Expression of Smad7 in Cholangiocarcinoma: Prognostic Significance and Implications for Tumor Metastasis

Huang, Qiang; Liu, Lei; Liu, Chenhai; Shao, Feng; Xie, Fang; Zhang, Chuanhai; Hu, Sanyuan

doi:10.7314/apjcp.2012.13.10.5161

Cited by 20 publications

(10 citation statements)

References 29 publications

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“…In addition, the lack of correlation between I-SMAD mRNA and protein levels was recently noticed in pancreatic cancer55. Although multiple IHC analyses of SMAD7 have firmly established the correlation of SMAD7 protein expression with better prognosis of cancer patients565758, the SMAD7 mRNA levels did not show such clinical relevance5960. Collectively, these studies underscore the importance of post-transcriptional regulation of SMAD7 to coordinate TGFβ signalling in developmental and pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells

et al. 2016

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The transforming growth factor β (TGFβ) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGFβ signalling, thus mediating a negative feedback loop that may potentially restrain TGFβ responses of cancer cells. Here, however, we show that TGFβ treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFβ activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGFβ treatment and prevents TGFβ-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFβ-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGFβ self-restraint and provide a mechanism to explain the unleashed TGFβ responses in metastatic cancer cells.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells

et al. 2016

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“…This process drives cancer progression and metastasis by promoting angiogenesis and inducing EMT [32]. Smad7 is highly expressed in cholangiocarcinoma and involved in cancer EMT and metastasis and is a potential prognostic cancer marker [20]. Smad7 also inhibits melanoma metastasis to bone [21].…”

Section: Introductionmentioning

confidence: 99%

NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7

et al. 2016

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Overexpression of neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a prognostic marker of many cancers, including hepatocellular carcinoma (HCC). However, the functions and mechanisms of NEDD9 are unclear. We found that upregulation of NEDD9 promoted migration, invasion and cell-to-extracellular matrix adhesion of HCC cells. NEDD9 also induced the epithelial-mesenchymal transition (EMT) and expression of matrix metalloprotein 2 (MMP2). Increased aldehyde dehydrogenase (ALDH) activity and CD133-positive cells were observed in HCC cells with high expression of NEDD9, corresponding to greater sphere formation in cancer stem cells (CSCs). NEDD9 deregulated Smad7 expression to inhibit Smad signaling and binding to the FAK-Src-Crk complex. We propose that this is the mechanism by which NEDD9 induced CSC properties.

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“…Three CNV-TFs ZSCAN1, RFX1 and NFIC targeted two SMAD proteins SMAD3 and SMAD7. Study of Huang et al showed that SMAD7 was highly expressed in cholangiocarcinoma and might be a potential prognostic indicator for clinical assessment [54]. ZSCAN1 also targeted TGFBR1 which can activate SMAD proteins.…”

Section: Resultsmentioning

confidence: 99%

Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma

Lian

et al. 2014

PLoS ONE

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BackgroundTranscriptional regulatory network (TRN) is used to study conditional regulatory relationships between transcriptional factors and genes. However few studies have tried to integrate genomic variation information such as copy number variation (CNV) with TRN to find causal disturbances in a network. Intrahepatic cholangiocarcinoma (ICC) is the second most common hepatic carcinoma with high malignancy and poor prognosis. Research about ICC is relatively limited comparing to hepatocellular carcinoma, and there are no approved gene therapeutic targets yet.MethodWe first constructed TRN of ICC (ICC-TRN) using forward-and-reverse combined engineering method, and then integrated copy number variation information with ICC-TRN to select CNV-related modules and constructed CNV-ICC-TRN. We also integrated CNV-ICC-TRN with KEGG signaling pathways to investigate how CNV genes disturb signaling pathways. At last, unsupervised clustering method was applied to classify samples into distinct classes.ResultWe obtained CNV-ICC-TRN containing 33 modules which were enriched in ICC-related signaling pathways. Integrated analysis of the regulatory network and signaling pathways illustrated that CNV might interrupt signaling through locating on either genomic sites of nodes or regulators of nodes in a signaling pathway. In the end, expression profiles of nodes in CNV-ICC-TRN were used to cluster the ICC patients into two robust groups with distinct biological function features.ConclusionOur work represents a primary effort to construct TRN in ICC, also a primary effort to try to identify key transcriptional modules based on their involvement of genetic variations shown by gene copy number variations (CNV). This kind of approach may bring the traditional studies of TRN based only on expression data one step further to genetic disturbance. Such kind of approach can easily be extended to other disease samples with appropriate data.

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Expression of Smad7 in Cholangiocarcinoma: Prognostic Significance and Implications for Tumor Metastasis

Cited by 20 publications

References 29 publications

MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells

MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells

NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7

Integrative Analysis of Transcriptional Regulatory Network and Copy Number Variation in Intrahepatic Cholangiocarcinoma

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