The Dual Role of Smad7 in the Control of Cancer Growth  and Metastasis

Stolfi, Carmine; Marafini, Irene; Simone, De; Pallone, Francesco; Monteleone, Giovanni

doi:10.3390/ijms141223774

Cited by 83 publications

(65 citation statements)

References 77 publications

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“…The results showed that miR-497 was significantly downregulated in breast cancer tissues compared with normal tissues, which was consistent with the Dan Li's findings (Li et al, 2011). As an inhibitor of TGF-b signaling, SMAD7 was overexpressed in numerous cancers and its abundance was positively associated with the cancer malignancy (Ekman et al, 2012;Stolfi et al, 2013). Nevertheless, in breast cancer, studies revealed that SMAD7 could exert both anti-and protumor effects.…”

Section: )supporting

confidence: 91%

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Liu

Zhou

Shi

et al. 2016

DNA and Cell Biology

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As an inhibitor of TGF-β signaling, SMAD7 was reported to play dual roles in breast cancer development and progression. It inhibited the cancer metastasis by blocking epithelial-mesenchymal transition, however, litter studies focused on its role in other cancer processes. In this study, miR-497 expression was found inversely correlated with SMAD7 expression in breast cancer tissues. Bioinformatics analyses defined a potential miR-497 response element within 3' untranslated region of SMAD7 that was validated in reporter gene experiments. Enforced miR-497 expression, accompanied with SMAD7 reduction, suppressed MDA-MB-231 and MCF-7 breast cancer cell growth by MTT and invasion assay, and, induced the S phase arrest detected by flow cytometry. Furthermore, upregulated miR-497 expression by mimics treatment significantly suppressed the tumor growth in the orthotopic nude mouse models. Finally, high expression of miR-497 conferred a better prognosis, indicated by Kaplan-Meier test, especially in HER2 overexpression and triple-negative breast cancer (TNBC). Taken together, our results identified the proliferation promoting role of SMAD7 in breast cancer and therefore established the regulations of SMAD7 in breast cancer by miR-497 through a posttranscriptional mechanism. Moreover, miR-497 might be deemed as a novel potential therapeutic target for the HER2 positive and TNBC in future.

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Section: )supporting

confidence: 91%

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Liu

Zhou

Shi

et al. 2016

DNA and Cell Biology

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“…As predicted, depletion of PAR2 but not PAR1 led to either a loss or at least a strong decrease in the responsiveness of the tested genes to TGF-β1 stimulation in all three cell lines (Figure 2A). PAR2 depletion in Panc-1 cells also resulted to a failure of TGF-β1 to induce the expression of factors involved in positive (GADD45b [31, 32]) and negative (Smad7 [33]) feedback regulation of Smad signalling (Figure 2B). These results provide another example of the importance of PAR2 expression for proper regulation of a wide variety of individual TGF-β target genes and provide a molecular explanation for the crucial role of PAR2 in TGF-β -induced migration and invasion (see Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Proteinase-activated receptor 2 promotes TGF-β-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-β type I receptor ALK5

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-β and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell-surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-β and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-β1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro. Likewise, the plasminogen activator-inhibitor 1 gene in primary cultures of aortic smooth muscle cells from PAR2−/− mice displayed a greatly attenuated sensitivity to TGF-β1 stimulation. PAR2 depletion in PDAC cells resulted in reduced protein and mRNA levels of the TGF-β type I receptor activin receptor-like kinase 5 (ALK5). Forced expression of wild-type ALK5 or a kinase-active ALK5 mutant, but not a kinase-active but Smad-binding defective ALK5 mutant, was able to rescue TGF-β1-induced Smad3 activation, Smad dependent transcription, and cell migration in PAR2-depleted cells. Together, our data show that PAR2 is crucial for TGF-β1-induced cell motility by its ability to sustain expression of ALK5. Therapeutically targeting PAR2 may thus be a promising approach in preventing TGF-β-dependent driven metastatic dissemination in PDAC and possibly other stroma-rich tumour types.

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“…Smad7-dependent activation of TGFβ signaling is able to induce the epithelial to mesenchymal transition (EMT) in CRC, allowing CRC cells to leave the tissue parenchyma and enter systemic circulation, followed by tumor invasion and metastasis [10]. Smad7 is an inhibitory Smad protein that interacts with TGFβ type I receptor, targeting it for proteasomal degradation and thereby inhibiting TGFβ-I-induced phosphorylation of Smad2/Smad3 [11].…”

Section: Introductionmentioning

confidence: 99%

miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition

et al. 2017

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BackgroundDespite advancements in the diagnosis and treatment of colorectal cancer (CRC), many patients die because of tumor metastasis or recurrence. Therefore, identifying new prognostic markers and elucidating the mechanisms of CRC metastasis and recurrence will help to improve the prognosis of the disease. As dysregulation of microRNAs is strongly related to cancer progression, the aim of this study was to identify the role of miR-4775 in the prognosis of CRC patients and the underling mechanisms involved in CRC progression.MethodsqPCR and in situ hybridization were used to evaluate the expression of miR-4775 in 544 pairs of paraffin-embedded normal and CRC tissues. Kaplan–Meier analysis with the log-rank test was used for survival analyses. Immunohistochemical staining was applied to investigate the expression of miR-4775-regulated Smad7/TGFβ pathway-associated markers. In vitro and in vivo invasion and metastasis assays were used to explore the function of miR-4775 in the progression of CRC.ResultsmiR-4775 was identified as a high-risk factor for CRC metastasis and recurrence, with high levels predicting poor survival among the 544 studied CRC patients. Furthermore, high miR-4775 expression promoted the invasion of CRC cells as well as metastasis and the epithelial to mesenchymal transition (EMT) via Smad7-mediated activation of TGFβ signaling both in vitro and in vivo. Downregulating miR-4775 or overexpressing Smad7 reversed the tumor-promoting roles of miR-4775/Smad7/TGFβ in vitro and in vivo.ConclusionmiR-4775 promotes CRC metastasis and recurrence in a Smad7/TGFβ signaling-dependent manner, providing a new therapeutic target for inhibiting the metastasis or recurrence of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0585-z) contains supplementary material, which is available to authorized users.

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The Dual Role of Smad7 in the Control of Cancer Growth and Metastasis

Cited by 83 publications

References 77 publications

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

microRNA-497 Modulates Breast Cancer Cell Proliferation, Invasion, and Survival by Targeting SMAD7

Proteinase-activated receptor 2 promotes TGF-β-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-β type I receptor ALK5

miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition

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