Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma

Jinawath, Artit; Akiyama, Yoshimitsu; Yuasa, Yasuhito; Pairojkul, Chawalit

doi:10.1007/s00432-006-0129-1

Cited by 18 publications

(20 citation statements)

References 26 publications

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“…COX-2 and p-ERK1/2 expression were found to be markedly lower in normal gallbladder tissues than in GBC tissues, and their expression levels were also lower in HIBEpiC cells than in GBC-SD and NOZ cells. These results were consistent with previous studies (9)(10)(11), indicating that aberrant COX-2 and ERK1/2 activation may serve key roles in GBC tumorigenesis, and verifying their potential as targets for GBC targeted therapy. As a member of the MAPK family of signal transduction molecules, ERK1/2 is involved in the process of cell growth, proliferation and differentiation.…”

Section: A B C Discussionsupporting

confidence: 93%

“…Extracellular signal-regulated kinase 1/2 (ERK1/2) is a member of the mitogen-activated protein (10,11), and that aberrant ERK1/2 activation is closely associated with tumorigenesis and progression in various tumor types (12,13). It has also been demonstrated that COX-2 and ERK1/2 may serve as potential therapeutic targets for certain tumors, and their specific inhibitors have shown encouraging outcomes for cancer patients (14).…”

Section: Introductionmentioning

confidence: 99%

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Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

et al. 2017

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Abstract. Cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinase 1/2 (ERK1/2) may serve as potential targets in various types of cancer; however, the roles of these proteins in gallbladder carcinoma (GBC) have not been reported previously. In the present study, the expression levels of COX-2 and phospho (p)-ERK1/2 in GBC were examined and the biological activities of celecoxib and PD184161 (specific inhibitors of COX-2 and p-ERK1/2, respectively) on the proliferation, cell cycle and apoptosis of the GBC-SD and NOZ human GBC cell lines were evaluated by a series of in vitro and in vivo studies. COX-2 and p-ERK1/2 protein expression levels were found to be significantly elevated in GBC tissues as well as in GBC-SD and NOZ cells. Treatments with celecoxib and PD184161 significantly inhibited GBC-SD and NOZ cell growth in a concentration-dependent manner, and their combination produced a synergistic inhibitory effect. In addition, celecoxib and PD184161 significantly inhibited tumor growth in xenograft nude mice. Celecoxib treatment led to G1 arrest via the upregulation of p21 and p27 expression in GBC-SD and NOZ cells, whereas PD184161 did not affect cell cycle distribution. The combination of celecoxib and PD184161 was able to promote cell apoptosis by triggering a collapse of mitochondrial membrane potential and activating caspase-3-mediated apoptosis. In conclusion, COX-2 and p-ERK1/2 protein may serve as potential targets for GBC chemotherapy, and the combination of celecoxib and PD184161 could significantly inhibit GBC cell growth, induce cell G1 arrest and trigger cell apoptosis of GBC cells. IntroductionGallbladder carcinoma (GBC) is the most common malignancy of the biliary system and the fifth most common gastrointestinal cancer worldwide, with an annual incidence of >10,000 and mortality rate of ~3,300 individuals. Its morbidity varies with racial, ethnic and regional factors (1). In recent years, numerous studies have reported an increase in the incidence of GBC in certain areas, including north India, Pakistan and Korea (2,3). As the majority of GBC patients are diagnosed when the cancer has reached an advanced stage, they have an extremely poor prognosis, with a median 5-year survival rate of 2-5% (4). Chemotherapy is considered to be the most valuable treatment to prolong the survival time and improve the quality of life of these patients. However, GBC shows resistance to the majority of currently used chemotherapeutic agents, and the real clinical effect of such agents is unsatisfactory (5). With rapid developments in cancer molecular and cell biology, targeted cancer therapies, which are drugs that interfere with specific molecules involved in cancer cell growth and survival, bring new hope for cancer patients. The growth and development of most tumors involves multiple genetic abnormalities, which diminishes the antitumor activities of the majority of single-targeted drugs in clinical applications. To date, GBC clinical trials have demonstrated that most single-targeted drugs for GBC ha...

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Section: A B C Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

et al. 2017

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“…CDX2 has been identified by Yamamoto et al 27 as a protein able to bind to the MUC2 promoter and initiate transcription, and subsequent studies by Mesquita et al have shown two functionally active CDX2-binding sites. 26 Ectopic expression of CDX2 has also been linked to MUC2 expression in gastric intestinal metaplasia, 69 Barrett's esophagus, 70 and cholangiocarcinoma, 71 suggesting an important regulatory role for CDX2 in MUC2 expression. We and others have reported that CDX2 may be somatically lost in some colorectal cancers either due to out-offrame allelic gains or losses of the microsatellite repeat within the CDX2-coding region, 29,72 epigenetic silencing via methylation, 73 or loss of heterozygosity.…”

Section: Discussionmentioning

confidence: 99%

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

et al. 2013

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Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (425% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all Po0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.

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“…Overexpression of pERK1/2 protein was seen in 49.2% of CCA cases. 34) ERKs can be activated by several stimuli including growth factors, cytokines and carcinogens. The ERK phosphorylation cascade is linked to cell surface receptor tyrosine kinases (RTKs) and other upstream signaling proteins with known oncogenic potential such as EGFR and human EGF receptor 2 (HER2) which are overexpressed in CCA.…”

Section: )mentioning

confidence: 99%

Berberine Induces Cell Cycle Arrest in Cholangiocarcinoma Cell Lines <i>via</i> Inhibition of NF-κB and STAT3 Pathways

Puthdee

Seubwai

Vaeteewoottacharn

et al. 2017

Biological & Pharmaceutical Bulletin

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Berberine is a natural compound found in several herbs. Anticancer activity of berberine was reported in several cancers, however, little is known regarding the effects of berberine against cholangiocarcinoma (CCA). In this study, the growth inhibitory effects of berberine on CCA cell lines and its molecular mechanisms were explored. Cell growth and cell cycle distribution were examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The expression levels of cell cycle regulatory proteins were determined by Western blot analysis. Berberine significantly inhibited growth of CCA cell lines in a dose and time dependent fashion. The inhibition was largely attributed to cell cycle arrest at the G1 phase through the reduction of cyclin D1, and cyclin E. Moreover, berberine could reduce the expression and activation of signal transducers and activator of transcription 3 (STAT3) and probably nuclear factor-kappaB (NF-κB) via suppression of extracellular signal-regulated kinase (ERK) 1/2 action. These results highlight the potential of berberine to be a multi-target agent for CCA treatment.

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Expression of phosphorylated ERK1/2 and homeodomain protein CDX2 in cholangiocarcinoma

Abstract: These results imply that pERK1/2 may be important for the differentiation of tubular-type CCA, while CDX2 is related to the intestinal phenotype of papillary-type CCA.

Cited by 18 publications

References 26 publications

Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype

Berberine Induces Cell Cycle Arrest in Cholangiocarcinoma Cell Lines <i>via</i> Inhibition of NF-κB and STAT3 Pathways

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