Overexpression of ZEB2 at the Invasion Front of Colorectal Cancer Is an Independent Prognostic Marker and Regulates Tumor Invasion <i>In Vitro</i>

Kahlert, Christoph; Lahes, Saleh; Radhakrishnan, P.; Dutta, Shamik; Mogler, Carolin; Herpel, Esther; Brand, Karsten; Steinert, Gunnar; Schneider, Martin; Mollenhauer, Martin; Reißfelder, Christoph; Klupp, Fee; Fritzmann, Johannes; Wunder, Christina; Benner, Axel; Kloor, Matthias; Huth, Cathrin; Contin, Pietro; Ulrich, Alexis; Koch, Moritz; Weitz, Juergen

doi:10.1158/1078-0432.ccr-10-2816

Cited by 132 publications

(109 citation statements)

References 33 publications

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“…The importance of evaluating the invasive front has been reported in several gastrointestinal malignancies [28][29][30][31]. In the present study, we examined RacGAP1 expression at the invasive front in gastric cancer and observed the association of its expression with tumor progression and poor prognosis.…”

Section: Discussionmentioning

confidence: 85%

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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Background Rac GTPase activating protein 1 (RacGAP1) plays a regulatory role in cell growth, transformation and metastasis. The aim of this study was to clarify the association between RacGAP1 expression and clinical outcome in patients with gastric cancer. Methods A total of 232 gastric cancer patients in our institute who underwent surgery without preoperative treatments were enrolled in this study. We investigated RacGAP1 expression using immunohistochemistry (IHC) and evaluated IHC scores calculated by the percentage of positive cells and intensity and its expression at the invasive front. RACGAP1 expression was also assessed. Results RacGAP1 expression was observed in the nuclei of gastric cancer cells. Evaluation by IHC score showed no significant correlations with clinicopathological variables except for histological differentiation. In transcriptional analyses, RACGAP1 expression was elevated in diffuse type gastric cancer than intestinal type without a significant difference. We observed significant correlations of Rac-GAP1 protein expression at the invasive front with older age, tumor size, lymph node metastasis, lymphatic invasion, vascular invasion and advanced stage. Patients with RacGAP1 protein expression at the invasive front had significantly poorer prognosis than those without it (P \ 0.0001). In multivariate analysis, lymph node metastasis, distant metastasis and positive RacGAP1 expression at the invasive front were independent prognostic factors (lymph node metastasis: P = 0.0106; distant metastasis: P = 0.0012; RacGAP1: P = 0.0011). Conclusions RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis. Our data suggest that RacGAP1 might play important roles in the progression of gastric cancer.

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Section: Discussionmentioning

confidence: 85%

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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“…BRAF mutation status was analyzed by Sanger sequencing as described previously. 27 In case of discordant results, a pyrosequencing-based assay was performed, using oligonucleotide primers and conditions described previously. 28 …”

Section: Braf Mutation Analysis and Microsatellite Instability Testingmentioning

confidence: 99%

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Capper

Voigt

Bozukova

et al. 2013

Intl Journal of Cancer

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The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1-and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n 5 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.Lynch syndrome, which represents one of the most frequent autosomal dominantly inherited cancer syndromes, is caused by germline mutations affecting DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2, followed by MSH6 and PMS2.

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“…Furthermore, ZEB1 influenced the expression of other key proteins mediated by the Wnt signaling pathway, including membrane-type 1 matrix metalloproteinase and laminin gamma chain 2 (LAMC2) (59). Therefore, indicating that LAMC2 and all proteins mediated by the Wnt signaling pathway were implicated in the invasion and dissection of colorectal cancer cells (67). Additionally, in human meningioma tumor tissues, the expression of miR-200a was negatively associated with β-catenin and cyclin D1 (68).…”

Section: Signals Regulated By the Mir-200 Family In Cancermentioning

confidence: 99%

“…This was observed in tumorigenesis for human solid tumors, including hepatocellular carcinoma, melanoma, colon, ovarian and prostate cancer (66). Nuclear accumulation of β-catenin is linked with EMT in invasive colorectal tumors, and the association between the Wnt pathway and EMT has been investigated (67). Levels of ZEB1 expression have no influence on β-catenin/transcription factor 4 transcriptional signaling in colon cancer cell lines, although ZEB1 immunopositivity has been confirmed in non-invasive colon cancer cells and in tumor-associated fibroblasts (67).…”

Section: Signals Regulated By the Mir-200 Family In Cancermentioning

confidence: 99%

“…Nuclear accumulation of β-catenin is linked with EMT in invasive colorectal tumors, and the association between the Wnt pathway and EMT has been investigated (67). Levels of ZEB1 expression have no influence on β-catenin/transcription factor 4 transcriptional signaling in colon cancer cell lines, although ZEB1 immunopositivity has been confirmed in non-invasive colon cancer cells and in tumor-associated fibroblasts (67). Furthermore, ZEB1 influenced the expression of other key proteins mediated by the Wnt signaling pathway, including membrane-type 1 matrix metalloproteinase and laminin gamma chain 2 (LAMC2) (59).…”

Section: Signals Regulated By the Mir-200 Family In Cancermentioning

confidence: 99%

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Members of the microRNA-200 family are promising therapeutic targets in cancer

Chen

Zhang

2017

Experimental and Therapeutic Medicine

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Abstract. MicroRNAs (miRs) are non-coding, single-stranded RNA molecules that regulate gene expression at the posttranscriptional level. Abnormal expression of miR may result in pathophysiological processes occurring that stimulate the development of various diseases. miRs are commonly dysregulated in cancer and may act as either oncogenes or tumor suppressors. Studies have indicated that members of the miR-200 family are involved in different aspects of cancer biology, including the epithelial-to-mesenchymal transition, tumor angiogenesis and chemoresistance by targeting and repressing the expression of several key messenger RNAs. The present review aims to summarize the role of the miR-200 family and its potential mechanism of action in tumor progression, which may advance the development of novel therapeutic drugs against tumor metastasis in clinical cancer treatment.

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Overexpression of ZEB2 at the Invasion Front of Colorectal Cancer Is an Independent Prognostic Marker and Regulates Tumor Invasion In Vitro

Cited by 132 publications

References 33 publications

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Members of the microRNA-200 family are promising therapeutic targets in cancer

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