Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma

Dohi, Osamu; Yasui, Kohichiroh; Gen, Yasuyuki; Takada, Hisashi; Endo, Mio; Tsuji, Kazuhiro; Konishi, Chika; Yamada, Naotaka; Mitsuyoshi, Hironori; Yagi, Nobuaki; Naito, Yuji; Tanaka, Shinji; Arii, Shigeki; Yoshikawa, Toshikazu

doi:10.3892/ijo.2012.1724

Cited by 68 publications

(60 citation statements)

References 22 publications

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“…Based on bioinformatical predication, a luciferase reporter assay was performed and PAX6 was identified as a novel target of miR-335, which has been demonstrated to be implicated in various types of cancer (14)(15)(16)(17)(18)(19)(20)(21)(22). However, the detailed role of miR-335 in the development and progression of various types of cancer remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…miR-335 has been demonstrated to be implicated in multiple types of malignant tumor, including small cell lung cancer, osteosarcoma, ovarian cancer, prostate cancer, hepatocellular carcinoma, meningioma and gastric cancer (14)(15)(16)(17)(18)(19)(20)(21)(22). Recently, Jiang et al have suggested that miR-335 upregulation is associated with advanced tumor progression in glioma and is an independent marker for the predication of the clinical outcome of patients with glioma (23).…”

Section: Introductionmentioning

confidence: 99%

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PAX6, a novel target of miR-335, inhibits cell proliferation and invasion in glioma cells

Cheng

Cao²,

Chen

et al. 2014

Molecular Medicine Reports

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Abstract. Paired box 6 (PAX6), a highly conserved transcription factor, is important in glioma. However, the molecular mechanisms involved remain unclear. The present study demonstrated that the expression of PAX6 was significantly reduced with the malignancy of glioma and also identified PAX6 as a novel target of microRNA (miR)-335, which was significantly upregulated in glioma. The inhibition of miR-335 increased the protein expression of PAX6, whereas the upregulation of miR-335 suppressed its expression in human glioma U251 and U87 cells. Furthermore, upregulation of miR-335 promoted U251 cell proliferation, colony formation and invasion, which was reversed by the overexpression of PAX6. Furthermore, the present study demonstrated that the effect of miR-335 on U251 cell invasion was via the modulation of matrix metalloproteinase (MMP)-2 and MMP-9 expression by targeting PAX6. In conclusion, the present study demonstrated that PAX6, as a novel target of miR-335, has an anti-oncogenic function in glioma, and thus PAX6 may serve as a therapeutic target for glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PAX6, a novel target of miR-335, inhibits cell proliferation and invasion in glioma cells

Cheng

Cao²,

Chen

et al. 2014

Molecular Medicine Reports

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“…miR-335 serves as a tumor suppressor miRNA, is transcribed from the genomic region on chromosome 7q32.2 (76) and is downregulated in various human digestive malignancies, such as pancreatic carcinoma, hepatocellular carcinoma, colorectal cancer and gastric cancer (77)(78)(79)(80). A similar result was also observed in GBC patients.…”

Section: Tumor Suppressor Micrornassupporting

confidence: 67%

The role of microRNAs in gallbladder cancer

Yang

Zhang

et al. 2016

Molecular and Clinical Oncology

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Abstract. MicroRNAs (also referred to as miRNAs or miRs) play a crucial role in post-transcriptional gene regulation and serve as negative gene regulators by controlling a variety of target genes and regulating diverse biological processes, such as cell proliferation, invasion, migration and apoptosis. Aberrant expression of miRNAs is associated with the development and progression of cancer. Recent studies have reported that miRNAs may repress or promote the expression of cancer-related genes via several different signaling pathways in gallbladder cancer (GBC) patients and may function as tumor suppressors or oncogenes, thus providing a promising tool for the diagnosis and therapeutics of GBCs. In this review, we summarize the role of dysregulawted miRNA expression in the signaling pathways implicated in GBC and discuss the significant role of circulating miRNAs in GBC. Therefore, miRNAs may serve as novel therapeutic targets as well as diagnostic or prognostic markers in GBC.

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“…Furthermore, the loss of endodermal organ-specific expression of Foxa2 might lead to de-differentiation of mature cell types and acquisition of a more naïve proliferative cellular status. By contrast, silencing miR-335 and its host gene MEST by methylation might cause inappropriate upregulation of its target genes, such as Foxa2, Sox17 and Sox4, and promote tumor growth in several cancer forms (Dohi et al, 2013;Huang et al, 2012). Overall, our findings allow for new perspectives in several disease related aspects, both for cell replacement and cancer therapy.…”

mentioning

confidence: 92%

“…Thus, our SCF and FVF miR sensor ESC lines might be valuable tools for understand the relationship between endoderm TF expression and cell-fate specification. Future analysis might allow us to model the effect of different levels of miR-335 on endoderm cell-fate specification in ESC differentiation culture.Furthermore, several cancers, such as breast, brain, lung, pancreas and gastric cancers, are associated with differential miR-335 expression Polytarchou et al, 2012;Yan et al, 2012;Dohi et al, 2013; Lynch et al, 2012;Vickers et al, 2012). The function of miR-335 in tumor initiation and progression is controversial.…”

mentioning

confidence: 99%

miR-335 promotes mesendodermal lineage segregation and shapes a transcription factor gradient in the endoderm

et al. 2014

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Transcription factors (TFs) pattern developing tissues and determine cell fates; however, how spatio-temporal TF gradients are generated is ill defined. Here we show that miR-335 fine-tunes TF gradients in the endoderm and promotes mesendodermal lineage segregation. Initially, we identified miR-335 as a regulated intronic miRNA in differentiating embryonic stem cells (ESCs). miR-335 is encoded in the mesoderm-specific transcript (Mest) and targets the 3′-UTRs of the endoderm-determining TFs Foxa2 and Sox17. Mest and miR-335 are co-expressed and highly accumulate in the mesoderm, but are transiently expressed in endoderm progenitors. Overexpression of miR-335 does not affect initial mesendoderm induction, but blocks Foxa2-and Sox17-mediated endoderm differentiation in ESCs and ESC-derived embryos. Conversely, inhibition of miR-335 activity leads to increased Foxa2 and Sox17 protein accumulation and endoderm formation. Mathematical modeling predicts that transient miR-335 expression in endoderm progenitors shapes a TF gradient in the endoderm, which we confirm by functional studies in vivo. Taken together, our results suggest that miR-335 targets endoderm TFs for spatio-temporal gradient formation in the endoderm and to stabilize lineage decisions during mesendoderm formation.KEY WORDS: Foxa2, Sox17, Endoderm, Mesendoderm, miR-335, Mir335, Gastrulation, Mouse INTRODUCTIONThe first lineage decision during mouse development occurs when the morula develops to the blastocyst stage at embryonic day (E) 2.5-3.5 (Rossant and Tam, 2009). During this time, the inner cell mass (ICM) of the blastocyst segregates from the trophectoderm (TE) that will form the placenta. The ICM further develops to the epiblast epithelium that will give rise to all differentiated cell types in the mammalian body. At E6.5, gastrulation starts and pluripotent Oct4 + epiblast cells undergo epithelial-mesenchymal transition (EMT) to ingress into the posterior primitive streak (PS) region to form mesoderm and definitive endoderm (DE), whereas the remaining epiblast cells will form the ectoderm (Beddington and Robertson, 1999;Tam and Loebel, 2007;Zorn and Wells, 2009). Both EMT and mesendoderm differentiation are induced by Wnt/β-catenin and Nodal/TGFβ signaling in the mouse embryo Arnold and Robertson, 2009). Wnt/β-catenin signaling leads to the activation of target genes in the epiblast, such as the Forkhead transcription factor a2 (Foxa2) (Sasaki and Hogan, 1993;Monaghan et al., 1993;Sawada et al., 2005) and the T-box transcription factor Brachyury (T; Herrmann, 1991;Yamaguchi et al., 1999;Arnold et al., 2000), which mark distinct mesendodermal progenitor cell populations in the posterior epiblast (Burtscher and Lickert, 2009). Genetic lineage tracing experiments revealed that Foxa2 + and T + mesendoderm progenitors give rise to anterior and posterior mesendoderm populations, respectively (Uetzmann et al., 2008;Horn et al., 2012; Kumar et al., 2007;Verheyden et al., 2005); however, how lineageinappropriate TF expression is prevented after...

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Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma

Cited by 68 publications

References 22 publications

PAX6, a novel target of miR-335, inhibits cell proliferation and invasion in glioma cells

PAX6, a novel target of miR-335, inhibits cell proliferation and invasion in glioma cells

The role of microRNAs in gallbladder cancer

miR-335 promotes mesendodermal lineage segregation and shapes a transcription factor gradient in the endoderm

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