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. 2011 Mar;6(3):388-94.
doi: 10.4161/epi.6.3.14056. Epub 2011 Mar 1.

Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma

Tung Nguyen  1 , Christine Kuo, Michael B Nicholl, Myung-Shin Sim, Roderick R Turner, Donald L Morton, Dave S B Hoon
Affiliations

Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma

Tung Nguyen et al. Epigenetics. 2011 Mar.

Abstract

Hypermethylation of the promoter region of tumor-related genes (TRGs) has been shown to silence gene expression during melanoma progression, whereas microRNA-29(miR-29) has been found to downregulate DNA methyltransferases DNMT3A and DNMT3B which were shown as essential to the methylation of TRGs. We hypothesized that the expression level of miR-29 is associated to TRG methylation status and may have prognostic utility in melanoma. AJCC stage I-IV cutaneous melanoma paraffin-embedded archival tissue (PEAT) specimens (n=149) were assessed. Expression of miR-29 isoforms a, b, and c were analyzed by reverse-transcription quantitative real-time polymerase chain reaction(RT-qPCR). Expression of DNMT3A and DNMT3B was assessed by immunohistochemistry(IHC) on defined clinically annotated tissue microarrays (TMA) of AJCC stage III melanoma lymph node metastases. Promoter region CpG island methylation status of RASSF1A, TFPI-2, RAR-β, SOCS, GATA4 and genomic repeat sequence MINT17 and MINT31 were previously evaluated in melanoma tissues. Only miR-29c isoform expression was correlated to advancing AJCC stages in melanoma. miR-29c expression was significantly downregulated in AJCC stage IV melanoma tumors compared to primary melanomas. Hypermethylation status of TRGs and non-coding MINT loci in different stages of melanoma showed an inverse association with miR-29c expression. Overall, an increase in miR-29c expression inversely correlated to both DNMT3A and DNMT3B protein expression in melanomas. Expression of DNMT3B and miR-29c were significantly (p=0.004 and p=0.002, respectively) associated with overall survival(OS) in AJCC stage III melanoma patients by multivariate analysis. The studies demonstrated that both miR-29c and DNMT3B have significant roles in melanoma progression, and may be useful epigenetic biomarkers for disease outcome.

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Figures

Figure 1
Figure 1
Expression of miR-29 in AJCC stage I and II primary melanomas (n = 11) versus stage III and IV metastatic melanomas (n = 8). Assessments of miR-29a (A) and miR-29b (B) show no significance between primary tumors and metastases. Expression of miR-29c (C) decreases in AJCC stage III and IV melanoma metastases versus stage I and II primary melanomas.
Figure 2
Figure 2
Comparing expression levels of miR-29c in AJCC stage I and II primary melanomas (n = 15) versus stage III LN metastases (n = 16) (p = 0.02) or stage IV distant metastases (n = 31) (p = 0.006).
Figure 3
Figure 3
Representative IHC staining with DNMT3A and DNMT3B antibodies. DNMT3A (A) and DNMT3B (B) are highly expressed in stage IV metastatic melanoma. (C) is the no-primary antibody control for the stage IV metastatic melanoma. DNMT3A (D) and DNMT3B (E) are weakly expressed in primary melanoma. (F) is the no-primary antibody control for the primary melanoma.
Figure 4
Figure 4
Box plots comparing IHC staining intensity of AJCC stage I and II primary tumors (n = 6), stage III metastatic tumors (n = 7) and stage IV metastatic tumors (n = 5) of DNMT3A (A) and DNMT3B (B).
Figure 5
Figure 5
Kaplan-Meier curve analysis of AJCC stage III patients grouped by high and low miR-29c (n = 87) and DNMT3B (n = 81) expression in their LN metastases: DFS (A) and OS (B) of miR-29c expression as assessed by RT-qPCR and OS (C) of DNMT3B IHC staining levels.
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