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microRNA-34a as a Therapeutic Agent against Human Cancer.

Saito Y, Nakaoka T, Saito H - J Clin Med (2015)

Bottom Line: Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis.Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells.Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. saito-ys@pha.keio.ac.jp.

ABSTRACT
microRNAs (miRNAs) are small non-coding RNAs that down-regulate expression of various target genes. Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis. We and other researchers have demonstrated that important tumor suppressor miRNAs are silenced by epigenetic alterations, resulting in the activation of target oncogenes in cancer cells. miR-34a was identified as a target of p53 and induces a G1 cell cycle arrest, senescence and apoptosis in response to DNA damage. miR-34a is an important tumor suppressor whose expression is epigenetically silenced in various human cancers. Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells. Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies. Restoring of miR-34a expression by epigenetic therapy and/or delivery of miR-34a mimics may be a promising therapeutic strategy against human cancer.

No MeSH data available.


Related in: MedlinePlus

Biogenesis of miR-34a. miR-34a genes are transcribed from TSS by RNA pol II to form pri-miR-34a, which is capped with 7-methylguanosine and polyadenylated (AAAAA). Drosha and its co-factor DGCR8 process pri-miR-34a into pre-miR-34a. Pre-miR-34a is transported into the cytoplasm and subsequently cleaved by Dicer into mature miRNAs. Mature miR-34a is then loaded into RISC, where miR-34a down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′UTR of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.
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jcm-04-01951-f001: Biogenesis of miR-34a. miR-34a genes are transcribed from TSS by RNA pol II to form pri-miR-34a, which is capped with 7-methylguanosine and polyadenylated (AAAAA). Drosha and its co-factor DGCR8 process pri-miR-34a into pre-miR-34a. Pre-miR-34a is transported into the cytoplasm and subsequently cleaved by Dicer into mature miRNAs. Mature miR-34a is then loaded into RISC, where miR-34a down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′UTR of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.

Mentions: The miR-34a gene is located at the chromosome 1p36 locus. As shown in Figure 1, the miR-34a gene is transcribed from a transcription start site located in the CpG island by RNA polymerase II (pol II) to form primary transcript (pri-miR-34a). DNA hypermethylation of the CpG island promoter region is one of the most common reasons for silencing of miR-34a [9,10]. Pol II-transcribed pri-miR-34a is capped with 7-methylguanosine and is polyadenylated. The nuclear RNase III enzyme Drosha and its co-factor DGCR8 process pri-miR-34a into precursor miR-34a (pre-miR-34a), which forms an imperfect stem-loop structure. Pre-miR-34a is transported into the cytoplasm by exportin 5 and subsequently cleaved by Dicer into mature miR-34a, which is then loaded into the RNA-induced silencing complex (RISC). The miR-34a/RISC complex down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′-untranslated regions (UTRs) of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.


microRNA-34a as a Therapeutic Agent against Human Cancer.

Saito Y, Nakaoka T, Saito H - J Clin Med (2015)

Biogenesis of miR-34a. miR-34a genes are transcribed from TSS by RNA pol II to form pri-miR-34a, which is capped with 7-methylguanosine and polyadenylated (AAAAA). Drosha and its co-factor DGCR8 process pri-miR-34a into pre-miR-34a. Pre-miR-34a is transported into the cytoplasm and subsequently cleaved by Dicer into mature miRNAs. Mature miR-34a is then loaded into RISC, where miR-34a down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′UTR of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663478&req=5

jcm-04-01951-f001: Biogenesis of miR-34a. miR-34a genes are transcribed from TSS by RNA pol II to form pri-miR-34a, which is capped with 7-methylguanosine and polyadenylated (AAAAA). Drosha and its co-factor DGCR8 process pri-miR-34a into pre-miR-34a. Pre-miR-34a is transported into the cytoplasm and subsequently cleaved by Dicer into mature miRNAs. Mature miR-34a is then loaded into RISC, where miR-34a down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′UTR of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.
Mentions: The miR-34a gene is located at the chromosome 1p36 locus. As shown in Figure 1, the miR-34a gene is transcribed from a transcription start site located in the CpG island by RNA polymerase II (pol II) to form primary transcript (pri-miR-34a). DNA hypermethylation of the CpG island promoter region is one of the most common reasons for silencing of miR-34a [9,10]. Pol II-transcribed pri-miR-34a is capped with 7-methylguanosine and is polyadenylated. The nuclear RNase III enzyme Drosha and its co-factor DGCR8 process pri-miR-34a into precursor miR-34a (pre-miR-34a), which forms an imperfect stem-loop structure. Pre-miR-34a is transported into the cytoplasm by exportin 5 and subsequently cleaved by Dicer into mature miR-34a, which is then loaded into the RNA-induced silencing complex (RISC). The miR-34a/RISC complex down-regulates specific gene products by translational repression via binding to partially complementary sequences in the 3′-untranslated regions (UTRs) of the target mRNAs such as CD44 or by directing mRNA degradation via binding to perfectly complementary sequences.

Bottom Line: Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis.Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells.Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. saito-ys@pha.keio.ac.jp.

ABSTRACT
microRNAs (miRNAs) are small non-coding RNAs that down-regulate expression of various target genes. Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis. We and other researchers have demonstrated that important tumor suppressor miRNAs are silenced by epigenetic alterations, resulting in the activation of target oncogenes in cancer cells. miR-34a was identified as a target of p53 and induces a G1 cell cycle arrest, senescence and apoptosis in response to DNA damage. miR-34a is an important tumor suppressor whose expression is epigenetically silenced in various human cancers. Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells. Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies. Restoring of miR-34a expression by epigenetic therapy and/or delivery of miR-34a mimics may be a promising therapeutic strategy against human cancer.

No MeSH data available.


Related in: MedlinePlus