Long non-coding RNAs are important players in cellular function

The word epigenetics for most is the synonym for changes in the chromatin structure and DNA. However, it has changed in the last decades, and new elements of cellular control in response to physiological or pathological signals have transformed our knowledge considering epigenetics. Now, in the “modern era of epigenetic research”, we look not only at the chromatin and DNA state but also, which seems more fascinating, the action of various molecular regulators, such as non-coding RNA (ncRNA) [1] (Fig. 1). ncRNAs consist of constitutive RNAs: tRNA, rRNA, snRNA, snoRNA, and a group of regulatory RNAs: siRNA, piRNA, miRNA, NAT, circRNA, and lncRNA [2–4]. Though long non-coding RNAs (lncRNAs) are not translated into proteins, they become over time valuable and significant molecules. The lncRNAs consist of over 200 nucleotides and their activity enables them not only to interact with proteins and other RNAs but also to regulate gene transcription and expression through changes in the structure of chromatin [5, 6]. Specified types of lncRNAs play a role in signaling, decoying, guiding, and building scaffolds for proteins and other RNA molecules [7].

Figure 1. Two main branches of epigenetics elements involved in cell function can be distinguished and they are based on DNA and RNA level. On the DNA level, three main changes include: A. DNA methylation: which involves changes in methylation by adding methyl groups to the DNA molecule and when appeared in the promoter region; B. Histone modification which is a chemical modification of amino acids that build the histone proteins causing changes in specific genes’ regions; and C. Chromatin remodeling: which causes changes in chromatin structure and generates accessible and no-accesible parts’ of the genome. On the RNA level it is the production of different types of non-coding RNA molecules which are involved in: D. Regulation of mRNA and ncRNA levels by sponging mechanism and influencing transcription process; and E. Modification of RNA molecules by capping, polyadenylation, alternative splicing, and editing. All of these processes cause modifications in gene transcription

Fragments encoding lncRNAs can occupy intergenic or intragenic positions. Specific intragenic genes can be located in intron, enhancer, promoter, or 3’UTR flanking regions [5, 6]. Here, it is important to mention that the lncRNAs of interest are closely related to genes that are encoded in the vicinity of the paired mRNA, resulting in their interaction with each other. lncRNAs appear to play an important role in the regulation of gene transcription in the nucleus or subsequent post-transcriptional modifications in the cytoplasm. Despite the opportunities afforded by lncRNA research, many difficulties are still encountered in fully understanding them due to their location in the genome. It should be noted that more than 50% of lncRNAs are long intergenic non-coding RNAs (lincRNAs) with no annotated proteins but some short peptides can also be found [8]. The direction of transcription and the distance at which the transcript responsible for encoding protein is located from the lncRNA lead to the division of this group of RNAs into four classes: i) located on the same strand, ii) convergent, iii) divergent, and iv) isolated, which are located at least 50 kb from the closest protein-coding gene [15]. The main challenges in understanding the mechanisms of lncRNAs behavior are caused by different expression levels depending on tissue localization [10], frequent heterogeneity of isoforms, and numerous repeats in transcriptional initiation regions [11]. Moreover, as lncRNAs have been shown to vary with different expression levels, the specificity of their function in different cell types changes [12]. As it emerged, dysfunction of the activity or cellular mechanisms of lncRNAs may appear through pathological states including tumor progression through influence not only on the chromatin structure but also on several transcription factors [13]. According to GENCODE, NCBI Refseq, LNCipedia, and NONCODE number of lncRNAs’ genes is estimated between 56’946 to 17’952 locus which gives 27’381 to 172’216 transcripts [14–17]. It is proven that aberration of both coding and non-coding RNAs play a crucial role in cancer biology [18]. lncRNAs regulate cell growth, cell cycle, cell phenotype, migration and invasion ability, and apoptosis [7]. The functions and activity of lncRNAs are still being investigated. More and more new elements are added, such as the possibility of interaction of lncRNAs with RNAi molecules, for example UCA1, CASC2, GAS5, FER1L4, WDFY3-AS2, TP53TG1, FENDRR or SNHG1 lncRNAs with miR-18a [19]. What is more interesting, lncRNAs, such as MIR31HG, can be host genes for miRNAs and play a dual role as lncRNA and as a primary-miRNA transcript.

MIR31HG is a member of long non-coding microRNA-host-genes

MIR31 host gene (MIR31HG) belongs to a group of long non-coding microRNA-host-genes (lnc-MIRHGs) distinguished from lncRNAs due to coding the microRNA gene and transcript. MIR31HG functions in two specified RNA forms, as a long transcript, lncRNA, and as a host gene, which under processing is changed into a short non-coding RNA molecule, microRNA named miR-31. Dhir et al. estimated the distribution of miRNA between lncRNA and protein-coding genes and it is 82.5% and 17.5%, respectively. These lncRNAs can be divided into lincRNA (57.1%), pseudogene (13.2%), antisense (16.0%), and other (19.0%) types of transcripts. Moreover, these lncRNAs are the source of about 17.5% of miRNAs in humans [20].

It should be noted that lnc-MIRHGs are an under-studied class of lncRNAs in contrast to the well-known microRNAs which are hosted by them [21].

It is worth mentioning that miRNAs are transcribed as pri-miRNAs whose structure includes a terminal loop, stem, and 50 and 30 single-stranded overhangs at the ends. According to miRbase and GENCODE, there are 1’917 human miRNA genes, 1’917 hairpin precursors, and 2’654 mature sequences, and 1’881 miRNA genes [22]. Pri-miRNA does not perform the gene silencing function, so it is post-transcribed through canonical or non-canonical miRNA biogenesis pathways [23]. miRNAs, concerning their relationship with MIRHGs, can be categorized into: i) intronic, ii) exonic, ii) exon-intron junction (SO-miRNAs), and iv) intergenic miRNAs. These localizations in the gene and genome influence their biogenesis [21]. There are two main proposed biogenesis models of MIRHG and its intragenic miRNA: i) synergetic model which includes mirtron processing, cooperative of the splicing machinery and microprocessor, and a splicing-independent manner of miRNA production with the presence of splicing factors, and the second model, ii) competition model where miRNA production is alternative- and non-alternative-splicing-mediated. A detailed description of these two models is presented by Sun et al. [21]. It was shown that there is a correlation in expression between the miRNA and the corresponding MIRHG. Moreover, miRNA molecules, which are usually located within 50 kb, are derived from a single transcript. When miRNAs originate from an intron region, their expression is often correlated with MIRHG expression [26]. It should be noted that the expression of MIRHG can be regulated by tumor cells, more specifically by the promoters. The changes in methylation of the above promoters result in an altered expression of the encoded miRNA [27]. Moreover, in the case of intragenic miRNAs and their host, a negative feedback loop can be created which regulates the level of both transcripts [21]. It is worth noting that the expression of miRNA and MIRHG pairs is not always related in this way, but in some cases, it offers great diagnostic possibilities [27].

MIRHGs function as primary transcripts of miRNAs but some evidence indicates they also have the ability to act the role as lncRNA transcripts. Some authors show the miRNA-independent role of lnc-MIRHGs such as MIR22HG, MIR100HG, MIR205HG/LEADeR, RMST, CYTOR, LINC01138, LINC-PINT, MIR503HG, NEAT1, PVT1, H19 or MIR222HG, which are fully described by Sun et al. [25]. MIRHGs can be categorized as oncogenes or tumor suppressors, but this function can be specific to the type of cancer. MIRHGs can: i) act as ceRNA elements, ii) interact with DNA elements, or iii) with proteins as well as vi) regulate the interaction with proteins [25]. All these capabilities and functions make them an astonishing group of RNA molecules. Therefore, in this review we will continue to focus on one of them, MIR31HG, presenting the current state of knowledge.

MIR31HG — localization in the genome and biogenesis

The MIR31HG molecule has been known in the past by names: LOC554202, hsa-lnc-31, or lncHIFCAR. It is localized on chromosome 9 and consists of 4 exons. The length of the whole MIR31HG is about 150–106 Kb [28, 29]. According to GeneCards The Human Gene Database, the latest assembly of genomic locations shows that MIR31HG Gene is situated on the minus strand orientation on chr9:21’380’073-21’591’766 (GRCh38/hg38) and its size is estimated as 211’694 bases [29]. Based on GeneHancer (GH) data, 3 different enhancers and 2 different promoter/enhancer regions were distinguished for the MIR31HG gene, which creates regulatory elements and has the transcription factor binding sites such as: different TRIM, ZNF, MYC, STAT3, ZEB2, NANOG or EZH2 proteins [29].

MIR31HG is over 200 nucleotides long and it is transcribed by RNA polymerase II and the mature transcript is polyadenylated. Augoff et al. showed that the MIR31HG (LOC554202) transcript is 2’246 bp long and it does not encode any protein products [27]. Moreover, the MIR31HG gene does not encode any short peptides which could be produced by this type of transcript [29]. These features cause MIR31HG to be indisputably classified as a long non-coding RNA (lncRNA). However, MIR31HG belongs to the unique subtype of lncRNAs because, in the first intron of MIR31HG, it harbors a sequence of other type of ncRNA molecule which is classified as a short-noncoding RNA, named miR-31. It should be noted that this first intron contains a CpG island, which is responsible for the transcription regulation of both types of ncRNA molecules [27]. What is interesting, the MIR31HG transcript is not post-translationally modified and 32 different transcriptional variants are distinguished with a length between 287 and 10’980 bp. It should be noted that no orthologs or paralogs for MIR31HG have been identified up to date [29].

The expression level of MIR31HG is tissue-specific and according to the GENE NCBI, the highest expression is observed in normal tissue taken from the urinary bladder and the lowest in the pancreas, liver, and heart [28].

The biological function of MIR31HG

It is known that MIR31HG plays an important role in cellular processes whose disturbance causes cancerogenesis or increases the rate of this process. The most described, where MIR31HG is involved, are cell proliferation, cell cycle, invasiveness, EMT process as well as apoptosis. However, MIR31HG has also been described in the context of angiogenesis, hypoxia, senescence, or inflammation (Fig. 2).

Figure 2. Dysregulation and function of MIR31HG as a potential biomarker in different types of cancers. Red arrows indicate an increase, and blue, a decrease in the level of MIR31HG expression in a tumor of a given location

Cell proliferation and cell cycle

One of the most characteristic biological functions linked with MIR31HG is its influence on cellular proliferation. Nie et al. were the first to observe that upregulation of MIR31HG caused lower cell proliferation of gastric cancer cells in vitro and in vivo and its knockdown caused a reversed effect partly by regulating E2F1 and p21 [30]. Similarly, in HNSCC (head and neck squamous cell carcinoma) cells the knockdown of MIR31HG affects proliferation, cell cycle arrest in G1 or S phase, and apoptosis. This effect was caused by decreasing expression of HIF1A and CCND1, and increasing p21 on mRNA and protein levels [31]. However, the opposite effect was observed in the case of breast cancer, where silencing of MIR31HG expression inhibits the proliferative ability of the cells, and its function is linked with the POLDIP2 expression level [32]. Similarly, in lung squamous cell carcinoma (LSCC), inhibition of MIR31HG causes reduced cell proliferation, but the molecular way was not clearly explained [33]. Another study showed that MIR31HG knockdown inhibits not only cancer cell migration but also colony formation and cell proliferation [34].

In addition to the tumors’ model, also in the case of human periodontal ligament stem cells, the influence of of MIR31HG on proliferation was found. Methylation of the MIR31HG promoter induced by mechanical force causes reduced expression of MIR31HG and upregulation of IL-6, DNMT1, and DNMT3B. The changes in the stem cells’ proliferation can be overcome by DNMT1 and DNMT3B knockdown, which interact with the upstream region of the MIR31HG promoter and induce its expression [35].

Invasiveness and EMT process

The migration and invasive ability are also linked with MIR31HG. It caused higher invasiveness of breast cancer cells [32] as well as of lung cancer cells [33]. It was observed that in the case of non-small-cell lung carcinoma (NSCLC), reduction of MIR31HG expression was associated with the EMT process and manifested by reduction of Twist1 and Vimentin expression and upregulation of E-cadherin. Authors stated that MIR31HG causes changes in the Wnt/β-catenin signaling pathway by reduction of GSK3β and β-catenin and also its knockdown was linked with phosphorylation of GSK3β [33]. It should be noted that MIR31HG, depending on the cellular state, does not induce cancer cell invasion but promotes paracrine senescence [36]. The role of MIR31HG in the EMT process was also observed in osteosarcoma, where upregulation of MIR31HG caused down-regulation of miR-361. This effect was manifested by upregulation in the protein levels of miR-361’s target genes, vascular endothelial growth factor (VEGF), forkhead box M1 (FOXM1), and Twist in in vitro model and patients samples, as well as by downregulation of E-cadherin observed in cell lines after upregulation of MIR31HG [37].

Apoptosis

Feng et al. based on nasopharyngeal carcinoma indicated that the knockdown of MIR31HG causes inhibition of apoptosis by negative regulation of the PI3K/AKT signaling pathway [38]. Moreover, based on U2OS and Saos-2 cell lines it was indicated that apoptosis could be regulated by the expression level of miR-361 and its targets, VEGF, FOXM1, and Twist, as well as by changes in anti-apoptosis of B-cell lymphoma 2 (BCL2) and cyclin D (CCND1) proteins levels whose expression was inhibited by artificial up-regulation of MIR31HG [37].

Inflammation

Gao et al.’s studies identified the elevation of MIR31HG in psoriatic skin. The expression of two types of keratin, KRT6 and KTR16, was significantly up-regulated in keratinocytes from patients with psoriasis in comparison to normal samples, and MIR31HG-dependent. As mentioned before, also the cell cycle was changed after MIR31HG silencing in keratinocytes and it was shown that there were more keratinocytes in the G2/M phase relative to cells in the S phase, indicating that MIR31HG knockdown inhibits the proliferation of HaCaT keratinocytes. Moreover, it was indicated that stimulation of proinflammatory interleukin 17A (IL-17A), interleukin 22 (IL-22), tumor necrosis factor alpha (TNF-α), and interleukin 1 alpha (IL-1α) cytokines was able to elevate MIR31HG expression. It should be noted that BAY, NF-κB inhibitor, and p65 regulations additionally showed that NF-κB activation has an impact on MIR31HG [39].

Senescence

Senescence can also be induced in the presence of oncogenes as a response aimed at tumor suppression, such a mechanism is called oncogene-induced senescence. A group of researchers has shown that MIR31HG is also involved in this induction [40]. Montes et al. based on cell models, showed that MIR31HG plays a dual role depending on the localization in cytoplasm and nucleus. MIR31HG is overexpressed and translocates to the cytoplasm during BRAF-induced senescence and by kinase RSK causes phosphorylation of YBX1.Finally, it changes the senescence-associated secretory phenotype (SASP) of cells by IL1A translation activation [41].

MIR31HG can be used as a biomarker

The potential role of MIR31HG as a biomarker was analyzed on both the Cancer Genome Atlas (TCGA) data and collected samples by specified research groups or cell lines. However, independent research about the same cancer type was done in only a few cases [33, 34, 42–53]. A growing number of studies indicate that MIR31HG plays an important role in cancer as an oncogene or as a suppressor. It was shown that MIR31HG is down-regulated in gastric cancer [30], bladder cancer [34, 42], hepatocellular carcinoma [57], pancreatic ductal adenocarcinoma [58], and glioblastoma [65]. Moreover, up-regulation of MIR31HG was indicated in the case of breast cancer [32], head and neck cancer cancers [31, 67, 68], melanoma [54], cervical carcinoma [56], osteosarcoma [57], non-small cell lung cancer [33, 43, 44], lung adenocarcinoma [44–47], colorectal cancer [48–51], thyroid cancer [52, 53], as well as papillary thyroid cancer [64]. It should be noted that two independent studies checking the role of MIR31HG in esophageal squamous cell carcinoma indicated opposite expression levels of this lncRNA [59, 60].

Figure 3. MIR31HG functions as a modulator of important biological and cellular processes including cell proliferation, apoptosis, cell cycle regulation, EMT process, metastasis, angiogenesis, hypoxia, senescence, and inflammation

MIR31HG can be used as a diagnostic biomarker and it is detectable in tissue as well as in biological fluids such as plasma [31, 60]. Moreover, MIR31HG could describe the more invasive types of cancer, with advanced tumor–nodules–metastases (TNM) stages, lymph node invasion as well as distant metastasis [31, 32, 43, 54, 57, 59, 60, 62] and its higher expression is associated with worse disease-free and overall survival (OS). However, the opposite meaning of MIR31HG as a prognostic biomarker is observed in the case of bladder cancer [42], hepatocellular carcinoma [57], esophageal squamous cell carcinoma [59], and gastric cancer [30]. For these cancers, a higher expression level of MIR31HG is negatively correlated with more advanced TNM-stage [30, 42, 57], with lower tumor nodule number, vascular invasion [57], metastasis [57, 59] or poor tumor differentiation [59]. Analysis of patients’ survival revealed that the higher expression levels of MIR31HG were associated with longer survival for these types of cancers [30, 57, 59].

In the end, it should be noted that Chang et al. indicated potential features of MIR31HG as a predictive biomarker, and higher levels of MIR31HG were associated with increased cisplatin resistance [55], but there is only one study exploring this problem. All studies and results describing MIR31HG as a biomarker are included in Table 1.

“Small but crazy”: miR-31

miR-31 is a short non-coding RNA, classified as microRNA (miRNA), and is the product of specific cleavage of MIR31HG transcript. miRNA molecules can be responsible for controlling many genes in a differentiated way [69, 70]. miR-31 affects many processes not only in normally functioning cells, but is also important in disease and cancer processes. Based on results obtained from different tissues and cancer cell lines it was demonstrated that miR-31 exhibits a whole spectrum of expression depending on tissue type. It is worth mentioning that the miR-31 precursor was present in all tested cell lines but its mature form was predominantly found in tumor cell lines [71]. miR-31 regulates cell proliferation by affecting the genes responsible for this process, such as LATS1, and CREG, in vascular smooth muscle cells [72, 73]. An excellent example is the mechanism studied in colon cancer cells when miR-31 overexpression targets E2F2, which acts as a tumor suppressor on colon cancer cell proliferation [74]. As for Ewing sarcoma, the effect of miR-31 was identified as a tumor suppressor. In cell lines transfected with miR-31, there was a significant reduction in Ewing sarcoma cell proliferation, as well as increased apoptosis resulting in a decrease in tumor invasiveness [75]. The expression level of miR-31 in cervical cancer, CIN, and normal uterine tissues was also examined. The results proved that the expression in cancer cells was elevated compared to non-tumor cells, and in addition, this phenomenon appeared to be associated with the occurrence of lymph node metastasis (LNM). It was demonstrated that such an effect increases cell proliferation, and cell migration, and thus invasiveness is also significantly increased, indicating that miR-31 acts as an oncogene in this case [76]. In patients with non-small cell lung cancer (NSCLC), a relationship was discovered between the expression levels of MIR31HG and, consequently, miR-31, and the proliferation and clonogenic growth of tumor cells. The study showed that reducing their expression in vitro also reduces the growth of NSCLC cells, supporting the fact that miR-31 had an oncogenic effect [77].

Moreover, miR-31 plays an important role in the induction of senescence in breast cancer cells. Obtained results showed that overexpression of miR-31 affected the repression of the polycomb group (PcG) protein BMI1, accompanied by the induction of cell aging. This offers the prospect of manipulating miR-31 expression to control senescence and oncogenesis in breast cancer [78]. Few studies are based on healthy tissues and the effects on the aging of non-tumorigenic cells. For example, miR-31 influences aging by regulation of dystrophin protein. Increased expression of miR-31 resulted in direct inhibition of the translation of this protein which causes aging and damaged processes in muscle cells [79]. Capri et al. examined the miRNA expression levels to determine the age match between donor and recipient in the case of hepatocytes. It was indicated that miR-31 is hyper-expressed in older donors, at levels up to 4.5 times higher than in younger individuals. Interestingly, these results were only noted in male patients, and female samples showed only a trend of increased expression with age [80]. Moreover, it was indicated in the case of endothelial cells (umbilical cord-derived), that the fold change of miR-31 was one of the most upregulated miRNAs during the aging process [81].

It should be noted that miR-31 regulates cell differentiation and has a role in determining cell fate. Li et al. investigated neural stem cells (NSCs) and the process of their differentiation into motor neurons (MNs) and correlated changes in miR-31 expression with different states. Initial studies showed high levels of expression of this molecule in NSCs derived, for example, from the spinal cord, while much lower levels in MNs. Comparison of the expression profiles led to the conclusion that high levels of miR-31 have a stemness-maintaining effect in NSCs by inhibiting differentiation, especially in MNs [82]. Neuronal precursor cells (NPCs) appeared to be another cell in which miR-31 plays a role in differentiation. It was shown that Lin28, c-Myc, SOX2, and Oct4 act to inhibit the activity and expression of miR-31, consequently, impairing the process of NPC differentiation into astrocytes and astrocyte maturation itself in gliomas. As later analyses showed miR-31 also downregulates selected stem cell factors mentioned above, which may suggest a reciprocal control of these molecules in astrocytogenesis, where miR-31 plays a key role [83].

However, based on the PubMed.org database, only 5 studies took into account both types of transcripts, miR-31 and MIR31HG. Tu et al. observed co-upregulation of miR-31 and MIR31HG in oral squamous cell carcinoma, with a linear correlation between both ncRNAs estimated to R = 0.304 and p = 0.047 in patients’ samples [84]. Another study, done by Chang et al. showed that artificial upregulation of MIR31HG caused the significant elevation of MIR31HG and miR-31 in two cancer cell lines [85]. Surprisingly, Qin et al., in lung adenocarcinoma, indicated no correlation between MIR31HG and miR-31, and the down-regulation of MIR31HG did not cause decreased levels of miR-31 [45]. Moreover, some evidence indicates that MIR31HG does not always regulate the level of miR-31. It was pointed out that MIR31HG regulates miR-361 and downstream targets influencing cellular phenotype of osteosarcoma cell lines [37].

It is surprising that for some studies the authors did not analyze the common correlation between miR-31 and MIR31HG, which makes it difficult to assess the actual interaction of these molecules with each other [86].

Not only miR-31, but also other miRNAs interact with MIR31HG

lncRNAs can not only affect protein-coding genes, but also other RNAs. The “sponge effect”, as it is commonly known, involves the action of lncRNA on individual miRNAs, which directly results in the reduction of its effect on most mRNAs [44]. Recent studies have shown that MIR31HG expression is markedly upregulated in pancreatic ductal adenocarcinoma (PDAC). However, knock-out of this molecule resulted in inhibition of PDAC cell growth, apoptosis, and ultimately reduced invasion. Here, the researchers noted the inverse correlation of MIR31HG and miR-193b in these cells. When miR-193b was overexpressed, MIR31HG levels decreased significantly and vice versa. Such results demonstrate the negative regulation of MIR31HG by miR-193b. Closer examination using a luciferase reporter and RIP assays suggested that miR-193b bound to MIR31HG by blocking the binding sites of this molecule to miRNA. This activity of both molecules speaks to MIR31HG acting as a sponge binding miR-193b to regulate miRNA targets [87].

Conclusions and future directions

Allis and Jenuwein named RNA “one of the master molecules of epigenetic control” [1]. Not so long ago, ncRNAs were perceived as genetic noise and ignored in all analyses and treated as background or experimental errors [5, 88]. The development of new techniques, such as massive RNA sequencing, bioinformatics and even artificial intelligence (AI), caused an unbelievable growth in the number of discoveries of different types of ncRNA molecules [89, 90]. The public release of data from the The Human Cancer Genome (TCGA) project made it possible to analyze the data in terms of searching for, for example, lncRNA, in 33 different cancers [91, 92]. The TCGA is an immeasurable source of knowledge used as the first source of data for selection of genes and later validated in in vivo and in vitro models. Unfortunately, not all studies adopt this model of analysis. The lack of validation based on an in vivo or in vitro model is questionable as an effect of errors accumulation or assumptions of mathematical models. On the other hand, results derived only from in vivo or in vitro studies can be misleading as the consequences of the cell lines used or the set of patients. It is essential to apply a holistic approach when a study is designed. The lack of comprehensive research causes the knowledge about specific types of ncRNAs still not to be fully defined or validated experimentally. Moreover, many different studies indicated that one lncRNA could behave differently depending on the cancer type [7]. In some cases only one study defines the role of lncRNA in a specific biological process or pathway, which should be verified by independent study. The lack of such an approach is also visible in the case of MIR31HG. The second important question concerns the potential use of lncRNA as a biomarker. lncRNAs have all the characteristics of biomarkers, but there are no standardized methods for their measurement and testing [10]. Another issue to consider is which transcript variant should be taken into account. As mentioned earlier, MIR31HG has 32 different transcriptional variants, with a length between 287 and 10’980 bp [29]. In some cases, not all variants are equal and they could be expressed in different ways depending on the specific cancer subtype, and have various diagnostic potencies [34]. Most studies regarding not only lncRNAs, but also other types of transcripts, do not explicitly point which transcript variant or variants are being analyzed. Moreover, this information is not included in the TCGA data either. This causes great difficulties in the adaptation of lncRNAs as biomarkers in clinical practice. However, many studies indicated that lncRNAs may become important tools to predict the development and eventual treatment of cancer in the future [10]. Will they be as useful as classic markers? We assume that the answer to this question will be known within the next decade.

Conflict of interest

Concerning publication of the article titled: Host gene and its guest: short story about relation of long-noncoding MIR31HG transcript and microRNA miR-31, written by Tomasz Kolenda, Anna Paszkowska, Alicja Braska, Joanna Kozłowska-Masłoń, Kacper Guglas, Paulina Poter, Piotr Wojtczak, Renata Bliźniak, Katarzyna Lamperska and Anna Teresiak, the authors declare:

Financial disclosure

Article titled: Host gene and its guest: short story about relation of long-noncoding MIR31HG transcript and microRNA miR-31, written by Tomasz Kolenda, Anna Paszkowska, Alicja Braska, Joanna Kozłowska-Masłoń, Kacper Guglas, Paulina Poter, Piotr Wojtczak, Renata Bliźniak, Katarzyna Lamperska and Anna Teresiak, was supported by the Greater Poland Cancer Center — grant No.: 12/2021 (248), 10/11/2021/PGN/WCO/03 and other institutions listed in the acknowledgment.

Funding

This work was supported by Greater Poland Cancer Centre — grant No.: 12/2021 (248), 10/11/2021/PGN/WCO/03

While writing this manuscript, Alicja Braska received a “The best in nature 2.0. The integrated program of the Poznań University of Life Sciences” scholarship from University of Life Sciences in Poznań; Joanna Kozłowska-Masłoń received a PhD program scholarship from Adam Mickiewicz University in Poznan; Kacper Guglas received a scholarship from the European Union POWER PhD program; Piotr Wojtczak is a PhD student at Doctoral Studies, Medical University of Lodz. We would like to thank all the institutions supporting our scientific work.

References