List of miRNAs involved in cancer and their respective mRNA targets.
Abstract
Approximately 80% of the human genome contains functional DNA, including protein coding genes, non-protein coding regulatory DNA elements and non-coding RNAs (ncRNAs). An altered transcriptional signature is not only a cause, but also a consequence of the characteristics known as the hallmarks of cancer, such as sustained proliferation, replicative immortality, evasion of growth suppression and apoptotic signals, angiogenesis, invasion, metastasis, evasion of immune destruction and metabolic re-wiring. Post-transcriptional events play a major role in determining this signature, which is evidenced by the fact that alternative RNA splicing takes place in more than half of the human genes, and, among protein coding genes, more than 60% contain at least one conserved miRNA-binding site. In this chapter, we will discuss the involvement of post-transcriptional events, such as RNA processing, the action of non-coding RNAs and RNA decay in cancer development, and how their machinery may be used in cancer diagnosis and treatment.
Keywords
- post-transcriptional control
- splicing
- microRNAs
- long non-coding RNAs
- mRNA decay
1. Introduction
The word cancer defines a group of diverse diseases, which share unique traits. Tumor cells display mechanisms of sustained proliferation, replicative immortality, evasion of growth suppression and apoptotic signals, angiogenesis, invasion, metastasis, evasion of immune destruction and metabolic re-wiring [1]. These characteristics represent a great challenge to cancer treatment being both a cause and a consequence of an abnormal gene expression profile. Efforts to understand the consequences of these different expression profiles and the mechanisms underlying them contribute to clarify cancer biology and, consequently, to predict response to and optimization of therapeutic approaches [2, 3, 4].
There are several layers of gene expression modulation including epigenetics, transcriptional modulation, RNA expression control, translational regulation and post-translational modifications. All these mechanisms work in an orchestrated manner leading to specific expression signatures and phenotypes. In this chapter, we focus on RNA expression control mechanisms, which take place after RNA polymerase recognition of the gene promoter and start of RNA synthesis, discussing their implications to malignant transformation and cancer progression.
2. mRNA processing
RNA processing takes place after the start of transcription, resulting in a mature mRNA which is able to fulfill its function. This process comprises: 5′-Cap addition, splicing and poly(A) addition. RNA splicing is a process in which portions of the pre-RNA, denominated introns, are excised and the remaining portions (exons) are bound to form the mature RNA. Both
The splicing profile of a certain tissue changes dramatically when compared with malignant cells with their normal counterparts [11, 12, 13]. This difference may result from mutations or single-nucleotide polymorphisms (SNPs) on acceptor, donor splice sites, enhancing or silencing sequences which lead to alterations in the exon/intron boundary recognition; or due to deregulated expression or change of function mutation in a
Cell survival outcome is a perfect example of the influence of AS in basic cellular mechanisms, with alternative isoforms of several apoptotic-related gene transcripts displaying opposite roles, when compared to their canonical variant, shifting the cell status from apoptosis-prone to the survival state (reviewed in [24]). Upon an apoptotic stimulus, cytochrome C is released from the mitochondria and forms a complex with Apaf-1. The N-terminal portion of Apaf-1 interacts with the N-terminal pro-domain of pro-caspase-9, leading to Caspase-9 activation, which, in turn, activates the Caspase-3 and -7 effector proteases (reviewed in [25]). Caspase-9, a key player in this process, has an alternative-splicing variant in which exclusion of the exon cassette 3, 4, 5 and 6 leads to a protein isoform which lacks part of its large subunit. This Caspase-9b isoform retains the domain which interacts with Apaf-1, but lacks the Caspase-9 catalytic site, thus acting like a dominant negative and inhibiting the apoptotic pathway [26, 27]. The ratio between these two isoforms modulates the propensity of the cells to respond to death stimuli, altering their chemo-sensitivity and, potentially, the treatment’s outcome. Interestingly, while Akt mediates exclusion of the exon cassette via phosphorylation of the RNA splicing factor SRp30a [28]; in this case, SRSF1 interacts with an intronic enhancer site at intron 6 favoring the exon cassette inclusion, which renders the cells more sensitive to chemotherapeutic agents as the combined therapy with daunorubicin and erlotinib [21]. Taking into account that SRSF1 is upregulated in non-small cell lung cancer cells, this case exemplifies the complexity of splicing as an expression regulator and how it can be explored to optimize therapy efficacy.
Another great source of transcripts variability is alternative polyadenylation (APA), since approximately 30% of human mRNAs display alternative polyadenylation sites [29]. Polyadenylation occurs in almost every mammalian transcript, a process in which an endonucleolytic cleavage is catalyzed by polyadenylation machinery proteins, immediately followed by polyadenylation (200–300 nucleotides, on average, in humans) of the 3′-end by poly(A) polymerases (reviewed in [30]). The resulting alternative transcripts will have different sizes, depending on the localization of the alternative poly(A) site, originating alternative 3′-untranslated regions (3′-UTR). Also, more rarely, when polyadenylation occurs inside the open reading frame region, it may originate truncated forms of the translated protein [31]. The 3′-UTR is extremely important to transcripts stability, localization and regulation by
A shift in the polyadenylation global pattern occurs in tumor cells, with the proximal poly(A) sites being favored, when compared to their normal counterparts [29]. Also, highly proliferative murine T lymphocytes favor shorter 3′-UTRs, which is also observed in colorectal cancer, but only for certain groups of genes, including those involved in cell cycle, nucleic acid-binding and processing factors. It has been proposed that such shortening would restrict miRNA modulation over the transcripts, increasing their expression [32, 33]. Such a mechanism is observed upon treatment of ER+ breast cancer cells with the proliferation stimulant 17β-estradiol. This treatment leads to APA of the
Curiously, mammalian RNAs can also be post-transcriptionally modified through a process called RNA editing. Well-known cases are the RNA editing enzymes adenosine and cytidine deaminases, which catalyze the conversion of adenine into inosine and of cytosine into uracil, respectively [35]. Adenosine deaminases acting on RNA (ADAR) enzymes act on double-stranded RNA regions, usually the secondary structure of a single mRNA molecule. Through a hydrolytic deamination at C6, ADAR enzymes catalyze adenine conversion into inosine, which pairs with cytosine. Cytidine deaminases are much more specific and different members of the APOBEC3 family are transcriptionally regulated by p53 [36]. Altered RNA editing signatures were found in different types of tumors, such as glioblastoma [37], breast [38] and gastric cancers [39, 40]. If located at a coding region, these editing events may cause a missense mutation. One example is ADAR-1 editing of the
The interaction of transcripts with long non-coding RNAs (lncRNAs) and microRNAs are important post-transcriptional regulatory mechanisms which will be further addressed in this chapter. RNA edition adds a layer of complexity to this apparatus. It is estimated that over 70% of potential editing sites within long non-coding RNAs may lead to changes in their secondary structure, a feature which is crucial for its target recognition [45]. If the editing takes place in a precursor miRNA, it can lead to alterations in its biosynthesis and target recognition, increasing their range of action [46, 47, 48]. Alterations in the mRNA 3′-UTR may alter its recognition by a specific miRNA or lncRNA [37, 40, 47]. Furthermore, RNA editing may also modulate RNA expression by regulating RNA decay. This is exemplified by the ADAR-1 interaction with the RNA binding protein HuR, which promotes HuR binding to the target transcript, increasing its stability [49].
3. miRNAs
Several RNA-based mechanisms evolved in eukaryotes to modulate gene expression or suppress invading material. In animals, the small non-coding RNAs (18–30 nucleotides) are subdivided into three major classes, namely microRNA (miRNA), small interfering RNA (siRNA) and PIWI-interacting RNA (piRNA). The main purpose of piRNAs are suggested to be silencing of transposable elements in germline cells [45], siRNAs and miRNAs seem to have evolved from an antiviral defense system into an ubiquitous gene expression modulation mechanism [46, 47]. Originally identified in
More than 60% of human protein-coding genes contain at least one conserved miRNA-binding site [57], encompassing every major cellular functional pathway. Therefore, miRNAs biogenesis needs to be under tight temporal and spatial control, and their deregulation is evidently associated with a wide range of human diseases, including cancer [58]. The first instance of the direct involvement of a miRNA in cancer was uncovered in 2002. A critical region at chromosome 13q14, frequently deleted in chronic lymphocytic leukemia (CLL), was shown to harbor miRNA genes miR-15a and miR-16-1. About 70% of CLL cases have null or reduced expression of these miRNAs, which normally control apoptosis by targeting BCL-2 [59, 60]. The following years revealed a remarkable number of additional examples, establishing the association of miRNAs and cancer to be the norm, rather than the exception. Currently, hundreds of human miRNAs are associated to the onset and progression of several malignancies, including lymphomas, colorectal carcinoma, breast cancer, lung cancer, thyroid cancer and hepatocellular carcinomas [61].
Several miRNAs may be differentially expressed in cancer patients, when compared to normal samples, acting either as oncogenes or tumor suppressors [62] ( Table 1 ). Most often, miRNAs are detected as tumor suppressors, with reduced expression in tumors when compared to normal tissues [63, 64]. These miRNAs have commonly been shown to negatively regulate protein-coding oncogenes. Thus, HER2 and HER3, two oncogenes which are significantly correlated with decreased disease-specific survival in breast cancer patients [65], are suppressed by miR-125a or miR-125b [66]. Additionally, the let-7 family of miRNAs targets several genes associated with cell cycle and cell division, including the RAS oncogene [67]. Inhibition of epidermal growth factor receptor by miR-128b in non-small cell lung cancer (NSCLC) [68] and miR-7 in glioma [69] are additional pertinent examples of miRNAs acting as tumor suppressors. However, several miRNAs have also been found to be overexpressed in cancer, being classified as oncomiRs, often repressing known tumor suppressors. Thus, overexpression of miR-155 and miR-21 is sufficient to induce lymphomagenesis in mice [70, 71].
miRNA | Cancer phenotype | Target mRNA | Cancer association | References |
---|---|---|---|---|
miR-15a | Tumor suppressor |
|
Chronic lymphocytic leukemia | [59, 60] |
miR-16-1 | Tumor suppressor |
|
Chronic lymphocytic leukemia | [59, 60] |
miR-125a | Tumor suppressor |
|
Breast cancer | [66] |
miR-125b | Tumor suppressor |
|
Breast cancer | [66] |
let-7 | Tumor suppressor |
|
Lung tumor | [67] |
miR128-b | Tumor suppressor |
|
Non-small lung cancer | [68] |
miR128-b | Tumor suppressor |
|
Acute lymphoblastic leukemia | [77] |
miR-7 | Tumor suppressor |
|
Glioma | [69] |
miR-155 | Oncogenic |
|
Lymphoma | [70, 71] |
miR-21 | Oncogenic |
|
Lymphoma | [70, 71] |
miR-127 | Tumor suppressor |
|
Prostate cancer | [75, 76] |
miR-372/373 | Oncogenic |
|
Testicular germ cell tumor | [170] |
miR-17 | Tumor suppressor |
|
Large B-cell lymphoma | [72, 171] |
miR-34 | Tumor suppressor |
|
Ovarian cancer | [73] |
miR-210 | Tumor suppressor |
|
Multiple myeloma | [172] |
miR-10b | Tumor suppressor |
|
Gastric cancer | [173] |
miR-126 | Tumor suppressor | ADAM9 | Breast cancer | [174] |
miR-335 | Tumor suppressor |
|
Breast cancer | [175] |
Mapping efforts have revealed that many miRNAs are located in fragile regions of the genome, which are deleted, amplified or translocated in cancer, directly altering miRNAs genes expression, hence leading to aberrant expression of downstream target mRNAs [59]. In addition to genomic alterations, miRNA expression is also modulated by tumor suppressor or oncogenic factors, which function as transcriptional activators or repressors to control pre-miRNA transcription. One of the first examples of this interaction is the transcriptional upregulation of the miR-17/92 cluster by the c-
The functional outcomes of miRNAs deregulation coincide with the hallmarks of malignant cells, namely: (1) self-sufficiency in growth signals (let-7 family), (2) insensitivity to anti-growth signals (miR-17-92 cluster), (3) apoptosis evasion (miR-34a), (4) limitless replicative potential (miR-372/373 cluster), (5) angiogenesis (miR-210) and (6) invasion and metastases (miR-10b). miRNAs have also been shown to regulate the generation of cancer stem cells (CSCs) [82, 83] and epithelial-mesenchymal transition (EMT), paramount for the metastatic process [84]. Thus, as breast cancer cells metastasize, expression of miR-126 and miR-335 is lost. Overexpressing these miRNAs in cancer cells decreases lung and bone metastasis in vivo [85].
The high number of human miRNAs, regulating a wide range of cancer-related processes, renders these small non-coding RNAs an ideal profiling tool. miRNA expression profiles can distinguish not only between normal and cancerous tissue, but also help to discriminate different subtypes of a particular cancer, or even specific oncogenic abnormalities [86], increasing the accuracy of tumor classification. These expression profiles were able to classify tumors according to their tissue of origin with accuracy higher than 90%. miRNAs regulation of cancer progression also allows these molecules to serve as efficient predictors of prognosis, tumor metastasis and therapy selection. Specific miRNA signatures have recently been shown to correlate to metastatic breast and colon tumors, arising as potent biomarkers to predict metastatic outcome. miRNA profiles may also be applied to select for more personalized and efficient therapies and to adjust the therapeutic scheme during treatment to achieve a better outcome. Noteworthy, in ovarian cancer, miRNA signatures are able to predict chemo-resistant tumors, while a polymorphism (SNP34091), which creates a new binding site for miR-191, was suggested as a modulator of tumor chemosensitivity [75].
miRNAs are highly stable molecules present in body fluids including plasma, blood, serum, urine, saliva and milk, being potential cancer biomarkers which may be found in different phases of the tumoral process [87, 88]. Although understanding of how miRNAs are selectively released from cells and how circulating miRNAs are related to disease remains largely unclear, circulating miRNAs may serve as novel diagnostic and prognostic biomarkers for human diseases, including cancer [89].
4. Long non-coding RNAs
Recent studies based on the Encyclopedia of DNA elements (ENCODE) project indicate that more than 80% of the human genome contains functional DNA that includes protein coding genes, non-protein coding regulatory DNA elements and non-coding RNAs (ncRNAs) [90]. Non-coding RNAs is a class of genetic regulators, containing short (<200 nucleotides) and long (>200 nucleotides) transcripts with novel abilities to be used as biomarkers due to their role in disease development and their implications for genomic organization [91, 92]. Short ncRNAs include ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). Regulatory long non-coding RNAs (lncRNAs) have been found in a large variety of organisms, ranging from yeasts to mammals, including mice and humans [93]. lncRNAs have emerged as a fundamental molecular class whose members play critical roles in genome regulation and in tissue development and maintenance [92]. Based on their positions relative to the protein coding genes in the genome, lncRNAs can be classified into natural antisense transcripts (NATs), long intronic ncRNAs and long intergenic ncRNAs (lincRNAs) [93].
Recent transcriptional profiling of multiple human tissues, including both normal and tumor samples, has led to the assumption that misregulation of lncRNAs could disrupt these delicate processes and lead to tumorigenesis [94, 95, 96, 97]. These studies have validated the tissue-specific expression of lncRNAs in normal tissues, and have identified large sets of lncRNAs which are aberrantly expressed in either a specific cancer or multiple types of cancer, suggesting these RNAs act as master regulators of gene expression [98, 99]. Differential expression of lncRNAs is increasingly recognized as a hallmark feature in cancer [100]. lncRNAs are a novel class of mRNA-like transcripts, which contribute to cancer development and progression, accelerating cancer cells proliferation, apoptosis, invasion and metastasis [101] ( Table 2 ).
LncRNA | Cancer phenotype | Molecular mechanism | Cancer association | References |
---|---|---|---|---|
|
Oncogenic, promotes metastasis and invasion | Interacts with PRC2 and LSD1 complex, promotes silencing of HOX genes in |
Overexpressed in liver, breast, lung and pancreatic tumors | [109, 176, 177] |
|
Tumor suppressor, induces growth arrest and sensitizes cells to apoptosis | Inhibits and binds glucocorticoid receptor (GR) from activating target genes | Downregulated in breast cancer | [178, 179] |
|
Oncogenic, promotes cell proliferation and tumor growth | Unknown | Breast cancer | [180] |
|
Oncogenic, promotes cell proliferation and metastasis | Related to alternative splicing and active transcription, regulation of gene expression | Overexpressed in lung, breast, pancreatic, colon, prostate and hepatocellular carcinomas | [117, 181, 182] |
|
Tumor suppressor, inhibits cell proliferation and induces apoptosis | Enhancing p53’s transcriptional activity on its target genes. Controls expression of gene loci through recruitment of PRC2 | Downregulated in multiple tumor types | [183, 184] |
|
Tumor suppressor; Inhibits cell proliferation, migration, invasion and tumor growth | Binds and inhibits miRNAs from targeting and repressing |
Locus lost in prostate cancer, colon cancer and melanoma | [185, 186, 187] |
|
Tumor suppressor and inhibits proliferation | Unknown | Breast cancer and dysregulated in many types of tumors | [128, 188] |
General mechanisms of lncRNA function implicated in cancer progression are associated with a wide-repertoire of biological processes. Among the main biological pathways, lncRNAs may be involved in epigenetic silencing, splicing regulation, translational control, regulation of apoptosis and cell cycle control [102]. Like protein-coding genes, lncRNAs can function as oncogenes or tumor suppressors. Many lncRNAs shuttle between the nucleus and the cytoplasm, suggesting that they may have dual functions, while others are restricted to the nucleus [103]. In the nucleus, lncRNAs are often part of the nuclear architecture and, in some cases, are critical for maintenance of sub-nuclear structures [104].
lncRNAs bind to and target chromatin regulators allowing connection between RNA and chromatin, acting on the control of gene expression at the transcriptional level [105]. Moreover, several lncRNAs mechanistic themes have emerged, both at the transcriptional and post-transcriptional levels, such as decoys, scaffolds and guides [106]. Examples of the mechanisms of action of some lncRNAs on the control of gene expression and mammalian cells regulation are described below.
lncRNAs can also participate in global cellular behavior by controlling cell growth. The growth-arrest-specific 5 (
The lncRNA
The maternally expressed gene 3 (
The
The lncRNA
The highly specific lncRNA expression signatures render them as attractive markers for accurate disease diagnosis and patients prognosis. In addition, advancement of RNA-based therapeutics opens new avenues for lncRNAs as new targets for cancer therapy.
5. mRNA decay
mRNA degradation is an important mechanism for post-transcriptional control of gene expression, controlling both the quality and the abundance of cellular mRNAs. Deadenylation of the mRNA is the default process, often representing a rate-limiting step in cytoplasmic mRNA decay, in which the poly(A) tail of the transcript is degraded through recruitment of deadenylase complexes [130, 131, 132]. In the literature, different deadenylases or poly(A)-specific ribonucleases have been described, namely PARN (poly(A)-specific ribonuclease), Pan2/Pan3 (poly(A) nuclease 2/3) complex and CCR4–NOT (carbon catabolite repression 4) complex [131, 133]. The PARN deadenylase is involved in destabilization of different transcripts related to cell cycle progression and cell proliferation [133, 134], as well as in degradation of oncogenic miRNAs, such as miR-21 [135]. In addition, its expression is altered in different tumors, such as gastric tumors [136] and acute leukemias [137].
Different proteins are able to interact with each other and promote the recruitment of deadenylases to the mRNA poly(A) tail. Members of BTG/Tob family, associated with anti-proliferative activities [138], are able to associate with both Caf1a and Caf1b (enzymatic subunits of the CCR4-NOT complex) [139], and, also, with PABPC1 (cytoplasmic poly(A)-binding protein) [139, 140], promoting mRNA poly(A) tail removal and cytoplasmic mRNA decay. Expression of the BTG/Tob proteins is classically associated with inhibition of cell cycle progression [138]. The Tob/Caf1 complex is also involved in the negative regulation of c-
AU-rich elements (ARE) are critical
In addition, deadenylase complexes could be recruited to the mRNA poly(A) tail through the action of miRNAs. GW182 proteins, which participate of the miRNA-induced silencing complex (miRISC), directly interact with PAN3 and NOT1 subunits, leading to recruitment of the PAN2-PAN3 and CCR4-CAF1-NOT deadenylase complexes to the 3′-UTR of target mRNAs [159]. Also, it has been described that PARN deadenylase binds to the 3′ UTR of p53 mRNA through recruitment mediated by miR-125b-loaded miRISC, promoting p53 mRNA decay [134]. Interestingly, this effect can be reverted by HuR proteins, which bind to the p53 AREs and increase p53 mRNA stability [134].
The deadenylation machinery is also an important target for antitumor agents and anticancer therapy. Cantharidin (an inhibitor of protein phosphatase 2A) inhibits the invasive ability of pancreatic cancer cells, with concomitant deadenylation-dependent degradation of MMP2 mRNA [20]. Resveratrol (3,5,4′-trihydroxystilbene), a naturally occurring compound, induces TPP expression in U87MG human glioma cells and leads to the decay of urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) mRNAs, promoting suppression of cell growth and inducing apoptosis [160].
Additionally, several mature mRNAs surveillance mechanisms guarantee quality and fidelity to encode a functional protein in a translation-dependent manner. The nonsense-mediated decay (NMD) pathway is the best understood surveillance mechanism; detecting and degrading transcripts which contain premature termination codons (PTCs), avoiding the expression of semi-functional and truncated proteins [161]. The UPF-1 (up-frameshift1) protein, a key component of the NMD mechanism, interacts with both Dcp2 and PARP, linking NMD with the decapping and deadenylation processes [162]. Low expression levels of UPF-1 protein as well as inactivation of UPF-1 function were described in several types of human cancer, suggesting that NMD downregulation is related to tumorigenesis. Decreased levels of UPF-1 were detected in lung adenocarcinoma in comparison to normal tissues, and its downregulation was correlated to poor prognosis and higher histological grade [163]. The pancreatic adenosquamous carcinoma (ASC) is an aggressive tumor which is associated with high metastatic potential and poor prognosis. In these tumors, a mutation that promotes
NMD can also be inhibited by a wide variety of cellular stresses, some of which are associated to the tumoral context [165]. In response to stress events, phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2α) is able to inhibit NMD. It has been described that phospho-eIF2α is necessary for oncogene c-
Several promising NMD targets mRNAs for cancer therapy have been proposed. The MDM4 protein, which is undetectable in normal tissues, is frequently upregulated in cancer cells, acting by inhibiting the p53 tumor-suppressor function [168]. The abundance of the MDM4 protein is controlled, at least in part, by alternative splicing mechanisms and the NMD pathway. In most normal adult tissues, the lack of exon 6 in the Mdm4-spliced variant leads to the production of an unstable transcript (Mdm4-S), which contains a PTC and is targeted to NMD [168]. On the other hand, the oncogenic splicing-factor SRSF3 supports exon 6 inclusion in the Mdm4 mRNA transcript (full-length Mdm4 variant), which is not efficiently degraded by NMD. Therapeutic strategies which lead to antisense oligonucleotide-mediated (ASO-mediated) Mdm4 exon 6 skipping efficiently decreases MDM4 abundance and inhibits tumor cell growth in melanoma and diffuse large B cell lymphoma models, as well as increases sensitivity to MAPK-targeting therapies [169].
6. Final considerations
Different post-transcriptional mechanisms have been associated with gene expression control, leading to complex transcriptional signatures in cancer. The mechanisms presented in this chapter constitute fine regulators of gene expression which influence multiple and highly relevant pathways in cancer development (summarized in Figure 1 ). Several splicing variants, miRNAs and lncRNAs, have been shown to act as possible oncoRNAs or as tumor suppressors. The functional roles of these RNAs are only beginning to be elucidated providing an uncharted resource for the development of diagnostic methods and novel cancer therapies.
Abbreviations
ADAR | Adenosine deaminases acting on RNA |
AGO | Argonaut |
Akt/PKB | Protein kinase B |
Apaf-1 | Apoptotic protease activating factor 1 |
APOBEC | Apolipoprotein B Mrna editing enzyme, catalytic polypeptide-like |
ARE | AU-rich elements |
AS | Alternative splicing |
ASC | Pancreatic adenosquamous carcinoma |
ASO | Antisense oligonucleotide |
AZIN1 | Antizyme inhibitor 1 |
BCL | B cell lymphoma gene family |
BrdU | Bromodeoxyuridine (5-bromo-2′-deoxyuridine) |
BTG | BTG anti-proliferation factor |
Caf1 | Chromatin assembly factor-1 complex |
Casp | Caspase |
CCR4 | C-C motif chemokine receptor 4 |
CCR4–NOT | Carbon catabolite repression 4 complex |
CD44 | CD44 molecule (Indian blood group) |
CD6 | Cluster of differentiation 6 |
CDC34 | Cell division cycle 34 |
CDS | Coding DNA sequence |
c-fos | Proto-oncogene c-Fos |
cIAP2 | Cellular inhibitor of apoptosis 2 |
CLL | Chronic lymphocytic leukemia |
c-Myc | Myc proto-oncogene |
CNOT1 | CCR4-NOT transcription complex subunit 1 |
CoREST | REST corepressor 1 |
CSCs | Cancer stem cells |
DBD | DNA-binding domain |
Dcp1 | Decapping protein 1 |
DDX | DEAD-box helixases |
DICER | Dicer 1, ribonuclease III |
DROSHA | Drosha ribonuclease III |
E2F1 | E2F transcription factor 1 |
eIF2α | Eukaryotic initiation factor 2 |
EMT | Epithelial-mesenchymal transition |
ENCODE | Encyclopedia of DNA elements |
ER | Estrogen receptor |
ER+ | Estrogen receptor-alpha-positive |
ERBB2/HER | Human epidermal growth factor receptor 2 |
EXP5 | Exportin 5 |
GAS5 | Growth-arrest-specific 5 |
GR | Glucocorticoid receptor |
GRE | Glucocorticoid response elements |
H19 | H19, imprinted maternally expressed transcript |
H3K4 | Histone H3 lysine 4 |
hnRNP | Heterologous nuclear ribonuclear particle |
HOTAIR | Hox transcript antisense intergenic RNA |
HOXC | Homeobox C cluster |
HuR | Human antigen R |
IGF2 | Insulin-like growth factor 2 |
lincRNAs | Long intergenic ncRNAs |
lncRNAs | long non-coding RNAs |
LSD1 | Lysine-specific histone demethylase 1 |
MALAT1 | Metastasis associated in lung adenocarcinoma transcript |
MAPK | mitogen-activated kinase-like protein |
MDM4 | MDM4, p53 regulator |
MEG3 | Maternally expressed gene 3 |
miRISC | miRNA-induced silencing complex |
miRNA/miR | microRNA |
MMP2 | Matrix metalloproteinase 2 |
NATs | Natural antisense transcripts |
ncRNAs | Non-coding RNAs |
NMD | Nonsense-mediated decay |
NSCLC | Non-small cell lung cancer |
ODC | Ornithine decarboxylase |
p53 | Tumor protein p53 |
PABPC1 | Cytoplasmic poly(A)-binding protein |
PABPC1 | Poly(A) binding protein cytoplasmic 1 |
Pan2/Pan3 | Poly(A) nuclease 2/3 complex |
PARN | Poly(A)-specific ribonuclease |
piRNA | PIWI-interacting RNA |
Pol II | RNA polymerase II |
PPB | Pleuropulmonary blastoma |
PR | Progesterone receptor |
PRC2 | Polycomb repressive complex 2 |
Pri-miRNA | miRNA primary transcript |
PTCs | Premature termination codons |
PTEN | Phosphatase and tensin homolog |
PTENP1 | Phosphatase and tensin homolog pseudogene 1 |
Ras | HRas proto-oncogene, GTPase |
REST | RE1-silencing transcription factor |
RISC | RNA-induced silencing complex |
rRNAs | Ribosomal RNAs |
siRNA | Small interfering RNA |
SLC7A11 | Solute carrier family 7 member 11 |
Slug | Snail family transcriptional repressor 2 |
Snail1 | Snail family transcriptional repressor 1 |
snoRNAs | Small nucleolar RNAs |
SNPs | Single-nucleotide polymorphisms |
snRNAs | Small nuclear RNAs |
snRNP | Small nuclear ribonucleoprotein particles |
SRP | Serine-rich protein |
SRSF1 | Serine and arginine-rich splicing factor 1 |
TGF-β | Transforming growth factor beta 1 |
Tob | Transducer of ERBB2 |
tRNAs | Transfer RNAs |
TTP | Tristetraprolin |
Twist1 | Twist family BHLH transcription factor 1 |
uPA | Urokinase plasminogen activator |
uPAR | Urokinase plasminogen activator receptor |
UPF-1 | Up-frameshift1 protein |
UTR | Untranslated region |
VEGF | Vascular endothelial growth factor |
XPO5 | Exportin 5 |
Xrn1 | 5′–3′ exoribonuclease 1 |
Zeb1 | Zinc finger E-box binding homeobox 1 |
Zfas1 | Znfx1 sntisense 1 |
Znfx1 | Zinc finger NFX1-type containing 1 |
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