Epigenetic Silencing of MiR-335 and Its Host Gene MEST in Hepatocellular Carcinoma

Overview

Journal Int J Oncol

Specialty Oncology

Date 2012 Dec 12

PMID 23229728

Citations 47

Authors

Osamu Dohi

Kohichiroh Yasui

Yasuyuki Gen

Hisashi Takada

Mio Endo

Kazuhiro Tsuji

Chika Konishi

Nobuhisa Yamada

Hironori Mitsuyoshi

Nobuaki Yagi

Yuji Naito

Shinji Tanaka

Shigeki Arii

Toshikazu Yoshikawa

Affiliations

Soon will be listed here.

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of target genes. Some tumor-suppressive miRNAs are known to be epigenetically silenced by promoter DNA methylation in cancer. In the present study, we aimed to identify miRNA genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for miRNA genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in HCC cells. It was found that miR-335, which is harbored within an intron of its protein-coding host gene, MEST, was downregulated by aberrant promoter hypermethylation via further methylation assays, including methylation-specific PCR, combined bisulfite and restriction analysis, bisulfite sequencing analysis and 5-aza-2'-deoxycytidine treatment. The expression levels of miR-335 significantly correlated with those of MEST, supporting the notion that the intronic miR-335 is co-expressed with its host gene. The levels of miR-335/MEST methylation were significantly higher in 18 (90%) out of 20 primary HCC tumors, compared to their non-tumor tissue counterparts (P<0.001). The expression levels of miR-335 were significantly lower in 25 (78%) out of 32 primary HCC tumors, compared to their non-tumor tissue counterparts (P=0.001). Furthermore, the expression levels of miR-335 were significantly lower in HCC tumors with distant metastasis compared to those without distant metastasis (P=0.02). In conclusion, our results indicate that expression of miR-335 is reduced by aberrant DNA methylation in HCC.

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References

Hatada I, Morita S, Kimura M, Horii T, Yamashita R, Nakai K . Genome-wide demethylation during neural differentiation of P19 embryonal carcinoma cells. J Hum Genet. 2008; 53(2):185-191. DOI: 10.1007/s10038-007-0228-0. View

Hatada I, Namihira M, Morita S, Kimura M, Horii T, Nakashima K . Astrocyte-specific genes are generally demethylated in neural precursor cells prior to astrocytic differentiation. PLoS One. 2008; 3(9):e3189. PMC: 2527128. DOI: 10.1371/journal.pone.0003189. View

Xiong Z, Laird P . COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res. 1997; 25(12):2532-4. PMC: 146738. DOI: 10.1093/nar/25.12.2532. View

Zen K, Yasui K, Nakajima T, Zen Y, Zen K, Gen Y . ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry. Genes Chromosomes Cancer. 2008; 48(2):109-20. DOI: 10.1002/gcc.20624. View

Dohi O, Takada H, Wakabayashi N, Yasui K, Sakakura C, Mitsufuji S . Epigenetic silencing of RELN in gastric cancer. Int J Oncol. 2009; 36(1):85-92. View

Shu M, Zheng X, Wu S, Lu H, Leng T, Zhu W . Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol Cancer. 2011; 10:59. PMC: 3129318. DOI: 10.1186/1476-4598-10-59. View

Scarola M, Schoeftner S, Schneider C, Benetti R . miR-335 directly targets Rb1 (pRb/p105) in a proximal connection to p53-dependent stress response. Cancer Res. 2010; 70(17):6925-33. DOI: 10.1158/0008-5472.CAN-10-0141. View

Hatada I, Fukasawa M, Kimura M, Morita S, Yamada K, Yoshikawa T . Genome-wide profiling of promoter methylation in human. Oncogene. 2006; 25(21):3059-64. DOI: 10.1038/sj.onc.1209331. View

Tavazoie S, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos P . Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008; 451(7175):147-52. PMC: 2782491. DOI: 10.1038/nature06487. View

10.

Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2):281-97. DOI: 10.1016/s0092-8674(04)00045-5. View

11.

Michael M, O Connor S, van Holst Pellekaan N, Young G, James R . Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003; 1(12):882-91. View

12.

Kim Y, Kim V . Processing of intronic microRNAs. EMBO J. 2007; 26(3):775-83. PMC: 1794378. DOI: 10.1038/sj.emboj.7601512. View

13.

Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H . Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004; 64(11):3753-6. DOI: 10.1158/0008-5472.CAN-04-0637. View

14.

Xu P, Guo M, Hay B . MicroRNAs and the regulation of cell death. Trends Genet. 2004; 20(12):617-24. DOI: 10.1016/j.tig.2004.09.010. View

15.

Rodriguez A, Griffiths-Jones S, Ashurst J, Bradley A . Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004; 14(10A):1902-10. PMC: 524413. DOI: 10.1101/gr.2722704. View

16.

Tome M, Lopez-Romero P, Albo C, Sepulveda J, Fernandez-Gutierrez B, Dopazo A . miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells. Cell Death Differ. 2010; 18(6):985-95. PMC: 3131940. DOI: 10.1038/cdd.2010.167. View

17.

Kozaki K, Inazawa J . Tumor-suppressive microRNA silenced by tumor-specific DNA hypermethylation in cancer cells. Cancer Sci. 2012; 103(5):837-45. PMC: 7659391. DOI: 10.1111/j.1349-7006.2012.02236.x. View

18.

He L, Hannon G . MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004; 5(7):522-31. DOI: 10.1038/nrg1379. View

19.

Bosch F, Ribes J, Cleries R, Diaz M . Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005; 9(2):191-211, v. DOI: 10.1016/j.cld.2004.12.009. View

20.

Calin G, Dumitru C, Shimizu M, Bichi R, Zupo S, Noch E . Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002; 99(24):15524-9. PMC: 137750. DOI: 10.1073/pnas.242606799. View