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Hypermethylation-mediated inactivation of miR-124 predicts poor prognosis and promotes tumor growth at least partially through targeting EZH2/H3K27me3 in ESCC

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Abstract

Accumulating evidences indicated that some microRNAs (miRNAs) play a critical role during the carcinogenesis. In the present study, we found that miR-124 is down-regulated in esophageal squamous cell carcinoma (ESCC) tissues. Three miR-124 encoding genes, including mir-124-1, mir-124-2, and mir-124-3, harboring CpG islands undergo methylation-mediated miR-124 inactivation in ESCC tissues. The methylation status of all these three genes was negatively associated with the expression of miR-124. The low expression of miR-124 and the hypermethylation of mir-124-1 and mir-124-3 were associated with the clinico-pathological parameters indicating the poor prognosis. In addition, promoter methylation of all three genes plus low expression of miR-124 was the independent poor prognostic marker for ESCC patients. In conclusion, miR-124 may function as a tumor suppressive miRNA, and hypermethylation-mediated inactivation of miR-124 may be useful for a poor prognostic marker for ESCC patients.

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Abbreviations

miRNAs:

microRNAs

ESCC:

Esophageal squamous cell carcinoma

EAC:

Esophageal adenocarcinoma

3′UTRs:

3′ Untranslated regions

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Acknowledgements

This work was supported by the Grants from the Ordinary University Considerable Distinctive Subjects Foundation of Hebei Province (No. 200552).

Funding

This work was supported by National Nature Science Foundation of China (No. 81001178), and Science Foundation of Hebei Province (No. 16967788D).

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Authors and Affiliations

  1. Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China

    Ziqiang Tian, Zhenhua Li, Yonggang Zhu & Guiying Wang

  2. Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China

    Lingjiao Meng, Fei Liu & Meixiang Sang

  3. The Second Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, People’s Republic of China

    Guiying Wang

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  1. Ziqiang Tian
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  2. Zhenhua Li
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Correspondence to Guiying Wang.

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10585_2019_9974_MOESM1_ESM.tif

Supplementary Fig. 1. The expression of miR-124-3p and EZH2 in ESCC cell lines. (A) The expression of miR-124-3p and EZH2 in four ESCC cell lines was detected by qRT-PCR. (B) The correlation between EZH2 and miR-124-3p expression in above four ESCC cell lines. Supplementary material 1 (TIFF 24 kb)

10585_2019_9974_MOESM2_ESM.png

Supplementary Fig. 2. The expression of miR-124 using 5S rRNA as an internal reference gene in primary tumor specimens. (A) Relative expression of miR-124-3p in ESCC tissues and corresponding normal tissues. Data are expressed as the Mean ± SEM of three independent replicate experiments (6.32 ± 0.21 vs. 3.12 ± 0.14, P < 0.001). (B) The expression of miR-124-3p was correlated with the tumor infiltration, lymphode metastasis, distant metastasis or recurrence, and clinical stage. Data are expressed as the Mean ± SEM of three independent replicate experiments (4.52 ± 0.20 vs. 2.24 ± 0.11, P < 0.001; 4.42 ± 0.18 vs. 3.26 ± 0.17, P < 0.01; 3.72 ± 0.12 vs. 2.17 ± 0.11, P < 0.001; 3.86 ± 0.16 vs. 2.37 ± 0.14, P < 0.001). (C) Relative expression of miR-124 in mir-124-1, mir-124-2, mir-124-3 methylation or unmethylation ESCC tissues. Data are expressed as the Mean ± SEM of three independent replicate experiments (4.16 ± 0.27 vs. 2.95 ± 0.15, P < 0.001; 4.43 ± 0.27 vs. 3.06 ± 0.13, P < 0.001; 4.97 ± 0.26 vs. 3.13 ± 0.14, P < 0.001). Supplementary material 2 (PNG 58 kb)

Supplementary material 3 (DOCX 14 kb)

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Tian, Z., Li, Z., Zhu, Y. et al. Hypermethylation-mediated inactivation of miR-124 predicts poor prognosis and promotes tumor growth at least partially through targeting EZH2/H3K27me3 in ESCC. Clin Exp Metastasis 36, 381–391 (2019). https://doi.org/10.1007/s10585-019-09974-1

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