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MicroRNA Expression Profiles in Thyroid Tumors


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  • 1. Endocr Pathol (2009) 20:85–91 DOI 10.1007/s12022-009-9069-z MicroRNA Expression Profiles in Thyroid Tumors Marina N. Nikiforova & Simon I. Chiosea & Yuri E. Nikiforov Published online: 8 April 2009 # Humana Press Inc. 2009 Abstract MicroRNAs (miRNAs) constitute a recently iden- [1]. miRNAs regulate gene expression by mechanism tified class of small endogenous noncoding RNAs that similar to short interfering RNA (siRNA), i.e., through act as negative regulators of the protein-coding gene complementary binding to 3′ untranslated region (UTR) of expression and may impact cell differentiation, proliferation target mRNA and using RNA interference (RNAi) pathway and survival, i.e., all fundamental cellular processes impli- (Fig. 1). However, miRNA and siRNA are quite distinct; cated in carcinogenesis. miRNA expression is deregulated in major differences in their structure and function are many types of human cancers, including thyroid cancer. The depicted in Table 1. miRNAs genes are estimated to purpose of this review is to summarize the existing findings account for 2–5% of human genes [2]. Many miRNA of miRNA deregulation in thyroid tumors and its potential genes are located within introns and exons of protein- role in thyroid cancer biology and molecular diagnostics. coding genes and in the intergenic regions. Frequently, miRNAs are located in clusters and transcribed as poly- Keywords microRNA (miRNA) . thyroid . cancer . cistrons and, therefore, have similar expression patterns [2, microarray 3]. For example, miR-221 and miR-222 are in one cluster located on chromosome X, and this explains their concor- dant expression patterns in several human carcinomas, Introduction including thyroid carcinomas [3]. Production and function of miRNAs involves multiple The central dogma of molecular biology, which describes steps and requires a large set of proteins [2] (Fig. 2). First, a the relationship between DNA that stores genetic informa- miRNA gene is transcribed by RNA polymerases II into a tion in the form of individual genes, their transcription into long hairpin structure known as primary miRNA (pri- messenger RNA (mRNA), and translation into protein, was miRNA) [4, 5]. The latter is processed by RNAse III recently challenged by the discovery of a new class of enzyme Drosha and its RNA binding partner DGCR8 into regulatory molecules—microRNAs (miRNAs). miRNAs an about 70-nucleotide-long precursor miRNA (pre- are coded by miRNA genes, which are transcribed into miRNA) [6] before nuclear export by Exportin-5 [7, 8]. In small (∼22 nt) single-stranded RNA molecules that are not the cytoplasm, pre-miRNA undergoes further processing by further translated into proteins. Instead, they function as the endonuclease enzyme Dicer into mature miRNA. negative regulator of coding gene expression and may Mature miRNA is incorporated into RNA-induced silencing impact cell differentiation, proliferation, and survival, all complex (RISC), an enzyme complex guiding the endonu- fundamental cellular processes implicated in carcinogenesis cleolytic activity of RNAi pathway [9], and binds to the 3′ untranslated region of mRNA. If the miRNA has perfect M. N. Nikiforova (*) : S. I. Chiosea : Y. E. Nikiforov complementarity to the 3′ UTR region of the target mRNA, Department of Pathology, it induces the mRNA cleavage. If the miRNA and mRNA University of Pittsburgh School of Medicine, do not match perfectly, it results in translational repression 200 Lothrop Street, Pittsburgh, PA 15213, USA and inhibition of protein synthesis (Fig. 2). The nonperfect e-mail: complementarity allows a single miRNA to target multiple
  • 2. 86 Endocr Pathol (2009) 20:85–91 DNA loss of heterozygosity, and breakpoint regions implicating RNAi Pathway genomic abnormalities as a cause of miRNA deregulation Transcription miRNA [16]. Some data support the existence of epigenetic reg- ulation of miRNA expression, such as by DNA hypo- methylation or hypermethylation of CpG islands in the mRNA miRNA promoter regions and by histone modification [17, 18]. Transcriptional factors may also be involved and Translation induce miRNA expression by activating the transcription of miRNA precursor (pri-miRNA) [19, 20]. Deregulation of the miRNA processing steps is documented in several Protein human cancers [21, 22] and may lead to changes in miRNA expression in a given neoplastic cell. Fig. 1 miRNA regulation of gene expression through the RNAi pathway miRNA Deregulation in Thyroid Cancer genes. It was approximated that one miRNA can potentially regulate more than 200 different genes. On the other hand, Most thyroid carcinomas originate from thyroid follicular many individual genes have in their 3′ UTR predicted target cells. The two most common cancer types are well- sites for multiple miRNAs, indicating the likelihood of a differentiated papillary carcinoma (PC) and follicular carci- combinatory action of several miRNAs on gene activity. noma (FC); the latter is further subclassified into conventional miRNA deregulation is common in cancer cells, and a and oncocytic types. Both PCs and FCs may progress to rapidly growing pool of studies provides evidence for poorly differentiated carcinoma (PDC) or may completely miRNA involvement in carcinogenesis. Specific subsets of loose differentiation and transform to anaplastic carcinoma overexpressed and downregulated miRNAs have been (AC). Follicular adenoma (FA) is a benign thyroid tumor and identified in various tumor types, suggesting that aberration can be of either conventional or oncocytic types. Medullary in miRNA expression is important in tumor development carcinoma (MC) originates from the thyroid C cells and and progression. Overexpression of a miRNAs could result accounts for less than 5% of thyroid tumors. in downregulation of tumor suppressor genes (oncogenic Our current understanding of miRNA deregulation in miRNAs or oncomiRs), and underexpression of miRNAs thyroid carcinomas is based on several independent studies could lead to upregulation of oncogenes (suppressor that collectively analyzed more than 200 thyroid tumors miRNAs) with subsequent effects on cell proliferation, [23–29]. Snap-frozen tissue was the most commonly used apoptosis, angioinvasion, and other carcinogenic actions miRNA source; however, the utility of formalin-fixed (Fig. 3). The list of miRNAs with known cancer gene paraffin-embedded (FFPE) tissue for miRNA analysis was targets is rapidly growing [10]. For example, let-7 nega- validated in a variety of human tissues [30] including tively regulates Ras [11], miR-221 and miR-222 down- thyroid [26, 27, 29]. regulate KIT receptor [12] and CDKN1B (p27/Kip1) Analysis of miRNA expression in normal thyroid tissue protein, a key player in cell cycle control [13], and miR- and in major types of thyroid tumors revealed that majority 16-1 and miR-15a downregulate BCL2 [14]. Unique of known miRNAs were expressed in normal thyroid signatures of miRNA expression are described in a variety tissues, whereas in thyroid neoplasms 32% of miRNAs of epithelial and lymphoid malignancies [15]. were found to be consistently upregulated, and 38% were The mechanisms of miRNA deregulation in neoplastic downregulated with more than a 2-fold change as compared cells are not well understood. miRNA genes appeared to be to normal tissue [24]. There was no global downregulation commonly mapped to minimal regions of amplification, of miRNA expression in less differentiated carcinomas Table 1 Comparison of miRNA and siRNA origin and function miRNA siRNA Size 18–24 nt 18–24 nt Origin Endogenous (miRNA genes) Endogenous or exogenous ds RNA (no siRNA genes) Conservation Phylogenetically conserved No conservation Target Regulate thousands of endogenous genes Few targets, usually exogenous (i.e., viral) Effect mRNA cleavage or translational repression mRNA cleavage
  • 3. Endocr Pathol (2009) 20:85–91 87 Cytoplasm Nucleus DICER pre-miRNA miRNA DGCR8 duplex DROSHA 5’ Cap AAAAA pri-miRNA Mature RNA Pol II miRNA miRNA gene RISC Partial Complementarity Perfect Complementarity RISC RISC ORF Target mRNA Target mRNA Translation Repression mRNA Cleavage Fig. 2 Schematic representation of the miRNA biogenesis. miRNA into mature miRNA by the endonuclease enzyme Dicer. Mature gene is transcribed by RNA polymerases II into primary miRNA (pri- miRNA is incorporated into the RISC and binds to the 3′ untranslated miRNA). The latter is processed by RNAse III enzyme Drosha and its region of mRNA. If the miRNA has perfect complementarity to the 3′ RNA binding partner DGCR8 into 70-nt-long pre-miRNA which is UTR region of the target mRNA, it induces the mRNA cleavage. If then transferred from the nucleus to the cytoplasm by the Exportin-5 the miRNA and mRNA do not match perfectly, it results in protein. In the cytoplasm, pre-miRNA undergoes further processing translational repression and inhibition of protein synthesis (PDCs and ACs) as compared to well-differentiated thyroid miRNA expression profile of C-cell-derived MCs is carcinomas (PCs, FCs, and MCs) in contrast to the reported significantly different from the miRNA profiles of thyroid study that found overall decrease in miRNA expression in tumors that originate from follicular cells [24]. Moreover, poorly differentiated tumors as compared with their well- even among tumors originating from the same cell type, differentiated counterparts in several types of cancer [31]. miRNA expression profiles had significant variability. From the early stages of miRNA discovery, it has been Papillary carcinomas, conventional follicular tumors (ade- known that miRNA expression profiles are tissue specific. nomas and carcinomas), and oncocytic follicular tumors A study of all major types of thyroid neoplasia showed that (adenomas and carcinomas) revealed separate clusters. Less Fig. 3 Putative role of suppres- Tumor suppressor miRNA sor miRNAs and oncogenic miRNAs in carcinogenesis Downregulation of suppressor miRNA miRNA Target mRNA ORF Overexpression of oncogenic mRNA / protein Cell proliferation Oncogenic miRNA (OncomiRs) Apoptosis Cancer Angiogenesis Downregulation of tumor suppressor mRNA /protein ORF RISC miRNA Target mRNA Overexpression of oncogenic miRNA
  • 4. 88 Endocr Pathol (2009) 20:85–91 differentiated tumors (PDCs and ACs) did not show tumors with no known mutations and the highest expres- individual clusters and were scattered within the PC and sion of miR-146b in PCs carrying RAS mutations [24]. FC clusters or separately, supporting their concept of step- Principal component analysis, used for unsupervised as- wise progression and dedifferentiation of thyroid tumors. sessment of the relationship between miRNA expression and mutation type, revealed formation of individual clusters for BRAF- and RET/PTC-positive tumors and tumors with miRNA Expression in Papillary Thyroid Carcinomas no known mutations [24] (Fig. 4). Only RAS-positive tumors did not show clear separation from other clusters. Most studies have focused on miRNA analysis of PC In addition, some differences in expression of individual (Table 2) [23–26, 29]. As evident from the table, most of miRNAs was found in thyroid cell lines carrying BRAF and the studies have identified several miRNAs (miR-146b, RET/PTC mutations as compared to normal thyroid cell miR-221, miR-222, miR-181b, miR-155, and miR-224) lines [37, 38]. However, none of the differently expressed upregulated in PCs. Of interest, many of these miRNAs miRNAs were noted in studies of human thyroid tumors were upregulated as compared to normal thyroid cells and [23–26, 29] providing evidence for significant differences hyperplastic nodules; however, one miRNA (miR-181b) in miRNA status between thyroid cells in vivo and in vitro. was found to be upregulated in both thyroid tumors and hyperplastic nodules [24]. miR-221 and miR-222 as Potential Regulators of the KIT and CDKN1B(p27Kip1) Genes Correlation of miRNA Expression with Somatic Mutations MiR-222 and miR–221 are most consistently upregulated in PC. One of the genes that appear to be targeted by these Genetically, PCs feature mutually exclusive (non-overlapping) miRNAs is KIT [12]. KIT is a tyrosine kinase receptor mutations in the RET, RAS, and BRAF genes [32], all capable involved in cell differentiation and growth. Reduced KIT to activate the mitogen-activated protein kinase signaling levels in PCs were reported more than a decade ago, but the pathway [33]. These mutations are associated with distinct mechanism of downregulation was not clear [39]. More gene expression profiles and distinct phenotypic features of recently, He et al. showed that downregulation of KIT protein PC [34]. BRAF mutation is linked to higher risk of PC correlates with strong overexpression of miR-221, -222, recurrence and increased mortality [35, 36]. and miR-146b [23]. Sequencing of miR-221 and -222 A study of miRNA expression in PCs with known binding domains of KIT 3′ UTR revealed a G3169A single mutations revealed a strong correlation between the miRNA nucleotide polymorphism within the miR-221 and miR-222 profile and mutational status. Papillary carcinomas positive recognition sites in several PCs. The G3169A variation is for BRAF, RET/PTC, and RAS mutations, and those with no expected to modify the miRNA binding to the KIT mRNA known mutations demonstrated significant differences in and decrease the efficiency of the miRNA-mediated the expression of certain miRNAs [24]. For example, miR- translational inhibition of KIT. Another direct consequence 187 was expressed at higher levels in PCs harboring RET/ of the mir-221 and miR-222 upregulation in PCs is PTC rearrangements; miR-221 and miR-222 were found at reduction in the levels of CDKN1B (p27Kip1) protein and the highest levels in BRAF- and RAS-positive tumors and increased progression to the S phase of cell cycle [13]. Of Table 2 Studies of miRNA in papillary thyroid carcinomas Number Specimen Profiling method Deregulated miRNAs References of cases type miRNAs up/downregulation PC, 15 Frozen tissue Microarray miR-146,-221,-222,-21, 220,-181a, Up [23] -155 miR-26a-1, -345, -138, -319 Down PC, 30 Frozen tissue Microarray miR-221,-222,-213, 220,-181b Up [25] PC, 20 FFPE tissue Microarray miR-221,-222,-21, -31, -172, -34a, Up [26] -213, -223,-181b, -224 miR-218, -300, -292, -345, -30c Down PC, 23 Frozen tissue qRT-PCR Array miR-187, -221, -222, -181b, -146b, Up [24] -155 PC, 10 FFPE tissue RT-PCR for individual miRNAs miR-146b,-221,-222 Up [29]
  • 5. Endocr Pathol (2009) 20:85–91 89 thyroid carcinomas and adenomas [24, 28], anaplastic and poorly differentiated thyroid carcinomas [24, 27], and med- ullary carcinoma [24] (Table 3). The most highly upregulated miRNAs in conventional FCs were miR-187, -224, -155, -222, and -221 and in OCs were miR-187, -221, -339, -183, -222, and -197 [24]. Interestingly, those miRNAs were not significantly upregulated in hyperplastic nodules. In a study by Weber et al., miR-197 and miR-346 were found to be upregulated in FCs as compared to FAs [28]. Moreover, in the in vitro experiments, the overexpression of these miRNAs induced cell proliferation of human non- neoplastic HEK293T cells, whereas the inhibition of miR- 197 and miR-346 led to growth arrest in FTC133 human thyroid cancer follicular cells, providing further evidence for their possible role in FC carcinogenesis [28]. miRNA analysis of ACs revealed upregulation of the several miRNAs that were also found to be overexpressed in well-differentiated tumors deriving from follicular cells, PC, PC BRAF positive iti PC, RET/PTC positive although the levels of overexpression were lower in ACs PC, PC RAS positive PC, PC no mutations [24]. In addition, miR-302c, -205, and -137 were found to Fig. 4 Principle component analysis of miRNAs expression in be upregulated more than 2-folds in ACs as compared to papillary thyroid carcinomas with various somatic mutations. Repro- hyperplastic nodules. Many miRNAs were downregulated duced with permission from: Nikiforova MN, et al. [24]; Copyright in ACs; in particular, a significant decrease in expression of 2008, The Endocrine Society miR-30d, miR-125b, miR-26a, and miR-30a-5p was detected [27]. In vitro, the overexpression of miR-125b note, the inverse relationship between the expression of and miR-26a was able to reduce cell growth and prolifer- Kip/Cip family members p27 and p57 and miR-221 and ation of two human AC-derived cell lines, suggesting a miR-222 was also observed in prostate carcinoma and possible role of these miRNAs in thyroid cancer progres- glioblastoma cell lines [40, 41]. sion and dedifferentation [27] miRNA Expression in Other Thyroid Tumors Diagnostic Implications of miRNA Profiling in Thyroid Tumors Although most observation reported so far have focused on miRNA expression in papillary thyroid carcinomas, we also Palpable thyroid nodules are common and affect 4–7% of start to gain insights into miRNA deregulation in follicular adults in the USA [42]. Although fine-needle aspiration Table 3 miRNA expression in thyroid tumors other than papillary carcinoma Thyroid tumor type miRNA deregulation References miRNA Up/downregulation Follicular carcinoma miR-197, -346 Up [28] Follicular carcinoma, conventional type miR-187, -221, -222, -224, -155 Up [24] Follicular carcinoma, oncocytic type miR-221, -224, -203, -183, -339, -31 Up [24] Follicular adenoma, conventional type miR-339, -224, -205, -210, -190, -328, -342 Up [24] Follicular adenoma, oncocytic type miR-221, -224, -203, -183, -339, -31 Up [24] Poorly differentiated carcinoma miR-187, -221, -129, -222, -146b, -339, -183 Up [24] Anaplastic carcinoma miR-222 (<2-folds) Up [27] miR-30d, 125b, 26a, 30a-5p Down Anaplastic carcinoma miR-302c, -205, -137, -187, -214, -155, -224, -222, -221 Up [24] Medullary carcinoma miR-323, -370, -129, -137, -10a, -124a, -224, -127, -9, -154 Up [24]
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