Dataset Information

Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

ABSTRACT: Heparanase (HPSE) is the only endo-?-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory elements and mining public microarray datasets, we identified SMAD family member 4 (Smad4) as a crucial transcription regulator of HPSE in NB. We demonstrated that Smad4 repressed the HPSE expression at the transcriptional levels in NB cells. Mechanistically, Smad4 suppressed the HPSE expression through directly binding to its promoter and repressing the lymphoid enhancer binding factor 1 (LEF1)-facilitated transcription of HPSE via physical interaction. Gain- and loss-of-function studies demonstrated that Smad4 inhibited the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Restoration of HPSE expression prevented the NB cells from changes in these biological features induced by Smad4. In clinical NB specimens, Smad4 was under-expressed and inversely correlated with HPSE levels, while LEF1 was highly expressed and positively correlated with HPSE expression. Patients with high Smad4 expression, low LEF1 or HPSE levels had greater survival probability. These results demonstrate that Smad4 suppresses the tumorigenesis and aggressiveness of NB through repressing the HPSE expression.

SUBMITTER: Qu H

PROVIDER: S-EPMC5011643 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

Qu Hongxia H Zheng Liduan L Jiao Wanju W Mei Hong H Li Dan D Song Huajie H Fang Erhu E Wang Xiaojing X Li Shiwang S Huang Kai K Tong Qiangsong Q

Scientific reports 20160906

Heparanase (HPSE) is the only endo-β-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory elements and mining public microarray datasets, we identified SMAD family member 4 (Smad4) as a crucial transcription regulator of HPSE in NB. We demonstrated that Smad4 repressed the HPSE expression at ...[more]

PMID: 27595937

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Project description:Background:NUDT21, an RNA binding protein, has been reported to play an important role in the regulation of multiple biological responses. Detection of NUDT21 expression may lead to the identification of a novel marker for breast cancer. Purpose:The aim of this study was to investigate the clinical significance and functional role of NUDT21 in breast cancer. Methods:The protein expression of NUDT21 was examined by immunohistochemistry (IHC) in 100 paraffin-embedded, archived breast cancer samples and 100 benign breast tissues. Then, the correlations between the NUDT21 expression and clinicopathologic characteristics and prognoses of the breast cancer patients were analyzed. In addition, the function of NUDT21 in breast cancer cell lines was detected by the methyl thiazolyl tetrazolium, colony formation and ?t?ranswell assays. Finally, mass spectrometry analysis and Western blotting were used to identify the proteins that interact directly with NUDT21. Results:IHC analysis revealed that the expression of NUDT21 was significantly lower in breast cancer tissues compared with benign breast disease tissues. The correlation analysis revealed that low expression of NUDT21 was positively correlated with tumor size, lymph node metastasis, and TNM stage. Also, Kaplan-Meier survival curves showed that patients with lower NUDT21 expression had shorter overall survival and relapse-free survival compared with higher NUDT21 expression. In addition, the knockdown of NUDT21 enhanced cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). Consistently, the overexpression of NUDT21 inhibited cell proliferation, migration, invasion, and EMT. In addition, NUDT21 directly interacted with CPSF6 and negatively regulated its expression. Moreover, the knockdown of CPSF6 reversed NUDT21 expression-induced cancer cell migration and invasion. Conclusion:NUDT21 might play a tumor-suppressive role by inhibiting cell proliferation and invasion via the NUDT21/CPSF6 signaling pathway in breast cancer cells.

Dataset Information

Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

Publications

Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

Similar Datasets

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