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Transcribed Ultra-Conserved Regions (T-UCRs) are a novel class of long non-coding RNAs derived from Ultra-Conserved Regions (UCRs) of DNA. The discovery of cancer-specific mutations in UCRs and their location in cancer-associated genomic regions suggests that T-UCRs also play a role in carcinogenesis. However, the mechanisms behind their actions remain unclear. Their interactions with microRNAs are not well understood and are currently a subject of debate. Like other non-coding RNAs, T-UCRs exhibit tissue- and disease-specific expression, making them promising candidates for biomarkers or therapeutic targets in cancer and other diseases. This chapter aims to review the current knowledge on the functional effects of T-UCRs in cancer and other diseases, discuss the role of T-UCRs as regulators and regulated, and present their potential as disease monitoring biomarkers.
*Address all correspondence to: maria.radanova@mu-varna.bg
1. Introduction
The genome is a malleable substance. A large portion of it is made up of so-called “dark matter”—non-coding protein genomic sequences. Until recently, the transcripts of this part of the genome were considered unnecessary and non-functional. However, it is now known that they carry important information and play a major role in regulating the phenotype. It has been proven that the “dark matter” of the genome is transcribed into various types of RNA, most of which do not encode proteins, known as non-coding RNAs [1]. Based on transcript length, non-coding RNAs are divided into two major groups. Those longer than 200 nucleotides are referred to as long non-coding RNAs (lncRNAs), while those shorter than 200 nucleotides are known as short non-coding RNAs (sncRNAs). Among the sncRNAs, well-studied microRNAs (miRs) are involved in the process of RNA interference [2]. Transcribed Ultra-Conserved Regions (T-UCRs) belong to the lncRNA group. T-UCRs are transcribed from 481 ultra-conserved DNA sequence regions (UCRs). T-UCRs were discovered in recent years and have quickly become a new field of exploration.
The chapter aims to provide a critical review of the current scientific understanding of the mechanisms of action of T-UCRs in pathological conditions, to present possible mechanisms for regulating their expression and to summarize research that demonstrates the diagnostic, prognostic, and predictive potential of T-UCRs as biomarkers.
UCRs were first described by Bejerano et al. and were found to be present on all chromosomes, except chromosomes 21 and Y, with an uneven distribution [3]. They are longer than 200 base pairs and are functional but do not encode proteins [4]. UCRs are often located in fragile sites and genomic regions associated with tumor-related genes, and 93% of them are transcribed in at least one normal human tissue [5]. They are characterized by absolute conservation, with no insertions or deletions, and are 100% identical in humans, rats, and mice [3].
Their initial classification of UCRs was made by Bejarano et al. with a focus on their intersection with protein-coding regions. The authors divided the 481 UCRs into three groups: 111 were classified as partly exonic (or exonic for short), 114 as possibly exonic due to inconclusive intersection with a protein-coding sequence, and the remaining 256 were classified as nonexonic [3]. The first two groups are randomly distributed along the chromosomes, while the nonexonic elements tend to cluster in introns or intergenic regions near transcription factors and developmental genes.
In 2010, Mestdagh et al. proposed a more detailed classification of UCRs. The genomic groups became five: exonic, intronic, exon-containing, intergenic, and partially exonic UCRs [6]. A large part of UCRs, more than 70% are intronic and intergenic and most of them are transcriptionally active [5, 6, 7]. The UCRs groups correspond to their transcription product T-UCRs (Figure 1).
Figure 1.
Different types of T-UCRs according to genomic localization of UCRs. (Figure created with BioRender.com.)
T-UCRs can be divided into two groups: intragenic and intergenic. The intragenic group includes T-UCRs whose UCRs are located within exons or introns of their host genes, such as exonic, intronic, or T-UCRs whose UCRs span an exon such as exon-containing, and partly exonic. Intergenic T-UCRs are those whose UCRs are located outside of current genomic annotations. This separation of T-UCRs is mainly based on the localization of their UCRs and is somewhat conditional. Moreover, many intronic UCRs have been discovered in the antisense orientation relative to their host gene. This suggests that their transcripts T-UCRs are not simply products of intronic transcription of known genes, but rather are genuine independent noncoding transcripts [3]. The T-UCRs which correspond to the sense genome sequence, referred to as “+”, and those that correspond to the antisense sequence, referred to as “+A”. The designation of T-UCRs includes this information, following the “uc.” (from ultraconserved) and the number indicating their chromosomal location (for example uc.346+ or uc.479+A).
In recent years, the number of studies on the functions of T-UCRs in the biology of different diseases has rapidly increased. These studies have been summarized and commented on in a number of review articles [4, 7, 8, 9, 10, 11, 12, 13, 14, 15]. However, the need for discussions on this topic remains at this stage because what is known about T-UCRs and UCRs is less than what is unknown. It is important to differentiate between the roles of T-UCRs and the UCRs from which they are transcribed. T-UCRs may not represent the entire RNA transcript, and their sequences often overlap with ultraconserved enhancers or are contained within other annotated genes. On the other hand, Fedorova et al. argued that ultra-conserved non-coding elements do not represent non-coding RNAs, as T-UCRs are assumed to be [16]. Although they share common functions with lncRNAs, T-UCRs also exhibit many specific ones. Additionally, they do not quite fit the view of ncRNAs, which primarily have evolutionary conservation in structure rather than in sequence [16]. To fully understand T-UCRs, it is necessary to clarify their structure, the factors that influence their expression, and their effects on both the host and neighboring genes.
3. Mechanisms of regulation of gene expression by T-UCRs
T-UCRs play a crucial role in regulating gene expression by influencing various processes, including pri-miR processing and maturation, mRNA degradation, transcription regulation, epigenetic modulation [7, 17].
Efforts to understand the general mechanisms of action of T-UCRs face challenges due to the fact that some of these mechanisms are also involved in regulating the expression of T-UCRs themselves. It remains unclear whether the pathogenic role of T-UCRs is more closely related to their direct participation in the regulation of the expression of disease-related genes or if the dysregulation of their own expression is the determining factor. This raises an interesting question: how can a T-UCR simultaneously act as both a regulator and a regulated entity?
3.1 Interaction between T-UCRs and mRNA
An established mechanism of action for T-UCRs includes their ability to directly bind to the 3’UTR of mRNAs, leading primarily to the degradation of the gene’s mRNA. For example, uc.206 specifically targets mRNA of the pro-apoptotic gene P53, promoting tumor cell growth in cervical cancer [18]. Additionally, uc.338 interacts directly within the 3’UTR of TIMP-1 mRNA and negatively regulates it at a post-transcriptional level. Through this mechanism, uc.338 decreases TIMP-1 but increases MMP9 expression in the TIMP-1-MMP9 signaling pathway, which may explain the tumor progression in colorectal and cervical cancers [19, 20]. HSPA12B mRNA is a direct target of uc.454. In this way, uc.454 may induce apoptosis of lung tumor cells by decreasing the expression of HSPA12B and affecting the ratio of Bcl-2/Bax [21]. Uc.454 can also inhibit migration and invasion in lung cancer by interacting with K-Ras at the posttranscriptional level, affecting the K-Ras/P63/MMP9 pathway [22]. A study by Goto et al. suggests that uc.416+A operates through a similar mechanism on the mRNA of several proteins. Uc.416+A is associated with cell growth through the downregulation of expression of inhibitors of proliferation, differentiation, and migration of tumors, such as IGFBP6, and the upregulation of proteins associated with malignant neoplasms, such as HOXB5 [23]. Mechanistically, uc.189 inhibits protein translation of EPHA2 mRNA by directly binding to its 3’UTR region and promotes the proliferation and lymph node metastasis in esophageal squamous cell carcinoma [24]. Uc.57 binds to BCL11A mRNA, which reduced tamoxifen resistance by inhibiting PI3K/AKT and MAPK signaling pathways [25]. All these studies were conducted in cancer models, where T-UCRs consistently act as negative regulators of mRNA expression. Uc.478 and uc.479 affect the expression of genes in non-cancerous conditions. Their overexpression is associated with decreased levels of GRIA3 mRNA and protein in human models of Rett syndrome [26].
Another interesting regulatory mechanism exercised by T-UCRs was presented by Zhang et al. [27]. The authors revealed a new regulatory relationship between T-UCRs and their host genes. They suggested that uc.189 positively regulates the expression of the splicing factor SRp20, but did not provide any mechanistic evidence to explain how this occurs [27].
3.2 Interaction between T-UCRs and proteins
Regarding the mechanisms of action of some T-UCRs, there is no evidence that they affect the expression of mRNAs, but functional analyzes show the levels of the corresponding proteins are significantly decreased when T-UCRs are overexpressed or increased when T-UCRs are silenced. This suggests a T-UCR-protein interaction. This is the case with uc.38 and PBX1. Zhang et al. found that uc.38 interacts with the protein and subsequently affects the expression of Bcl-2 family members, ultimately inducing apoptosis in breast cancer cells [28]. Shi et al. also revealed that T-UCRs can directly interact with proteins. In their study, uc.51 physically interacts with NONO and promotes the proliferation and migration of breast cancer cells [29].
As a type of lncRNAs, T-UCRs may have the ability to specifically bind with one or more proteins or function as scaffolds for protein complexes involved in the regulation of gene expression. Similar capabilities of T-UCRs were reported by Zambalde et al. who identified 17 proteins that interact with uc.147 either directly or indirectly [30]. For some of these interactions, Zambalde et al. suggested a role for uc.147 as a regulator of protein functions. The authors hypothesized that uc.147 could serve as a scaffold for two protein complexes: one between RHOA and CIT, and another among six proteins (WDR18, TEX10, PES1, NOP53, DKC1, and ZC3HAV1) that participate in RNA processing and regulation. Additionally, the authors found correlations between the expression of uc.147 and neighboring genes, as well as downstream UCRs uc.148 and uc.149. Zambalde et al. do not exclude the possibility that uc.147 also uses another regulatory mechanism in breast cancer—acting as a decoy for miR-190 [30].
When discussing the mechanisms of action of T-UCRs in regulation of the gene expression, it is important to mention also a less well-known lncRNA-dependent epigenetic mechanism, called by Wang et al. an “epigenetic switch point” [31]. Sun et al. discovered that uc.323 can directly interact with EZH2, which is the primary component of the histone modification complex PRC2 responsible for the N-methylation of histones. This interaction can inhibit H3K27me3 at the promoter regions of CPT1b and regulate its transcription. Thus uc.323 ameliorated cardiac hypertrophy [32]. Studies by Panatta et al. and Mancini et al. suggest that T-UCRs mediate another epigenetic mechanism. According to these authors, uc.291 modulates chromatin remodeling activity by negatively regulating ACTL6A, the catalytic subunit of the SWI/SNF chromatin remodeling complex. This releases chromatin and allows for the transcription of epidermal differentiation complex genes. In cutaneous squamous cell carcinoma, downregulation of uc.291 reduces SWI/SNF complex activity, leading to a de-differentiation phenotype [33, 34].
3.3 Interaction between T-UCRs and microRNAs
The interaction between T-UCRs and microRNAs (miRs) is another way for T-UCRs to exert their regulatory functions. This interaction can modulate the activity of miRs. The effects of this can be seen through the degradation or inactivation of T-UCRs’ targets, miRs, and primary miRs (pre-miR), or through the influence on the expression of mature miRs [9].
Table 1 presents examples of T-UCRs that act as competitive endogenous RNAs (ceRNAs) and prevent binding of miRs to their target mRNAs in T-UCRs/miR/mRNA axis.
Inhibites the proliferation tumor cells by increasing FBXW8 and CDK4 ubiquitination, which lead to negatively regulation of CDK4 and a block of the G0/G1 transition
Another aspect of the interaction between T-UCRs and miRs is connected to the influence of T-UCRs on the expression of mature miRs.
Liz et al. describe a possible mechanism by which T-UCRs regulate the maturation of miRs [49]. In their study, they found that uc.283+A interacts with the stem region of pri-miR-195, preventing its processing by the Drosha/DGCR8 microprocessor complex. Similarly, Zhang et al. found that another T-UCR, uc.339, prevented the Drosha/DGCR8 splicing complex from binding to pri-miR-339, inhibiting the production of mature miR-339 [46]. Uc.372 regulates the cleavage of both pri-miR-195 and pri-miR-4668 from pri-to-pre-miR by sponging them, suppressing their maturation [47]. In contrast, a new study shows that uc.160+ enhances the processing of the pri-miR-376 cluster and A-to-I editing during miR-376 maturation [50].
Is the interaction between T-UCRs and miRs direct, or is there a mediator involved? This is another question that the study by Terreri et al. addresses [36]. The authors found that the interaction between T-UCRs and miRs can be mediated by the polycomb protein Yin Yang 1 (YY1). Specifically, YY1 mediates the binding between uc.8+ and miR-596 in bladder cancer. The authors suggest that the binding of YY1 to T-UCR may alter its conformation, inhibiting the binding of miR-596 [36]. This finding reveals a new player in the interaction between T-UCRs and miRs, another factor in gene expression regulation.
In their study, Terreri et al. shed another new light on the relationship between T-UCRs and miRs. They found that silencing uc.8+ increased the expression of miR-596, making it available to bind to other T-UCRs such as uc.283+, which in turn reduced its level. Terreri et al. believed that the interaction between T-UCRs and miRs occurs in networks that modulate the availability of these non-coding RNAs. The authors referred to this as an example of inter epigenetic regulation [36].
A recent study by Corrà et al. provided further evidence of this network interaction between T-UCRs and miRs in breast cancer [51]. The authors found that silencing uc.183 and uc.96 increased the levels of pre-miR-221 and miR-221, but also that miR-221 itself reduced the expression of uc.183, uc.110, and uc.84. This raises the question of which of the two has a regulatory function, T-UCRs or miR? This question is further complicated by the fact that the study found that treatment with anti-cancer drugs affects the expression of T-UCRs, but not the expression of miR-221.
Although the number of studies investigating the mechanisms of action of T-UCRs is increasing, their primary functions remain unclear. It is important to determine whether T-UCRs exhibit most of the functions described for other classes of lncRNAs or if new, specific functions will be discovered. A key feature that distinguishes T-UCRs from other lncRNAs is their bi-directional interaction with miRs—both regulating and being regulated by them.
There are also other studies that have reported on the role of T-UCRs in a number of pathological processes, but the underlying regulatory mechanistic interactions remain unclear and warrant further investigation [52, 53, 54, 55].
Despite attempts to systematically present and summarize the mechanisms of action of T-UCRs, it cannot be categorically stated that there is a manifestation of a single mechanism during functional activity. Different manifestations of action from one T-UCR in different diseases cannot be ruled out, similar to other non-coding RNAs, although the trend in this regard with T-UCRs is significantly weaker. An idea of the diversity of mechanisms of action, their effects and the behavior of one T-UCR in different types of cancer can be given by uc.338, which is one of the most studied T-UCRs.
It is believed that uc.338 stimulates cell growth and promotes the transition from the G1 to S phase of the cell cycle, leading to increased cell migration and invasion in hepatocellular carcinoma, lung, colorectal, and cervical cancers. Uc.338 stimulates cell growth through the PI3K/AKT pathway, potentially by down-regulating p21 and up-regulating cyclin D1 [56], or in association with BMI1, by modulating the transcription of CDKN1A and partially repressing p21 [57]. Around 400 potential target genes with uc.338-binding sites were identified, many of which are involved in cell proliferation [58]. Moreover, PAI-RBP1 (plasminogen activator inhibitor-1 RNA-binding protein) was identified as a potential RNA-binding partner of uc.338 [58]. Additionally, as mentioned above, silencing uc.338 inhibits cell migration and invasion by directly regulating TIMP1 [19, 20], and after knocking down uc.338, p53 activity increased by almost 30% [58].
The expression of T-UCRs is regulated through several mechanisms, including miRs, CpG island methylation, and histone modifications. These mechanisms are all forms of epigenetic influence. In some cases, these mechanisms work together. For example, the expression of uc.160+ is simultaneously affected by miR-155 and the methylation of the host gene promoter [59, 60].
4.1 Role of microRNAs
It is crucial to further investigate the regulatory role of T-UCRs through miRs. Moreover, there is evidence indicating that miRs significantly influence the regulation of T-UCRs transcription, particularly in cancer.
MiRs as regulators of T-UCRs expression are presented mainly in cancer (Table 2). The majority of studies paid attention to the sequence complementarity between T-UCRs and miRs. This effect was first reported by Galin et al. who found that the expression levels of two T-UCRs, uc.160+ and uc.346+A, could be directly regulated in vivo by a single miRNA, miR-155, in chronic lymphocytic leukemia [5]. The role of miR-155 as a regulator of uc.160+ has also been confirmed in gastric cancer [59]. In neuroblastoma, nine T-UCRs have been suggested to be regulated by five miRNAs [61]. However, the role of miRNAs as regulators of T-UCR expression remains uncertain. This is evidenced by research conducted by the group led by Wataru Yasui, who found in 2016 that miR-153 directly suppresses uc.416+A in a model of gastric cancer [23], but in 2018 claimed that uc.416+A modulates epithelial-to-mesenchymal transition through the regulation of miR-153 in renal cell carcinoma [48]. The effect of miR-596 on uc.283 expression discussed above [36] also indicates that there is no clear, unambiguous mechanism linking miRNAs and T-UCRs.
Another way in which T-UCRs expression is regulated is through the hypermethylation of CpG islands in their promoter regions. This effect, which results in the downregulation and inactivation of three T-UCRs (uc.160+, uc.283+A, and uc.346+), was found by Lujambio et al. [62] and conformed for uc.160+ expression by Honma et al. [60]. They also revealed that silencing of uc.160+ led to the activation of MAPK signaling via repression of PTEN expression. Hudson et al. in turn confirmed the silencing of uc.283+A due to CpG islands hypermethylation [62]. Moreover, they with Lujambio et al. reported that treatment with DNA hypomethylating agent 5-aza-2-deoxycytidine (5-Aza-dC) upregulated the T-UCRs expression in human colon cancer and prostate cancer cells [62]. Goto et al. provided further evidence for this mechanism by discovering that in gastric and prostate cancer, uc.158+A is downregulated due to DNA methylation in the promoter region upstream of its transcription gene [23]. Hudson et al. discovered that five additional T-UCRs (uc.308+A, uc.434+A, uc.241+A, uc.285+, and uc.85+) were epigenetically downregulated, and their expression could be restored by treatment with a combination of 5-Aza-dC and histone deacetylase inhibitor trichostatin A (TSA) [63]. It seems that this mechanism, of influencing the expression of T-UCRs, leads to the silencing of those T-UCRs that have tumor-suppressive functions.
4.3 Role of histone mark
According to Mestdagh et al. both intergenic and intragenic T-UCRs are marked by trimethylation of lysine 4 on histone H3 (H3K4me3), a marker for transcriptional initiation [6]. The authors compared the distribution of active H3K4me3 marks between T-UCRs, miRNAs, and protein-coding genes in order to understand the structure and function of T-UCR transcriptional units. They found that the distribution of active H3K4me3 marks in T-UCRs is different from that of protein-coding genes, but it shows a remarkable resemblance to that of miRs. As a result, the authors hypothesized that there may be commonalities in the transcriptional organization between these two classes of ncRNAs—T-UCRs and miRs, and differences between T-UCRs and protein-coding genes [6].
4.4 Role of other factors
The studies by Vannini et al. and Guo et al. present some established influences on the expression of T-UCRs, but the underlying mechanisms remain unknown [45, 47]. Vannini et al., observed that the tumor-suppressor TP53 directly and negatively regulates uc.339. They proposed that the deregulation of uc.339 and its manifestation as an oncogene may be caused by mutations in the TP53 gene, which frequently occurs in non-small cell lung cancer. In their study, Guo et al., discovered that the upstream transcription factor 1 (USF1) regulates the expression of uc.372 in non-alcoholic fatty liver disease. They also noted that INSM2, which shares a promoter with uc.372, is involved in this regulation. The authors found that the knockdown of INSM2 decreases the level of uc.372 and suppresses USF1’s regulation of uc.372. The regulation of T-UCRs expression by transcription factors has also been described in more recent studies on uc.147 and uc.43+ [64, 65].
Another factor affecting T-UCRs transcription is hypoxia. Hypoxia can induce T-UCRs such as uc.475+, uc.63+/+A, uc.73+A, uc.106+, and uc.134+A (also known as hypoxia-induced noncoding ultraconserved transcripts, HINCUTs) [66]. While HIF-1α-binding sites have been discovered upstream promoter regions of uc.475+ and uc.63+, the mechanism by which other HINCUTs are induced by hypoxia remains unknown [67].
Despite their strong conservatism, UCRs are not resistant to variations. In 2010, Wojcik et al., claimed that UCRs are sites of very low natural variation in the general population [68]. De Grassi et al. argued that UCRs accumulate fewer mutations overall, including fewer nearly neutral mutations [69]. Depletion of prevalent neutral SNPs in UCRs was also confirmed by Silla et al. [70]. Halligan et al. argued that UCRs receive more strongly selected deleterious mutations than protein-coding genes or nearby regulatory elements [71]. Habic et al. unlike Wojcik et al., and De Grassi et al., found that the polymorphism density within UCRs is higher than the genomic average, but in support of Halligan et al. believe that SNPs in UCRs may be less stable or rarer, with deleterious consequences in populations than those outside of UCRs [72]. However, only a small portion of the established SNPs in UCRs have a proven association with human diseases. It is interesting to note that many mutations within UCRs are not fixed [16]. Habic et al. propose that not all of these regions are subject to the same level of purifying selection [72]. Silla et al. suggest that UCRs are not under selective pressure as a continuous stretch of DNA, but rather experience differential evolutionary pressure at the single nucleotide level [70]. Therefore, the question arises, can the hypothesis that UCRs are subject to stronger negative selection [73] be considered as a general principle for UCRs?
In their paper, Habic et al. [72] summarize the studies in the literature about the associations between the presence of SNPs in UCRs and the appearance of different disorders. They found 37 polymorphism/phenotype associations covering diseases such as: different types of muscular dystrophies; adolescent idiopathic scoliosis; amyotrophic lateral sclerosis; renal diseases; as well as eye-related diseases; and cancer [72]. Few studies examining the association between SNPs in UCRs and disease mention that the analyzed polymorphisms are located within conserved genomic regions. This makes it challenging to organize and categorize them systematically.
Studying SNPs in UCRs presents an opportunity to easily detect disease biomarkers. Several studies have established an association between individual SNPs in UCRs and disease risk, especially cancer risk [74, 75, 76]. Additionally, SNPs within UCRs may serve as valuable prognostic and predictive biomarkers, as demonstrated in studies by Lin et al. and Bao et al. [76, 77]. Rs8004379 SNP in uc.368+ is significantly associated with biochemical recurrence in localized prostate cancer as well as a decreased risk for prostate cancer-specific mortality in patients with advanced disease. In their analysis of the functional consequences of this SNP, Bao et al. made an interesting conclusion [77]. Given the localization of rs8004379 within an intron of the tumor suppressor NPAS3 gene, they suggested that the rs8004379 C allele may affect the expression of NPAS3 and be associated with a decreased risk of recurrence and mortality in prostate cancer patients after treatment. Rs7849 in uc.298 in a study by Lin et al. was found to be associated with an increased risk of disease recurrence in stage II patients [76]. Also, rs10211390 in uc.54 is associated with an increased risk of recurrence after 5-fluorouracil-based chemotherapy in patients with stage II and III colorectal cancer. The authors believed that individual outcomes following chemotherapy can be predicted based on the rs7849 and rs6590611 genotypes [76].
6. Clinical significance of T-UCRs in cancer and other diseases
In recent years, the number of studies focused on T-UCRs has notably grown. A significant part of them includes functional analyses to confirm the impact of T-UCRs in disease pathogenesis. However, these studies often do not provide details about the specific mechanisms of action and direct interactions of these T-UCRs [5, 39, 67, 78, 79, 80, 81]. Another large group of studies is descriptive, providing information about the association of T-UCRs levels with clinicopathological features of patients or reporting changes in T-UCRs expression in response to therapy. The results of this second group of studies provide an opportunity to select T-UCRs as potential diagnostic, prognostic, and predictive biomarkers. A large portion of these studies is summarized in Table 3, where information about the type of disease, the expression levels of T-UCRs, and their association with the clinical characteristics of studied patients is presented.
T-UCRs/expression
Cancer type/disease
Association with clinicopathological characteristics
Possible biomarker
Reference
uc.8+/downregulated
BlC
Pathological grade pathological stage worst overall survival tumors at advanced stages—T-UCR prevalent in cytoplasma
T-UCRs with clinical, predictive and prognostic significance.
Source: ACS—acute coronary syndrome; ALL—acute lymphoblastic leukemia; AS—atherosclerosis; BC—breast cancer; BlC—bladder cancer; CC—cervical cancer; CD—Crohn’s disease; CLL—chronic lymphocytic leukemia; CpG ODN—oligodeoxynucleotides that contain unmethylated CG dinucleotides; CRC—colorectal cancer; CSCC—cervical squamous cell carcinomas; EAC—endometrial adenocarcinomas; EC—esophagus cancer; ESCC—oesophagal squamous cell carcinomas; GC—gastric cancer; HBI—Harvey-Bradshaw Index (to evaluate the activity and severity of CD and to monitor the effect of treatment); HBV—hepatitis B-related HCC; HCC—hepatocellular carcinoma; LC—lung cancer; MIBC—muscle-invasive bladder cancer; NSCLC—non-small cell lung cancer; TB—tuberculosis; PC—prostate cancer.
Examining the functions of T-UCRs individually and searching for a single target for one T-UCR is an approach that is increasingly being replaced by more complex ones, such as constructing three-component regulatory networks—T-UCRs-miRNAs-mRNAs. Simultaneously tracking multiple T-UCR interactions within a single disease allows for the evaluation of the potential diagnostic and prognostic values of T-UCRs, as demonstrated in the study by Khalafiyan et al., where five T-UCRs including uc.8, uc.169, uc.342, uc.360, and uc.417 were found to be correlated with the overall survival of gastric cancer patients [95]. On the other hand, three-component regulatory networks provide an opportunity for a comprehensive understanding of the underlying gene expression regulation processes involved in pathogenesis.
Calin et al. first reported that dysregulation of several T-UCRs is associated with disease [5]. Later, Scaruffi et al. presented two T-UCR panels for high-risk prediction in neuroblastoma patients [61]. The first panel included 28 T-UCRs significantly associated with prognosis, while the second panel of 15 upregulated T-UCRs discriminated short- from long-survivors with high sensitivity and specificity. In 2014, Fassan et al. presented two panels of T-UCRs for biological profiling in the transformation of Barrett’s mucosa [96]. One is for distinguishing Barrett’s esophagus from the squamous epithelium and another is for evaluating progression from normal to adenocarcinoma. Zambalde et al. presented two panels of T-UCRs as diagnostic biomarkers for breast cancer and a third panel that distinguished with high sensitivity and specificity luminal A from triple-negative patients [87]. Finally, we come to studies such as that by Ciaramella et al. in which the authors propose a new biomarker panel of T-UCRs using machine learning techniques [97]. This signature panel of 13 T-UCRs is able to efficiently discriminate between normal and bladder cancer patient samples or patients with different survival extents, identifying sub-types of bladder cancer patients with different prognoses regardless of cancer grade. The implementation of Artificial Intelligence methodologies in medical applications represents a significant challenge in our time.
As the number of studies on T-UCRs continues to grow, it is expected that more specific information will be uncovered about their structure, functions, and potential therapeutic applications. Understanding how T-UCRs operate in normal cells will provide insight into why and how genomic ultraconservation is maintained. A key challenge is to identify the role of T-UCRs in maintaining tissue homeostasis. By clarifying their role and mechanism of action in normal cells, it may be possible to understand the consequences of their dysregulation in pathological conditions. Increasingly, research is focusing on T-UCRs as potential molecular biomarkers or as new drug targets, particularly in cancer treatment. As biomarkers, T-UCRs are promising for both diagnosis and assessing prognosis because it is known that for some T-UCRs, the levels of expression and their localization within the cell vary at different stages of cancer. T-UCRs also hold potential as a basis for therapeutic strategies or drug combinations. The therapies are aimed at destroying cancer cells or reversing the tumor phenotype, as well as influencing mechanisms related to resistance.
Research on T-UCRs requires a complex approach due to the diverse interactions they are involved in and the intricate mechanisms regulating their expression.
In nearly 20 years since the first description of UCRs by Bejerano et al., scientific interest and research on them and T-UCRs have grown significantly. The interest directed towards T-UCRs is justifiably great, as their physiological significance in both normal and pathological conditions has been demonstrated. However, our understanding of their functions and the mechanisms through which they are realized still sheds little light on “dark matter”. T-UCRs, as a type of lncRNA, exhibit more characteristic features than common functions with other ncRNAs. Their interactions with miRs or proteins reveal the richness of the genetic regulatory machinery, but also provide an opportunity for its precise influence through the development of new RNA-based therapies.
glioma tumor suppressor candidate region gene 2 protein
PBX1
pre-B-cell leukemia homeobox 1
PES1
Pescadillo Ribosomal Biogenesis factor 1
POM121
transmembrane nucleoporin pseudogene
PRC2
polycomb repressor complex 2
RHOA
Ras homolog family member A
TEX10
testis expressed 10
TIMP1
tissue inhibitor of metalloproteinase 1
WDR18
WD Repeat Domain 18
ZC3HAV1
Zinc finger antiviral 1
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Written By
Maria Radanova
Reviewed: 25 August 2023Published: 03 October 2023
Open access peer-reviewed chapter - ONLINE FIRST
