MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3

Selaru, Florin M.; Olaru, Alexandru; Kan, Takatsugu; David, Stefan; Cheng, Yulan; Mori, Yuriko; Yang, Jian; Paun, Bogdan C.; Jin, Zhe; Agarwal, Rachana; Hamilton, James P.; Abraham, John M.; Georgiades, Christos; Alvarez, Hector A.; Vivekanandan, Perumal; Yu, Wayne; Maitra, Anirban; Torbenson, Michael; Thuluvath, Paul J.; Gores, Gregory J.; LaRusso, Nicholas F.; Hruban, Ralph H.; Meltzer, Stephen J.

doi:10.1002/hep.22838

Cited by 244 publications

(221 citation statements)

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“…In contrast, the opposite evidence demonstrates that the transcriptional output of Foxo3a is the suppression rather than activation of FasL (7) The growing evidence has shown that miR-21 is highly expressed in a variety of malignant tumors (25). It is up-regulated in laryngeal carcinoma tissues (27) and human cholangiocarcinoma (10). miR-21 is higher in estrogen receptor-␣-positive tumors, and estradiol inhibits miR-21 expression in MCF-7 human breast cancer cells (28).…”

Section: Discussionmentioning

confidence: 99%

“…miR-21 has been shown to suppress other apoptotic proteins. For example, it can suppress tissue inhibitor of metalloproteinases 3 (10). miR-21 targets the network of p53, transforming growth factor-␤, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells (43).…”

Section: Foxo3a Targeting Mir-21mentioning

confidence: 99%

“…It promotes cell transformation by targeting the programmed cell death 4 gene (9). miR-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and the tissue inhibitor of metalloproteinase 3 (10). Given the important role of FasL in apoptosis, it is not yet clear whether FasL can be a target of miR-21 in the apoptotic machinery.…”

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confidence: 99%

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Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Wang

2010

Journal of Biological Chemistry

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MicroRNAs are a class of small non-coding RNAs and participate in the regulation of apoptotic program. Although miR-21 is able to inhibit apoptosis, its expression regulation and downstream targets remain to be fully elucidated. Here we report that the transcriptional factor Foxo3a initiates apoptosis by transcriptionally repressing miR-21 expression. Our results showed that doxorubicin could simultaneously induce the translocation of Foxo3a to the cell nuclei and a reduction in miR-21 expression. Knockdown of Foxo3a resulted in an elevation in miR-21 levels, whereas enforced expression of Foxo3a led to a decrease in miR-21 expression. In exploring the molecular mechanism by which Foxo3a regulates miR-21, we observed that Foxo3a bound to the promoter region of miR-21 and suppressed its promoter activity. These results indicate that Foxo3a can transcriptionally repress miR-21 expression. In searching for the downstream targets of miR-21 in apoptosis, we found that miR-21 suppressed the translation of Fas ligand (FasL), a pro-apoptotic factor. Furthermore, Foxo3a was able to up-regulate FasL expression through down-regulating miR-21. Our data suggest that Foxo3a negatively regulates miR-21 in initiating apoptosis. miRNAs 2 are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Recently, the work on miRNAs renovates our understanding about apoptotic regulation. They can be classified as either pro-or anti-apoptotic miRNAs (1, 2). For example, miR-1 participates in the initiation of apoptosis (3), whereas miR-21 is able to inhibit apoptosis (4). miRNAs are expressed at a constant level under physiological condition, and their functions depend on their expression levels. It remains a challenging question as to how their expression is regulated in the apoptotic program.The forkhead family of transcription factors is characterized by the presence of a conserved 100-amino acid DNA binding domain and participate in regulating diverse cellular functions such as apoptosis, differentiation, metabolism, proliferation, and survival (5). Foxo3a is a substrate of protein kinase Akt, and its transcriptional output is controlled via phosphorylation. In the absence of cellular stimulation and when Akt is inactive, Foxo3a is localized within the nucleus where it performs transcription of target genes. However, upon phosphorylation by Akt at Thr-32, Ser-253, and Ser-315, it binds to 14-3-3 and cannot exert the transcriptional function (6).Fas ligand (FasL) is a potential transcriptional target of Foxo3a, but the transcriptional output can be either activation or suppression. It has been reported that Foxo3a can stimulate FasL expression, thereby triggering apoptosis (6). However, there is also evidence showing that Foxo3a decreases the expression of FasL (7). The molecular mechanism by which Foxo3a regulates FasL expression remains further elusive. miR-21 has been shown to regulate apoptosis by targeting a variety of apoptotic factors. It contributes to glioma malignancy by down-regulating matrix meta...

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Section: Discussionmentioning

confidence: 99%

Section: Foxo3a Targeting Mir-21mentioning

confidence: 99%

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Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Wang

2010

Journal of Biological Chemistry

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“…[51][52][53] These effects appears to be linked to the survival advantage imparted by miR-21 via the direct targeting of proapoptotic genes, such as the tumor suppressor lipid-phosphatase, PTEN, which controls the phosphatidyl inositol 3-phosphate kinase (PI3K) signaling pathway [54][55][56] and programmed cell death 4 (Pdcd4) protein. 53,[57][58][59][60][61][62] The latter also has a role in TGF-b-induced apoptosis.…”

Section: 3mentioning

confidence: 99%

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

et al. 2014

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MicroRNAs (miRNAs) constitute a large class of short RNAs (e.g., 20-24 nucleotides in length), whose main function is to posttranscriptionally regulate the expression of protein-coding genes. Their importance in tumorigenesis has been demonstrated over the past decade, and correspondingly, they have emerged as potential therapeutic molecules and targets. Liver cancer is one of the most common neoplastic diseases worldwide, and it currently has a poor prognosis owing to largely ineffective therapeutic options. Liver cancer is also an excellent model for testing miRNA-based therapy approaches as it can be easily targeted with the systemic delivery of oligonucleotides. In recent years, the role of miRNAs in hepatocellular carcinoma (HCC) has been established with molecular studies and the development of animal models. These studies have also provided the basis for evaluating the therapeutic potential of miRNAs, or anti-miRNAs. In general, the safety of miRNAs has been proven and antitumor activity has been observed. Moreover, because of the absence or presence of mild side effects, the prophylactic use of miRNA-based approaches may be foreseen.

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“…For instance, miR-21 functions as an oncogene by regulating many tumor suppressor genes and is upregulated in many human malignancies [9,10], including breast cancer [11,12], glioblastoma [13], hepatocellular carcinoma [14], cholangiocarcinoma [15], lung cancer [16], tongue squamous cell carcinoma [17], gastric cancer [18,19], colorectal cancer [20,21], and prostate cancer [22]. Moreover, evidence is accumulating that many age-related diseases are also associated with impaired cell signaling cascades.…”

Section: Introductionmentioning

confidence: 99%