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DNA Methylation of MicroRNA-124a Is a Potential Risk Marker of Colitis-Associated Cancer in Patients with Ulcerative Colitis

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Abstract

Background

Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation.

Aim

We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients.

Methods

Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry.

Results

Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3 %, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2 %, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors.

Conclusions

MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC.

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Abbreviations

UC:

Ulcerative colitis

CAC:

Colitis-associated cancer

ER:

Estrogen receptor

miRNA:

MicroRNAs

CDK6:

Cyclin-dependent kinase 6

S-CRC:

Sporadic colorectal cancer

MSP:

Methylation-specific polymerase chain reaction

PCR:

Polymerase chain reaction

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Yuko Ueda, Takayuki Ando, Sohachi Nanjo & Toshiro Sugiyama

  2. Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo, Japan

    Toshikazu Ushijima

Authors
  1. Yuko Ueda
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  2. Takayuki Ando
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  3. Sohachi Nanjo
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  4. Toshikazu Ushijima
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  5. Toshiro Sugiyama
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Correspondence to Toshiro Sugiyama.

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Ueda, Y., Ando, T., Nanjo, S. et al. DNA Methylation of MicroRNA-124a Is a Potential Risk Marker of Colitis-Associated Cancer in Patients with Ulcerative Colitis. Dig Dis Sci 59, 2444–2451 (2014). https://doi.org/10.1007/s10620-014-3193-4

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  • DOI: https://doi.org/10.1007/s10620-014-3193-4

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