The Interplay Between miR-148a and DNMT1 Might be Exploited for Pancreatic Cancer Therapy

Zhan, Qimin; Fang, Yuan; Deng, Xiaxing; Chen, Hao; Jin, Jianbin; Lü, Xiang; Peng, Chenghong; Li, Hongwei; Shen, Baiyong

doi:10.3109/07357907.2015.1025794

Cited by 22 publications

(21 citation statements)

References 20 publications

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“…miR-148a-3p is located at the 7p15.2 chromosomal region, which has been implicated to act as a tumor suppressor in many cancers. 27, 28, 29, 30 Recent studies indicated that miR-148a suppressed the BMP signaling pathway in cancer progression and suppressed cancer cell invasion and metastasis in gastric cancer. 31, 32, 33 It has been reported that miR-148a suppresses hepatocellular carcinoma cell EMT and metastasis by targeting Met/snail signaling.…”

Section: Discussionmentioning

confidence: 99%

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

Wang

Liang

et al. 2016

Cell Death Dis

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miR-148a-3p downregulation has emerged as a critical factor in cancer progression yet, the underlying mechanisms of miR-148a-3p expression pattern and its function in bladder cancer remains to be elucidated. Here, we illustrate that miR-148a-3p is frequently downregulated in bladder cancer and that its expression may be regulated by DNA methylation. DNA methyltransferase 1 (DNMT1) and miR-148a-3p function in a positive feedback loop in bladder cancer. miR-148a-3p overexpression functions as a tumor suppressor in bladder cancer cells. miR-148a-3p inhibits bladder cancer cell proliferation and epithelial–mesenchymal transition (EMT) by regulating ERBB3/AKT2/c-myc and ERBB3/AKT2/Snail signaling. ERBB3, DNMT1 and AKT2 are downstream miR-148a-3p target genes. Furthermore, the miR-148a-3p/ERBB3/AKT2/c-myc signaling axis establishes a positive feedback loop in the regulation of bladder cancer. Taken together, our study demonstrates novel regulatory circuits involving miR-148a-3p/ERBB3/AKT2/c-myc and DNMT1 that controls bladder cancer progression, which may be useful in the development of more effective therapies against bladder cancer.

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Section: Discussionmentioning

confidence: 99%

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

Wang

Liang

et al. 2016

Cell Death Dis

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“…In recent studies, aberrant DNMT1 expression has been shown to induce miR-148a silencing and DNMT1 has been shown to be a target of miR-148a in several tumor types [27]. Therefore, miRNA-148a upregulation reduces DNMT1 expression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-148a overexpression improves the early development of porcine somatic cell nuclear transfer embryos

Wang

Cao

et al. 2017

PLoS ONE

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Incomplete epigenetic reprogramming of donor cell nuclei is one of the main contributors to the low efficiency of somatic cell nuclear transfer (SCNT). To improve the success of SCNT, somatic cell DNA methylation levels must be reduced to those levels found in totipotent embryonic cells. Recent studies have demonstrated that miR-148a can affect DNA methylation via DNMT1 modulation in various cancers. Therefore, the focus of this study was to examine the influence of miR-148a on DNA methylation in donor cells and in SCNT embryo development. Thus, a stable cell line overexpressing miR-148a was established and used to produce SCNT embryos. Upon examination, DNMT1 was found to be a miR-148a target in porcine fetal fibroblasts (PFF). Furthermore, miR-148a overexpression in PFFs significantly decreased DNMT1 expression and global DNA methylation levels (P < 0.05). Moreover, miRNA-148a expression levels in SCNT embryos were significantly lower at the 2-cell and 4-cell stages when compared to IVF and parthenogenetic embryos. The group overexpressing miRNA-148a also showed a significant increase in blastocyst formation and total cell numbers (P < 0.05). Additionally, miR-148a overexpression altered the immunofluorescence signal of 5-mC and H3K9ac, and enhanced pluripotent gene (Oct4 and Nanog) expression levels during embryo development. These results indicate that miR-148a overexpression enhances the developmental potential of SCNT embryos and modifies epigenetic status.

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“…Previous reports have demonstrated that DNMT1 is overexpressed in pancreatic cancer tissues and cell lines; furthermore, increased DNMT1 expression is markedly correlated with poor prognosis (18,19). DNMT1 has also been verified as a target for miR-148a in gastric (20) and breast cancer (5), and hepatocellular carcinoma (21) and pancreatic cancer (12). Furthermore, hypermethylation of the miR-148a promoter is associated with DNMT1 overexpression in pancreatic cancer (12).…”

Section: The Interaction Between Mir-148a and Dnmt1 Suppresses Cell Mmentioning

confidence: 93%

“…miR-148a is also downregulated in pancreatic cancer tissues and several pancreatic cell lines (10,11). In addition, DNA methyltransferase 1 (DNMT1) (12), cholecystokinin b receptor (13), b-cell lymphoma 2 (13), cell division cycle 25b (14) and erb-b2 receptor tyrosine kinase 3 (15) have been identified as target genes of miR-148a. DNA methylation is one of the epigenetic mechanisms affecting cell fate via the regulation of gene expression.…”

Section: The Interaction Between Mir-148a and Dnmt1 Suppresses Cell Mmentioning

confidence: 99%

“…DNMT1 has also been verified as a target for miR-148a in gastric (20) and breast cancer (5), and hepatocellular carcinoma (21) and pancreatic cancer (12). Furthermore, hypermethylation of the miR-148a promoter is associated with DNMT1 overexpression in pancreatic cancer (12). Therefore, the interaction between miR-148a and DNMT1 may regulate the expression of TSGs in pancreatic cancer.…”

Section: The Interaction Between Mir-148a and Dnmt1 Suppresses Cell Mmentioning

confidence: 99%

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The interaction between miR‑148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer

et al. 2018

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DNA methylation is an epigenetic mechanism that cells use to control gene expression, which serves an important role in tumorigenesis. DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of the pattern of DNA methylation. Overexpression of DNMT1 is observed in numerous malignant tumors, including pancreatic cancer, and results in silencing of several key tumor suppressor genes (TSGs). Recent studies have suggested that microRNAs (miRNAs/miRs) contribute to the regulation of DNMT1 expression, and promoter hypermethylation caused by DNMT1 overexpression is associated with the dysfunction of some miRNAs. The present study aimed to reveal the interaction between miR‑148a and DNMT1, and its effects on cell proliferation, migration and invasion of pancreatic cancer cells. Initially, the expression levels of DNMT1 and miR‑148a were detected in pancreatic cancer tissues and AsPC‑1 cells by reverse transcription‑quantitative polymerase chain reaction (PCR). Secondly, the regulatory effects of DNMT1 on miR‑148a were evaluated using methylation‑specific PCR. Furthermore, bioinformatics analysis and dual luciferase reporter assay were used to verify the target relationship between miR‑148a and DNMT1. Finally, in vitro rescue experiments were conducted to evaluate the effects of miR‑148a on the expression of TSGs and the malignant phenotype in AsPC‑1 cells. The results demonstrated that DNMT1 was aberrantly upregulated in pancreatic cancer, and was responsible for hypermethylation of the miR‑148a promoter. Furthermore, DNMT1 was revealed as a direct target of miR‑148a by dual luciferase reporter assay, and restoration of miR‑148a could reactivate TSGs, such as p16, preproenkephalin and Ras association domain family member 1 by targeting DNMT1 in the AsPC‑1 pancreatic cancer cell line. These results indicated that an interaction exists between miR‑148a and DNMT1 in pancreatic cancer. Notably, miR‑148a overexpression significantly inhibited cell proliferation, migration and invasion in AsPC‑1 cells. Therefore, miR‑148a may serve as a novel therapeutic target for the treatment of pancreatic cancer.

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The Interplay Between miR-148a and DNMT1 Might be Exploited for Pancreatic Cancer Therapy

Cited by 22 publications

References 20 publications

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

MicroRNA-148a overexpression improves the early development of porcine somatic cell nuclear transfer embryos

The interaction between miR‑148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer

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