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Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.

ABSTRACT: Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/?-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/?-catenin signaling that also has undefined ?-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-related genes including the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and Ral-binding protein 1-associated Eps domain-containing 2 (REPS2), which are involved in detoxification of chemotherapeutic agents. Nuclear DKK-1 expression is lost along CRC progression; however, it remains high in a subset (15%) of CRC patients (n = 699) and associates with decreased progression-free survival (PFS) after chemotherapy administration and overall survival (OS) [adjusted HR, 1.65; 95% confidence interval (CI), 1.23-2.21; P = 0.002)]. Overexpression of ALDH1A1 and REPS2 associates with nuclear DKK-1 expression in tumors and correlates with decreased OS (P = 0.001 and 0.014) and PFS. In summary, our findings demonstrate a novel location of DKK-1 within the cell nucleus and support a role of nuclear DKK-1 as a predictive biomarker of chemoresistance in colorectal cancer.

SUBMITTER: Aguilera O

PROVIDER: S-EPMC4467410 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.

Aguilera Óscar Ó González-Sancho José Manuel JM Zazo Sandra S Rincón Raúl R Fernández Agustín F AF Tapia Olga O Canals Francesc F Morte Beatriz B Calvanese Vincenzo V Orgaz José L JL Niell Núria N Aguilar Susana S Freije José M JM Graña Osvaldo O Pisano David G DG Borrero Aurea A Martínez-Useros Javier J Jiménez Benilde B Fraga Mario F MF García-Foncillas Jesús J López-Otín Carlos C Lafarga Miguel M Rojo Federico F Muñoz Alberto A

Oncotarget 20150301 8

Sporadic colorectal cancer (CRC) insurgence and progression depend on the activation of Wnt/β-catenin signaling. Dickkopf (DKK)-1 is an extracellular inhibitor of Wnt/β-catenin signaling that also has undefined β-catenin-independent actions. Here we report for the first time that a proportion of DKK-1 locates within the nucleus of healthy small intestine and colon mucosa, and of CRC cells at specific chromatin sites of active transcription. Moreover, we show that DKK-1 regulates several cancer-r ...[more]

PMID: 25788273

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Project description:BackgroundEpithelial ovarian cancer (EOC) is an aggressive disease with poor prognosis. The expression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) correlates with the malignant progression of several cancers. However, the relationship between the subcellular localization of CIAPIN1 and clinical characteristics in EOC remains unclear.MethodsImmunohistochemistry was performed to detect CIAPIN1 expression in 108 EOC tissues. CIAPIN1 expressions in eight fresh EOC tissues were detected by Western blotting. The relationship between CIAPIN1 subcellular expression and patients' clinicopathological features, including prognosis, was evaluated. Immunohistochemistry and immunofluorescence were employed to assess the CIAPIN1 subcellular localization in the EOC cell lines A2780 and HO8910. In addition, all patients were followed up to assess the prognostic value of CIAPIN1 in patients with EOC.ResultsCIAPIN1 is highly expressed in EOC, but is present at low levels in paired non-cancerous ovarian epithelial tissues. The results of Western blotting were in accordance with the immunohistochemical results. Poor differentiation of the tumors and EOC cell lines correlated with higher levels of CIAPIN1 nuclear expression. CIAPIN1 nuclear expression significantly correlated with the Federation International of Gynecology and Obstetrics (FIGO) stage and histological differentiation (P?=?0.034 and P?<?0.0001, respectively). Moreover, nuclear localization of CIAPIN1 was selected as an unfavorable prognostic factor by both univariate and multivariate analyses ( P?<?0.001). However, no significant correlations were observed between cytoplasmic localization of CIAPIN1 and clinicopathological parameters.ConclusionsCIAPIN1 might play a crucial role in the differentiation of EOC cells. Elevated expression of nuclear CIAPIN1 negatively correlated with the survival of EOC patients, suggesting that nuclear CIAPIN1 might serve as a prognostic biomarker for EOC patients.

Project description:ImportanceAt present, patients with colorectal cancer (CRC) are risk stratified using TNM histologic features. More recently, an association between a mesenchymal phenotype and a high risk of disease recurrence and micrometastases has been recognized.ObjectiveTo investigate the association of the epithelial to mesenchymal transition (EMT)-inducing transcription factor ZEB2 (zinc finger E box-binding homeobox 2), survival outcomes, and the efficacy of ZEB2 as a biomarker when added as refinement to TNM staging after curative intent surgery for CRC.Design, setting, and participantsZEB2 expression was assessed using a previously validated scoring system as part of a prospective, observational, masked diagnostic study from January 1, 2008, to December 31, 2013. Data were prospectively collected and analyzed for association with oncologic outcomes from January 1, 2017, to December 31, 2018. An initial test cohort from an academic university medical center of 126 consecutive patients with CRC and, subsequently, an independent validation cohort of 210 patients were examined. ZEB2 positivity was scored by 2 independent, masked pathologists. External validity was tested using an open access gene expression portal. Nomograms were developed with or without ZEB2.Main outcomes and measuresSystemic and local recurrence of CRC.ResultsThe test cohort consisted of 126 consecutive patients (mean [SD] age, 72.7 [11.7] years; 61 [48.4%] male) and the validation cohort of 210 patients (mean [SD] age, 72.0 [10.6] years; 111 [52.9%] male). A total of 52 tumors (41.3%) in the test cohort and 104 (49.5%) in the validation cohort were scored nuclear ZEB2 positive. Survival analysis by the log-rank test found that ZEB2 expression was associated with a significant reduction in overall survival and disease-free survival in both cohorts. Cox proportional hazards regression analysis highlighted ZEB2 as an independent biomarker of shorter overall survival and disease-free survival. Analysis of node-negative disease (n = 222) identified ZEB2 as an independent biomarker of early recurrence and reduced survival. External validation confirmed these findings. Addition of ZEB2 expression to nomograms composed of conventional TNM risk factors improved the ability to identify patients at high risk of recurrence demonstrated by the improvement in concordance index in both test (0.73 to 0.77) and validation (0.82 to 0.87) cohorts.Conclusions and relevanceThe findings suggest that expression of ZEB2 is associated with poor oncologic outcome and distant recurrence. The study also found that the addition of ZEB2 to existing TNM classification improved the ability to stratify patients for risk of recurrence. The results of this study suggest that addition of ZEB2 expression status to the TNM staging system improves the ability to stratify patients at high risk of recurrence.

Dataset Information

Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.

Publications

Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer.

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