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DACH1 is a novel predictive and prognostic biomarker in hepatocellular carcinoma as a negative regulator of Wnt/β-catenin signaling.

Liu Y, Zhou R, Yuan X, Han N, Zhou S, Xu H, Guo M, Yu S, Zhang C, Yin T, Wu K - Oncotarget (2015)

Bottom Line: In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression.In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes.Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.

ABSTRACT
The cell fate determination factor Dachshund (DACH1) functions as a novel suppressor in the progression of various neoplasms. Previous study has suggested that hypermethylation of promoter region was responsible for the reduction of DACH1 expression in hepatocellular carcinoma (HCC), and associated with the progression of HCC, but the clinical significance and the exact molecular mechanisms of DACH1 in the progression of HCC remain unclear. In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression. Notably, Kaplan-Meier analysis further indicated DACH1 could be an independent prognostic factor for the overall survival of HCC. Further, mechanistic studies revealed that overexpression of DACH1 inhibited the growth and migration of HCC cell line, which were dependent in part on the inactivation of Wnt pathway via phosphorylation of GSK3β to suppress β-catenin. In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes. Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.

No MeSH data available.


Related in: MedlinePlus

DACH1 is an independent prognostic factor of overall survival in HCC patientsIn a seven years cohort, representative images of the cancerous and adjacent tissue from the longest survival patient and the shortest one were shown by using HE and IHC staining (A). The quantification of data was displayed as mean ± SE (B). Kaplan-Meier survival curve of DACH1 alone (C) or combined with Ki-67 (D) were analyzed.
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Figure 3: DACH1 is an independent prognostic factor of overall survival in HCC patientsIn a seven years cohort, representative images of the cancerous and adjacent tissue from the longest survival patient and the shortest one were shown by using HE and IHC staining (A). The quantification of data was displayed as mean ± SE (B). Kaplan-Meier survival curve of DACH1 alone (C) or combined with Ki-67 (D) were analyzed.

Mentions: To understand the value of DACH1 in the prediction of HCCs’ prognosis, we examined expression of DACH1 in different tissue microarray containing 90 pairs of HCC samples, which provided survival data and detailed information about AFP and Ki-67 expression. The profiles of DACH1, AFP and Ki-67 of two representative cases were shown in Fig. 3A, Case1 had the longest survival and case 2 had shortest survival in this cohort. In comparison of adjacent tissues, the majority of HCC cancerous samples showed drastic reduction of DACH1 and increased expression of AFP and Ki-67 in this seven years cohort (Fig. 3B). Segregation of these patients into DACH1-high and low expression groups did not reveal significant relationship with clinicopathological parameters of sex, age, liver cirrhosis, tumor size, location, pathological type or the expressions of AFP, but noticeably associated with tumor grading (p = 0.033), TNM staging (p = 0.037) and Ki-67 profiles (p = 0.037) (Table 2). Median overall survival time of the DACH1-high and DACH1-low cases was 29 and 17 months, respectively, indicating significant difference of survival (Kaplan Meier log-rank test, p = 0.001, Fig. 3C). As expected, low expression of Ki-67 tended to predict better clinical outcome, but it did not reach the statistical significance in part for the limited sample size and variation of data (Kaplan Meier log-rank test, p = 0.170). Combined examination of DACH1 with Ki-67 would provide more precise information for the clinical outcome of HCC patients. Apparently, patients characterized by high levels of DACH1 and negative Ki-67 index had the longest OS in this study. However, there was no statistical significance between the DACH1-/Ki-67+ and DACH-/Ki-67− patients (Fig. 3D).


DACH1 is a novel predictive and prognostic biomarker in hepatocellular carcinoma as a negative regulator of Wnt/β-catenin signaling.

Liu Y, Zhou R, Yuan X, Han N, Zhou S, Xu H, Guo M, Yu S, Zhang C, Yin T, Wu K - Oncotarget (2015)

DACH1 is an independent prognostic factor of overall survival in HCC patientsIn a seven years cohort, representative images of the cancerous and adjacent tissue from the longest survival patient and the shortest one were shown by using HE and IHC staining (A). The quantification of data was displayed as mean ± SE (B). Kaplan-Meier survival curve of DACH1 alone (C) or combined with Ki-67 (D) were analyzed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496171&req=5

Figure 3: DACH1 is an independent prognostic factor of overall survival in HCC patientsIn a seven years cohort, representative images of the cancerous and adjacent tissue from the longest survival patient and the shortest one were shown by using HE and IHC staining (A). The quantification of data was displayed as mean ± SE (B). Kaplan-Meier survival curve of DACH1 alone (C) or combined with Ki-67 (D) were analyzed.
Mentions: To understand the value of DACH1 in the prediction of HCCs’ prognosis, we examined expression of DACH1 in different tissue microarray containing 90 pairs of HCC samples, which provided survival data and detailed information about AFP and Ki-67 expression. The profiles of DACH1, AFP and Ki-67 of two representative cases were shown in Fig. 3A, Case1 had the longest survival and case 2 had shortest survival in this cohort. In comparison of adjacent tissues, the majority of HCC cancerous samples showed drastic reduction of DACH1 and increased expression of AFP and Ki-67 in this seven years cohort (Fig. 3B). Segregation of these patients into DACH1-high and low expression groups did not reveal significant relationship with clinicopathological parameters of sex, age, liver cirrhosis, tumor size, location, pathological type or the expressions of AFP, but noticeably associated with tumor grading (p = 0.033), TNM staging (p = 0.037) and Ki-67 profiles (p = 0.037) (Table 2). Median overall survival time of the DACH1-high and DACH1-low cases was 29 and 17 months, respectively, indicating significant difference of survival (Kaplan Meier log-rank test, p = 0.001, Fig. 3C). As expected, low expression of Ki-67 tended to predict better clinical outcome, but it did not reach the statistical significance in part for the limited sample size and variation of data (Kaplan Meier log-rank test, p = 0.170). Combined examination of DACH1 with Ki-67 would provide more precise information for the clinical outcome of HCC patients. Apparently, patients characterized by high levels of DACH1 and negative Ki-67 index had the longest OS in this study. However, there was no statistical significance between the DACH1-/Ki-67+ and DACH-/Ki-67− patients (Fig. 3D).

Bottom Line: In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression.In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes.Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.

ABSTRACT
The cell fate determination factor Dachshund (DACH1) functions as a novel suppressor in the progression of various neoplasms. Previous study has suggested that hypermethylation of promoter region was responsible for the reduction of DACH1 expression in hepatocellular carcinoma (HCC), and associated with the progression of HCC, but the clinical significance and the exact molecular mechanisms of DACH1 in the progression of HCC remain unclear. In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression. Notably, Kaplan-Meier analysis further indicated DACH1 could be an independent prognostic factor for the overall survival of HCC. Further, mechanistic studies revealed that overexpression of DACH1 inhibited the growth and migration of HCC cell line, which were dependent in part on the inactivation of Wnt pathway via phosphorylation of GSK3β to suppress β-catenin. In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes. Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.

No MeSH data available.


Related in: MedlinePlus