOI: 10.3892/ol.2018.8670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 03/29/2017] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to examine the diagnosis of methylation of CDX2 gene promoter in colorectal cancer (CRC) and assessed its value in the prediction of treatment efficacy. Sixty patients who were diagnosed as CRCs for the first time, 60 patients with hyperplastic polyps (HPs) and adenomas, and 60 patients with inflammatory lesions or healthy patients (control group) were included in the present study. The methylation levels of CDX2 gene promoter were detected by methylation-specific polymerase chain reaction (MSP), and the expression levels of CDX2 mRNA were detected by fluorescence quantitative PCR. Treatment options, such as surgery, radiotherapy and chemotherapy, were chosen on the basis of TNM staging of CRC patients. The tumor-free survival, relapse rate and mortality were also recorded. The methylation rate was 71.67% (43/60) and significantly higher in the CRC group as compared to the HP/adenoma and control groups, P<0.05. Moreover, they showed further increase with higher degree of TNM staging. The expression levels of CDX2 mRNA was significantly lower in the CRC group in comparison to HP/adenoma and control groups, P<0.05, and showed a further decrease with a higher degree of TNM staging. The tumor-free survival was shorter, and the relapse rate and mortality were higher in patients with positive methylation in the CRC group, P<0.05. Multivariate logistic regression analysis demonstrated that TNM staging and positive methylation were independent risk factors of mortality. In conclusion, higher methylation degree of CDX2 gene promoter resulted in decreased expression of CDX2 gene, and was closely associated with TNM staging and prognosis. TNM staging and positive methylation were independent risk factors of mortality for CRC patients.
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Affiliation(s)
- Yunshuai Wang
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Zhaohui Li
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Wenxian Li
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Shuaifeng Liu
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Baowei Han
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
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Wang Y, Li Z, Li W, Liu S, Han B. Methylation of promoter region of CDX2 gene in colorectal cancer. Oncol Lett 2016; 12:3229-3233. [PMID: 27899987 PMCID: PMC5103925 DOI: 10.3892/ol.2016.5109] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 06/07/2016] [Indexed: 12/31/2022] Open
Abstract
The incidence of colorectal cancer is on the increase owing to changes in daily diet. In the present study, the methylation status of caudal type homeobox transcription factor 2 (CDX2) gene in lesion tissue of colorectal cancer (CRC) was investigated. Additionally, the correlation between the promoter methylation of CDX2 gene, CRC and gene expression in patients with CRC and normal population was examined. Between April 2014 and May 2015 78 cases with CRC were enrolled in the study. Using methylation-specific polymerase chain reaction (PCR), the promoter methylation of CDX2 in normal tissues and colorectal tissues was examinned. Through the fluorescence quantitative PCR technique, the expression levels of CDX2 gene were determined in a normal population and lesion tissue of patients with CRC. At the same time, we evaluated the levels of the CDX2 gene product in the normal population and lesion tissue of patients with CRC. The results showed that the methylation rate of the promoter region of CDX2 gene in normal colorectal tissue was 43.5%, whereas that in the lesion tissue of CRC was 78.5%. The result was statistically significant (P<0.05). The quantity of mRNA and protein expression of CDX2 gene in colorectal and normal tissue was significantly different (P<0.05). In conclusion, the methylation of the CDX2 gene promoter region was associated with risk of CRC, i.e., methylation of the promoter region of CDX2 gene favors the occurrence of CRC.
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Affiliation(s)
- Yunshuai Wang
- Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Zhaohui Li
- Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Wenxian Li
- Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Shuaifeng Liu
- Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
| | - Baowei Han
- Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P.R. China
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Kong J, Sai H, Crissey MAS, Jhala N, Falk GW, Ginsberg GG, Abrams JA, Nakagawa H, Wang K, Rustgi AK, Wang TC, Lynch JP. Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia. Oncotarget 2015; 6:32980-3005. [PMID: 26460825 PMCID: PMC4741744 DOI: 10.18632/oncotarget.5431] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/02/2015] [Indexed: 01/06/2023] Open
Abstract
Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1β transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1β double transgenic mice had half as many metaplastic nodules as control L2-IL-1β mice. This effect was not due to a reduction in esophageal IL-1β mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2::L2-IL-1β mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1β mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2::L2-IL-1β mice is CD8+ T cell dependent, which CD11b+Gr-1+ cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+ cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2::L2-IL-1β double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+ cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+ immature myeloid cells.
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Affiliation(s)
- Jianping Kong
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hong Sai
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mary Ann S. Crissey
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nirag Jhala
- Department of Pathology, Temple University, Philadelphia, PA, USA
| | - Gary W. Falk
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gregory G. Ginsberg
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Julian A. Abrams
- Division of Gastroenterology, Columbia University, New York, NY, USA
| | - Hiroshi Nakagawa
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kenneth Wang
- Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA
| | - Anil K. Rustgi
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Timothy C. Wang
- Division of Gastroenterology, Columbia University, New York, NY, USA
| | - John P. Lynch
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Li S, Chen X, Zhou L, Wang BM. Farnesoid X receptor signal is involved in deoxycholic acid-induced intestinal metaplasia of normal human gastric epithelial cells. Oncol Rep 2015; 34:2674-82. [PMID: 26324224 DOI: 10.3892/or.2015.4207] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/21/2015] [Indexed: 11/06/2022] Open
Abstract
The farnesoid X receptor (FXR) signaling pathway is known to be involved in the metabolism of bile acid, glucose and lipid. In the present study, we demonstrated that 400 µmol/l deoxycholic acid (DCA) stimulation promotes the proliferation of normal human gastric epithelial cells (GES-1). In addition, DCA activated FXR and increased the expression of intestinal metaplasia genes, including caudal-related homeobox transcription factor 2 (Cdx2) and mucin 2 (MUC2). The treatment of FXR agonist GW4064/antagonist guggulsterone (Gug.) significantly increased/decreased the expression levels of FXR, Cdx2 and MUC2 protein in DCA-induced GES-1 cells. GW4064/Gug. also enhanced/reduced the nuclear factor-κB (NF-κB) activity and binding of the Cdx2 promoter region and NF-κB, the most common subunit p50 protein. Taken together, the results indicated that DCA is capable of modulating the expression of Cdx2 and the downstream MUC2 via the nuclear receptor FXR-NF-κB activity in normal gastric epithelial cells. FXR signaling pathway may therefore be involved in the intestinal metaplasia of human gastric mucosa.
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Affiliation(s)
- Shu Li
- Department of Gastroenterology and Hepatology, Tianjin General Hospital, Tianjin Medical University, Heping, Tianjin 300052, P.R. China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin General Hospital, Tianjin Medical University, Heping, Tianjin 300052, P.R. China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin General Hospital, Tianjin Medical University, Heping, Tianjin 300052, P.R. China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin General Hospital, Tianjin Medical University, Heping, Tianjin 300052, P.R. China
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Kononov AV, Mozgovoĭ SI, Shimanskaia AG, Grishchenko RK, Nazarov AN. [Immunohistochemical detection of biomolecular markers for metaplastic mucosal atrophy in gastric biopsy specimens]. Arkh Patol 2015; 76:44-50. [PMID: 25842925 DOI: 10.17116/patol201476644-50] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To estimate the validity of the signs of metaplastic atrophic gastritis to elaborate a marker principle of its detection. SUBJECTS AND METHODS Two hundred diagnostic cases morphologically diagnosed with chronic gastritis were selected for examination. The validity of the histological and immunohistochemical signs/markers reflecting a gland abnormality (hyperplasia of smooth muscle cells and argyrophilic and elastic fibers) and a cell phenotype change (intestinal and pyloric metaplasia): CDX-2, Shh, villin, CD10, MUC2, and MUC5AC was estimated in gastric biopsy specimens with atrophic gastritis forms verified in accordance with international classifications. The validity of the signs/markers was assessed, by calculating the sensitivity, specificity, prognostic value of positive and negative results, and positive and negative likelihood ratios. RESULTS There were 3 molecules: CDX-2 is a nuclear transcription factor associated with intestinal differentiation; CCD10 is a brush border membrane-bound mycin and MUC2 is an intestinal-type mycin, which showed a high validity like the markers of metaplastic atrophic gastritis. An algorithm that could probably evaluate atrophic gastritis was elaborated for the successive immunohistochemical identification of the above-mentioned marker. CONCLUSION The proposed technical decision to verify atrophic gastritis by the biomarker method may be not an alternative, but complementary technique of identifying the form of atrophic gastritis.
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Affiliation(s)
- A V Kononov
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - S I Mozgovoĭ
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - A G Shimanskaia
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - R K Grishchenko
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
| | - A N Nazarov
- GBOU VPO "Omskaia gosudarstvennaia meditsinskaia akademiia" Minzdrava Rossii, Rossiĭskaia Federatsiia
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Freund JN, Duluc I, Reimund JM, Gross I, Domon-Dell C. Extending the functions of the homeotic transcription factor Cdx2 in the digestive system through nontranscriptional activities. World J Gastroenterol 2015; 21:1436-1443. [PMID: 25663763 PMCID: PMC4316086 DOI: 10.3748/wjg.v21.i5.1436] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 11/25/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis, also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut. At the molecular level, structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made of three alpha helixes arranged in a helix-turn-helix motif, preceded by a transcriptional domain and followed by a regulatory domain. The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells. Yet, this transcription factor also acts trough original nontranscriptional mechanisms. Indeed, the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-κB pathways, in double-strand break DNA repair and in premessenger RNA splicing. These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.
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Olsen J, Espersen MLM, Jess P, Kirkeby LT, Troelsen JT. The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review. Surg Oncol 2014; 23:167-76. [PMID: 25126956 DOI: 10.1016/j.suronc.2014.07.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/05/2014] [Indexed: 12/22/2022]
Abstract
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.
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Affiliation(s)
- J Olsen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark; Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - M L M Espersen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark; The Molecular Unit, Department of Pathology, Herlev University Hospital, DK-2730 Herlev, Denmark.
| | - P Jess
- Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - L T Kirkeby
- Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - J T Troelsen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
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Sun DZ, Jiao JP, Ju DW, Ye M, Zhang X, Xu JY, Lu Y, He J, Wei PK, Yang MH. Tumor interstitial fluid and gastric cancer metastasis: an experimental study to verify the hypothesis of "tumor-phlegm microenvironment". Chin J Integr Med 2012; 18:350-358. [PMID: 22549391 DOI: 10.1007/s11655-012-1085-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To extract tumor interstitial fluid (TIF) from MKN-45 gastric cancer which is similar to "muddy phlegm" in Chinese medicine and observe influences of MKN-45 tumor interstitial fluid (MKN-45 TIF) intervention on metastasis of gastric cancer and on the expressions of vascular endothelial growth factor (VEGF), kinase insert domain containing receptor (KDR), epithelial-cadherin (E-cad), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1) and telomerase genes and proteins in primary tumor tissue. METHODS An MKN-45 tumor-bearing model was established in 50 nude mice. The modeled animals were equally randomized to 5 groups: the simple tumor-bearing group (model group), the normal saline (NS) via tail vein injection (i.v.) group (NS i.v. group), MKN-45 TIF i.v. group (TIF i.v. group), NS intraperitoneal injection (i.p.) group (NS i.p. group), and MKN-45 TIF i.p. group (TIF i.p. group). The TIF and NS intervention groups received injection (i.p. or i.v.) of MKN-45 TIF or NS twice a week, 0.2 mL at a time. After 8 weeks, the primary tumors were removed, weighed and HE stained to observe tumor metastasis. The primary tumor tissues were analyzed by immunohistochemistry and real-time quantitative PCR to detect expressions of VEGF, KDR, E-cad, COX-2, ICAM-1, and telomerase genes and proteins in different groups. RESULTS There were significant differences in tumor weight between TIF intervention groups and the model and NS intervention groups. Tumor metastasis was observed in all 5 groups, but the tumor metastasis rate in TIF intervention groups was significantly higher than those in the model and NS intervention groups. The gene and protein expressions of gastric cancer-related factors VEGF, KDR, COX-2, ICAM-1 and telomerase were unregulated while the gene and protein expressions of E-cad were downregulated in TIF intervention groups. CONCLUSIONS TIF promotes tumor growth, invasion and metastasis of gastric cancer. These findings provide preliminary experimental clues for verifying the hypothesis of "tumor-phlegm microenvironment".
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Affiliation(s)
- Da-zhi Sun
- Institute of Traditional Chinese Medicine Research, Chinese People's Liberation Army General Hospital, Beijing, China
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Renouf B, Soret C, Saandi T, Delalande F, Martin E, Vanier M, Duluc I, Gross I, Freund JN, Domon-Dell C. Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells. Nucleic Acids Res 2011; 40:3456-69. [PMID: 22189105 PMCID: PMC3333856 DOI: 10.1093/nar/gkr1242] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Cdx2, a gene of the paraHox cluster, encodes a homeodomain transcription factor that plays numerous roles in embryonic development and in homeostasis of the adult intestine. Whereas Cdx2 exerts a tumor suppressor function in the gut, its abnormal ectopic expression in acute leukemia is associated to a pro-oncogenic function. To try to understand this duality, we have hypothesized that Cdx2 may interact with different protein partners in the two tissues and set up experiments to identify them by tandem affinity purification. We show here that Cdx2 interacts with the Ku heterodimer specifically in intestinal cells, but not in leukemia cells, via its homeodomain. Ku proteins do not affect Cdx2 transcriptional activity. However, Cdx2 inhibits in vivo and in vitro the DNA repair activity mediated by Ku proteins in intestinal cells. Whereas Cdx2 does not affect the recruitment of Ku proteins and DNA-PKcs into the DNA repair complex, it inhibits DNA-PKcs activity. Thus, we report here a new function of Cdx2, acting as an inhibitor of the DNA repair machinery, that may contribute to its tumor suppressor function specifically in the gut.
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Coskun M, Olsen J, Seidelin JB, Nielsen OH. MAP kinases in inflammatory bowel disease. Clin Chim Acta 2011; 412:513-20. [PMID: 21185271 DOI: 10.1016/j.cca.2010.12.020] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Revised: 12/16/2010] [Accepted: 12/17/2010] [Indexed: 12/16/2022]
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The role of CDX2 in intestinal homeostasis and inflammation. Biochim Biophys Acta Mol Basis Dis 2010; 1812:283-9. [PMID: 21126581 DOI: 10.1016/j.bbadis.2010.11.008] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 11/19/2010] [Accepted: 11/22/2010] [Indexed: 12/17/2022]
Abstract
Many transcription factors are known to control transcription at several promoters, while others are only active at a few places. However, due to their importance in controlling cellular functions, aberrant transcription factor function and inappropriate gene regulation have been shown to play a causal role in a large number of diseases and developmental disorders. Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa caused by dysregulation of the intestinal immune homeostasis. The aetiology of IBD is thought to be a combination of genetic and environmental factors, including luminal bacteria. The Caudal-related homeobox transcription factor 2 (CDX2) is critical in early intestinal differentiation and has been implicated as a master regulator of the intestinal homeostasis and permeability in adults. When expressed, CDX2 modulates a diverse set of processes including cell proliferation, differentiation, cell adhesion, migration, and tumorigenesis. In addition to these critical cellular processes, there is increasing evidence for linking CDX2 to intestinal inflammation. The aim of the present paper was to review the current knowledge of CDX2 in regulation of the intestinal homeostasis and further to reveal its potential role in inflammation.
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13
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Wang Q, Takei Y, Kobayashi O, Osada T, Watanabe S. Cyclooxygenase 2 modulates killing of cytotoxic T lymphocytes by colon cancer cells. J Clin Biochem Nutr 2009; 45:163-70. [PMID: 19794924 PMCID: PMC2735628 DOI: 10.3164/jcbn.09-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Accepted: 02/22/2009] [Indexed: 12/23/2022] Open
Abstract
Although anti-cancer effects of cyclooxygenase 2 (COX2) inhibitors have been reported, most studies focused on the direct effects of COX2 inhibiters on colon cancer cells. On the other hand, several types of cancers express Fas ligand (FasL) and/or TRAIL and mediate apoptosis of T cells in vitro. The “counter-attack” machinery may account for the mechanisms by which tumors evade host immune surveillance. In this study we determined if COX2 inhibitor could modulate effector molecules of cell death on colon cancer cells changing their effects on cytotoxic T lymphocytes. Colon adenocarcinoma cells, HCA7 and HCT116, the former COX2-positive and the latter COX2-negative, were pre-incubated with/without a COX2 inhibitor, NS398. Subsequently, the cells were co-cultured with Jurkat T cell leukemia cells and damage to Jurkat cells was determined. Treatment with NS398 resulted in reduction of expression of FasL and TRAIL in HCA7 cells, whereas NS398 did not affect the expression of FasL and TRAIL in HCT116 cells. The number of viable Jurkat cells was diminished when cells were co-cultured with naive, non-pretreated HCA7 or HCA116 cells. Preincubation of HCA7 cells with NS398 before co-culture blunted the HCA7 cell-induced cell toxicity on Jurkat cells. In contrast, pretreatment with NS398 failed to inhibit the HCT116-induced Jurkat cell killing. Our results suggest that COX2 regulates the expression of FasL and TRAIL on COX2-positive colon cancer cells thereby evoking a counter-attack against cytotoxic T cells, which may lead to compromised host immune responses.
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Affiliation(s)
- Quanxin Wang
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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László CF, Fayad S, Carpenter OL, George KS, Lu W, Abdel-Razak Saad AA, Wu S. The role of translational regulation in ultraviolet C light-induced cyclooxygenase-2 expression. Life Sci 2009; 85:70-6. [PMID: 19422838 PMCID: PMC2718691 DOI: 10.1016/j.lfs.2009.04.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 04/15/2009] [Accepted: 04/28/2009] [Indexed: 12/24/2022]
Abstract
AIMS The role of ultraviolet C light (UVC)-induced phosphorylation of the eukaryotic initiation factor 2 (eIF2) in the regulation of cyclooxygenase-2 (COX-2) expression at both transcriptional and translational levels is investigated. MAIN METHODS Western analysis was used to determine COX expressions. Immunoprecipitation after [(35)S]-Met/Cys metabolic labeling was used to determine the rate for COX-2 synthesis and turnover. Quantitative real-time PCR was used to determine COX-2 mRNA levels. Ingenuity Pathways Analysis 6 was used for mapping COX-2 activation network. KEY FINDINGS UVC induces COX-2 expression in wild-type mouse embryo fibroblasts (MEF(S/S)) and that the inducibility is reduced in MEF(A/A) cells in which the phosphorylation site, Ser-51 in the eIF2alpha, is replaced with a nonphosphorylatable Ala (S51A). UVC-induced transcription of COX-2 is delayed in MEF(A/A) cells, which correlates with NF-kappaB activation as previously reported (Wu, S, Tan, M, Hu, Y, Wang, JL, Scheuner, D, Kaufman, RJ, Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. The Journal of Biological Chemistry, 279, 34898-34902, 2004). The translational efficiency of COX-2 is higher in MEF(A/A) cells than in MEF(S/S) cells at 4 h, but not at 24 h post-UVC. The translation efficiency is correlated to the ratio of activated COX-2 binding protein HuR/TIAR. In addition, the newly synthesized COX-2 protein is more stable in MEF(A/A) cells than in MEF(S/S) cells. The results demonstrated a complex and dynamic regulation of COX-2 expression. SIGNIFICANCE UVC induces a prolonged expression of COX-2. While transcriptional regulation of COX-2 expression is intensively studied, the role of translational regulation of COX-2 synthesis upon UVC-irradiation is not yet clear. This study elucidated a novel eIF2alpha phosphorylation-centered network for the regulation of COX-2 expression after UVC-irradiation.
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Affiliation(s)
- Csaba F. László
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
| | - Sherine Fayad
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
- Department of Bioscience and Technology, Institute of Graduate Studies and Research, University of Alexandria, Alexandria, Egypt
- Desert Research Institute, Cairo, Egypt
| | - Oliver L. Carpenter
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
| | - Kimberly S. George
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
| | - Wei Lu
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
| | - Abir Adel Abdel-Razak Saad
- Department of Bioscience and Technology, Institute of Graduate Studies and Research, University of Alexandria, Alexandria, Egypt
| | - Shiyong Wu
- Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA
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