MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer [J]

Department of Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
FEBS letters (Impact Factor: 3.17). 01/2011; 585(1):207-13. DOI: 10.1016/j.febslet.2010.11.039
Source: PubMed


Both deregulation of tumor-suppressor genes and misexpression of microRNAs (miRNAs) have been implicated in the development of pancreatic cancer, but their relationship during this process remains less clear. Here, we report that the expression of miR-483-3p is strongly enhanced in pancreatic cancer tissues compared to side normal tissues using a miRNA-array differential analysis. Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are inversely correlated in human clinical specimens. Ectopic expression of miR-483-3p significantly represses DPC4/Smad4 protein levels in pancreatic cancer cell lines, and simultaneously promotes cell proliferation and colony formation in vitro. Our findings identify miR-483-3p as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/Smad4-driven pancreatic cancer.

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    • "MiRNA-421 is also aberrantly overexpressed in PDAC cells and functions to promote cell proliferation and colony formation in vitro. MiRNA-421 also directly suppresses SMAD4 and its downstream genes, such as p21, p15 and Id3 (Hao et al., 2011). SMAD7 is also reported as a negative regulator of invasion and metastasis of pancreatic cancer cells by antagonising TGF-β signaling pathway through several mechanisms (Bai et al., 2002; Shi et al., 2004; Wang et al., 2009). "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.
    Preview · Article · Aug 2015 · Journal of Genetics and Genomics
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    • "This study suggested that miR-494 might be developed as a prognostic marker or a therapeutic target for patients with PDAC. Other studies have shown that in human PDAC specimens, the expression levels of both miR-421 and miR-483-3p are inversely correlated to SMAD4 expression and ectopic expression of these miRNAs significantly represses SMAD4 protein levels in PDAC cell lines, suggesting that they are potent regulators of SMAD4 in PDAC [89, 90]. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "Ectopic expression of miR-421 decreased levels of DPC4/Smad4 protein, and promoted proliferation and colony formation in vitro, suggesting that miR-421 promotes oncogenesis by acting on DPC4/Smad4[46]. A similar study showed that up-regulated miR-483-3p also targets DPC4/Smad4 in PDAC tissues[47]. "
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    ABSTRACT: Pancreatic adenocarcinoma and hepatocellular carcinoma are devastating human malignancies that are characterized by poor prognosis, late onset, and a lack of known biomarkers. New diagnostic and therapeutic molecular targets are desperately needed to develop novel and effective treatment strategies. MicroRNAs (miRNAs) are an emerging class of molecules with roles in various cellular processes, including growth, survival, and apoptosis. Most importantly, aberrant expression of miRNAs has been implicated in cancer pathogenesis. miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma indicate selective overexpression of oncogenic miRNAs and down-regulation of tumor suppressive miRNAs in these cancers. This review summarizes results from key studies conducted to characterize the miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma and describes the potential mechanisms by which some oncogenic or tumor suppressive miRNAs act. Furthermore, this review outlines novel therapeutic strategies for targeting miRNAs.
    Full-text · Article · Aug 2011 · Chinese journal of cancer
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