MicroRNA Expression Profiling and DNA Methylation Signature for Deregulated MicroRNA in Cutaneous T-Cell Lymphoma

Abstract

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.

Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides

“…Recently, we have reported a microRNA signature for MFt (Sandoval et al, 2015), highly concordant with other reported in the literature (van Kester et al, 2011). No discordances were found in up or downregulated microRNAs and most of upregulated microRNAs in our cohort of MFt were described previously.…”

“…Several epigenetically disrupted genes and microRNAs have been identified in MFt (Sandoval et al, 2015;Jones et al, 2014;Ferrara et al, 2012;Gallardo et al, 2004). Thus we analysed the possible association between Notch activation in MFt and the DNA methylation patterns at Notch1 pathway associated genes.…”

“…Specific epigenetic mechanisms have been identified as responsible to activate Notch signaling in different malignancies with no detectable Notch genomic abnormalities (Wong et al, 2011). Among them, CpG islands methylation at both coding genes and microRNAs have been associated with CTCLs but also with other types of cancer (Sandoval et al, 2015;Esteller, 2008;Quintavalle et al, 2013). Promoter DNA methylation is a general epigenetic mechanism that plays a central role in the coordination of gene transcription in healthy normal cells.…”

miR-141-3p Suppresses Expression of Androgen Receptors and Functions as a Tumor Suppressor Gene in Prostate Carcinogenesis

“…Using deep-sequencing analysis, we found that miR-141-3p expression was decreased by 1.26-fold in early PCa compared to that in BPH (P < 0.05), and confirmed a similar 1.17-fold decrease in early PCa compared to that in BPH (P = 0.2053) by qRT-PCR. In addition, miR-141-3p expression levels vary in different tumors, with overexpression observed in bladder [16], urothelial [17], breast [18] [19], ovarian [20], endometrioid [21], cholangiocytes [22] and colorectal cancers [23] and NSCLC [24], while expression is downregulated in gastric cancer [25], hepatocellular carcinomas [26] [27], renal cell carcinoma [28], lymphatic metastatic pancreatic cancer [29], pituitary tumors [30], craniopharyngioma [31], head and neck cancer [32], osteosarcoma [33], and cutaneous T cell lymphoma [34]. These reports provide compelling evidence for a role of miR-141-3p as an oncogene or tumor suppressor in different tumors and at different stages.…”

Distinct miRNA profile in prognosis of early CTCL

“…This important task may prove particularly challenging, given the vast mutational diversity reported in MF and Sézary syndrome, a type of CTCL closely related to MF. [5][6][7][8][9][10] In summary, identification of the predictive set of 3 miRNAs holds promise of early stratification of MF patients into groups with high and low risk of progression. However, a number of questions need to be answered before the true significance of this novel classifier and its potential impact on clinical care of MF patients can be fully determined.…”