The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.


Introduction
The MYC family of proto-oncogenes consists of three genes-C-MYC, L-MYC, and N-MYC [1]. The name of the family was coined after the discovery of homology between the human gene C-MYC, overexpressed in various tumors, and the oncogene v-Myc, carried by the avian myelocytomatosis virus (myelocytomatosis) [2]. Subsequently, homologs of c-Myc were discovered for humans: N-Myc [3], and L-Myc [4]. This review focuses on the most studied proto-oncogene of this family, C-MYC (or simply MYC).
C-Myc is an extraordinary transcription factor, as it has been shown to affect the expression of up to 15% of all genes in the human body [5]. It controls the expression of genes involved in a wide range of cellular processes, such as transcription, translation, cell cycle [6,7], cell adhesion [8], and others. Along with other factors of the MYC family, C-Myc has an important role in mammalian embryogenesis, especially in the development of cartilage, the liver, the thymus, submandibular glands, and brown adipose tissue [9][10][11]. This factor is also crucial for the normal development and activation of various populations of lymphocytes [12][13][14]. To regulate transcription, c-Myc forms a heterodimer with the transcription factor Max. Together, they can bind to a conserved E-box sequence (CACGTG) to activate or enhance the transcription of various genes. Moreover, c-Myc can bind to other Disruption of the cell division mechanism is one of the main characteristics of malignant tumors. Many studies have demonstrated a correlation between the expression of the MYC gene and the rate of cell proliferation [25][26][27][28][29] (Figure 1). C-Myc controls the expression of a number of key cell cycle regulators by stimulating or suppressing the expression of certain miRNAs. Thus, an increase in the level of c-Myc activates the synthesis of a number of positive regulators of proliferation: cyclins D and E, cyclin-dependent kinases CDK4 and 6, negative regulators of cell division, an inhibitor of cyclin-dependent kinase Disruption of the cell division mechanism is one of the main characteristics of malignant tumors. Many studies have demonstrated a correlation between the expression of the MYC gene and the rate of cell proliferation [25][26][27][28][29] (Figure 1). C-Myc controls the expression of a number of key cell cycle regulators by stimulating or suppressing the expression of certain miRNAs. Thus, an increase in the level of c-Myc activates the synthesis of a number of positive regulators of proliferation: cyclins D and E, cyclin-dependent kinases CDK4 and 6, negative regulators of cell division, an inhibitor of cyclin-dependent kinase 1B (CDKN1B), and retinoblastoma protein (RB1). C-Myc also suppresses the expression VEGF family factors was also shown in non-small cell lung cancer [71]. Moreover, c-Myc stimulates the expression of miRNAs that control the synthesis of a number of angiogenesis inhibitors: members of the TGF-β signaling pathway (TGF beta receptor 2 (TGFBR2) and mothers against decapentaplegic homolog 4 (SMAD4)), thrombospondin 1 (THBS1), and connective tissue growth factor (CTGF) [30,76,77].
As can be seen from the above data, c-Myc is involved in almost all mechanisms of oncogenesis of various types of tumors. At the same time, it should be noted that a small change in MYC expression (sometimes less than two-fold) is often enough to change the processes of oncogenesis [78][79][80]. For effective and long-term suppression of the expression of this proto-oncogene, it is necessary to know in detail the mechanisms that control the transcription of this gene, the stability of its mRNA and its translation, as well as the factors responsible for the stability of the Myc factor itself [25,46,81] (Figure 2). Biomedicines 2021, 9, x FOR PEER REVIEW 5 of 39 family factors was also shown in non-small cell lung cancer [71]. Moreover, c-Myc stimulates the expression of miRNAs that control the synthesis of a number of angiogenesis inhibitors: members of the TGF-β signaling pathway (TGF beta receptor 2 (TGFBR2) and mothers against decapentaplegic homolog 4 (SMAD4)), thrombospondin 1 (THBS1), and connective tissue growth factor (CTGF) [30,76,77]. As can be seen from the above data, c-Myc is involved in almost all mechanisms of oncogenesis of various types of tumors. At the same time, it should be noted that a small change in MYC expression (sometimes less than two-fold) is often enough to change the processes of oncogenesis [78][79][80]. For effective and long-term suppression of the expression of this proto-oncogene, it is necessary to know in detail the mechanisms that control the transcription of this gene, the stability of its mRNA and its translation, as well as the factors responsible for the stability of the Myc factor itself [25,46,81] (Figure 2). The bromodomain-containing protein 4 (BRD4) is a universal transcription regulator which also controls the transcription of the MYC proto-oncogene ( Figure 2). Inhibition of BRD4 by thienotriazolodiazepine JQ1 in colorectal cancer cells reduces MYC expression and inhibits cell proliferation [82]. A similar effect is observed in retinoblastoma cells, where BRD4 inhibition induces cell cycle arrest and apoptosis [83]. In neuroblastoma, lung carcinoma, colon adenocarcinoma, and melanoma cells, dual PI3K/BRD4 inhibition by SF2523 contributes to a decrease in c-Myc levels and markedly inhibits the growth and metastasis of cancer cells [84,85]. Another bromodomain-containing protein, bromodomain PHD transcription factor (BPTF), can activate MYC expression. It has been shown that suppression of BPTF transcription and the use of BPTF inhibitors lead to a decrease in the expression of the MYC gene [86,87].
Proteins that interact directly with the c-Myc protein can also affect its gene transcription. In lung and breast cancer cells, a correlation was shown between the expression of the ZNF121 and MYC genes: during the siRNA-mediated knockdown of ZNF121, MYC expression decreased and, accordingly, when ZNF121 was overexpressed, MYC expression increased [88,89] (Figure 2). Among other things, suppression of the ZNF121 gene reduced the rate of proliferation in breast cancer cells [89].
It has been shown that in human fibroblasts, FOXO3a binds to the region in the c-MYC promoter, and this interaction activates the transcription of the c-MYC gene [90]. On the other hand, the interaction of the promoter of this gene with the proteins of the SMAD family leads to the suppression of expression of the MYC gene [91,92]. IGF2BP1/2/3 (mRNA-binding proteins of insulin-like growth factor 2) are able to bind to many mRNAs, including the c-Myc mRNA, recognizing the GG(m6A)C sequence, and The bromodomain-containing protein 4 (BRD4) is a universal transcription regulator which also controls the transcription of the MYC proto-oncogene ( Figure 2). Inhibition of BRD4 by thienotriazolodiazepine JQ1 in colorectal cancer cells reduces MYC expression and inhibits cell proliferation [82]. A similar effect is observed in retinoblastoma cells, where BRD4 inhibition induces cell cycle arrest and apoptosis [83]. In neuroblastoma, lung carcinoma, colon adenocarcinoma, and melanoma cells, dual PI3K/BRD4 inhibition by SF2523 contributes to a decrease in c-Myc levels and markedly inhibits the growth and metastasis of cancer cells [84,85]. Another bromodomain-containing protein, bromodomain PHD transcription factor (BPTF), can activate MYC expression. It has been shown that suppression of BPTF transcription and the use of BPTF inhibitors lead to a decrease in the expression of the MYC gene [86,87].
Proteins that interact directly with the c-Myc protein can also affect its gene transcription. In lung and breast cancer cells, a correlation was shown between the expression of the ZNF121 and MYC genes: during the siRNA-mediated knockdown of ZNF121, MYC expression decreased and, accordingly, when ZNF121 was overexpressed, MYC expression increased [88,89] (Figure 2). Among other things, suppression of the ZNF121 gene reduced the rate of proliferation in breast cancer cells [89].
It has been shown that in human fibroblasts, FOXO3a binds to the region in the c-MYC promoter, and this interaction activates the transcription of the c-MYC gene [90]. On the other hand, the interaction of the promoter of this gene with the proteins of the SMAD family leads to the suppression of expression of the MYC gene [91,92]. IGF2BP1/2/3 (mRNA-binding proteins of insulin-like growth factor 2) are able to bind to many mRNAs, including the c-Myc mRNA, recognizing the GG(m6A)C sequence, and by this binding, it stabilizes the mRNA. It has been shown that suppression of IGF2BP1/2/3 expression in cervical cancer and liver cancer cells leads to a decrease in the amount of c-Myc protein, as well as to a decrease in the rate of proliferation [93] (Figure 2).
AU-rich element RNA-binding protein 1 (AUF1) binds to AU-rich mRNA regions and triggers the mRNA degradation process. It has been shown that the suppression of AUF1 does not lead to a change in the level of MYC mRNA, but reduces the amount of c-Myc protein in cells, which suggests that AUF1 may affect the translation of this mRNA ( Figure 2). In addition, suppression of AUF1 led to a decrease in the rate of proliferation in leukemia, colon cancer, and cervical cancer cells [94,95].
C-Myc is a short-lived protein, so the mechanisms responsible for its stability and degradation play an important role in tumor development. In tumors with a high level of c-Myc, improper functioning of the mechanisms of its ubiquitination can be observed. It is important to note that different types of ubiquitin ligases have different effects on the stability of this transcription factor ( Figure 2). For example, ubiquitin ligase FBXW7 and E3 ubiquitin ligase adapter SPOP promote the degradation of c-Myc [96,97], while ubiquitin ligases SKP2 and HUWE1, on the contrary, improve the stability of this protein.
In multiple myeloma, suppression of HUWE1 expression leads to a decrease in c-Myc levels and inhibition of tumor growth [98]. Enzymes deubiquitinating c-Myc have also been shown to affect its stability. Thus, suppression of USP28 and USP36 reduces the c-Myc level and suppresses cell proliferation [99,100]. Glycosyltransferase OGT has been shown to enhance cell proliferation by stabilizing the c-Myc protein by combining it with β-N-acetylglucosamine [101]. Increased OGT expression was found in many tumors, including prostate [102], breast [103], lung, and colon cancers [104]. Lowering the level of OGT mRNA leads to a decrease in c-Myc protein in prostate cancer cells [102]. Another protein, cancer inhibitor of protein phosphatase 2A (CIP2A), has increased expression levels in colorectal cancer [105], stomach cancer [106], prostate cancer [107], and multiple myeloma [108]. CIP2A has been shown to prevent the degradation of the c-Myc protein by inhibiting the activity of phosphatase PP2A. Phosphatase PP2A dephosphorylates c-Myc at serine 62, which is necessary for ubiquitination by ubiquitin ligase FBXW7 and initiation of degradation [109] (Figure 2).
A more detailed understanding of the regulation of MYC expression in cancer cells opens up new targets for drug discovery and new approaches in the treatment of cancer. Recently, many groups of scientists have confirmed that non-coding RNAs play an important role in regulating cellular processes, blocking or activating the transcription and translation of this gene, or interacting with the c-Myc protein directly. In tumor cells, shifts in the expression of many non-coding RNAs may be involved in tumor development [110,111]. It is important that the expression of some RNAs is specific to certain types of cancer. This makes non-coding RNAs a convenient target for suppressing tumor development with minimal possible impact on healthy cells [112]. Among other things, non-coding RNAs have shown themselves to be a promising marker for the diagnosis of oncogenic diseases [113]. This diagnostic method is convenient, as non-coding RNAs can be easily detected in the cells and biological fluids of the patient. For example, the detection of lncRNA PCA3 in urine is widely used as a marker of prostate cancer [114]. Similarly, the lncRNA AA174084 in gastric juice is a potential biomarker for the early diagnosis of gastric cancer [115].
In this review, we will examine in more detail the effect of miRNAs, long non-coding RNAs, and circular RNAs on the expression of the MYC proto-oncogene in various types of cancer.

miRNAs
MicroRNAs (miRNAs) are a class of small, endogenous, single-stranded non-coding RNA molecules. They act as a sequence-specific tool that is widely used in nature to regulate gene expression. At the moment, several dozens of miRNA variants that affect the expression of the MYC gene have been analyzed. Most of these miRNAs bind directly to the mRNA of the MYC gene [30]. Others affect its level by regulating genes that control the stability of the c-Myc protein. For example, miR-375-3p suppresses the expression of the CIP2A gene, the product of which is involved in the stabilization of c-Myc due to the phosphorylation of Ser62 [116]. Another example in mouse hepatoma cells is miR-24 regulating the OGT gene that increases the stability of the c-Myc protein by combining with β-N-acetylglucosamine [117].
As described above, high expression of the MYC gene is characteristic of many types of cancers. In this regard, it is not surprising that in tumors, the levels of most miRNAs that control the expression of the MYC gene are often reduced. The possibility of using miRNA complementary to the MYC gene sequence is being considered as a targeted therapy for cancer [118,119]. The use of miRNA leads to a reduced survival rate of tumor cells of different types of cancer, suppression of their reproduction, and migration [120][121][122][123]. It is important to note that for some miRNAs that bind to the mRNA of the MYC gene, a protective effect for tumor cells was also revealed. Thus, it was shown that Hodgkin's lymphoma cells can have a high level of miR-24-3p, which limits the expression of CDKN1B/P27kip1 and MYC genes and also protects cells from apoptosis [124]. On the other hand, a reduced level of miR-24-3p is observed in breast cancer and nasopharyngeal carcinoma cells, increasing the metastatic potential of tumor cells [125,126]. In another study, it was found that hepatocellular carcinoma cells with a lower level of miR-17-5p have greater metastatic activity, but a lower survival rate compared to cells of this tumor with more highly expressed miRNA [127]. Several studies have shown that the expression of many miRNAs differs significantly both in normal human tissues and in different types of tumors [128,129]. Thus, to study the possibility of using miRNA in therapy, it is necessary to take into account which RNAs control c-Myc levels in different types of cancer and their mechanisms.
The expression, stability, and activity of miRNAs of the let-7 f various factors. The most interesting is the regulatory loop with crease in the level of c-Myc boosts the expression of the LIN28A and products trigger the degradation of the let-7 family miRNAs [203] cially expressed miRNAs can lead to stimulation of the endogeno by suppressing the MYC expression. It has also been shown that t this family increases in breast cancer cells in response to estrogen. effect serves to limit the stimulation of MYC expression by the sam other way to regulate miRNA activity is to inactivate them by bind RNAs, so-called competing endogenous RNAs (ceRNA). Thus, ceR let-7b in breast cancer cells, activating epithelial-mesenchymal tra and CCAT1 RNA binds miRNA of the let-7 family in hepatocellula ulating their proliferation and migration [140]. The role of ceRNA precisely in the next section. MiR-34 is another miRNA family that controls the expression of the MYC gene in various tumor types (Table 1). Reduced expression of miRNAs of this family in tumor cells is associated with increased metastatic activity in patients with prostate cancer [194], as well as breast, lung, and colon cancers, melanoma, and head and neck tumors [153]. An artificial increase in the expression of these miRNAs leads to suppression of the proliferation of gastric [163] and prostate [192] cancers, head and neck tumors [173], and B-cell lymphoma [204] and also suppresses the tumor transformation of kidney epithelial cells [199]. It has been shown that the tissue-specific factor gastrokine-1 stimulates the expression of miR-34a in gastric cancer cells, suppressing the expression of proto-oncogenes MYC ( Figure 3) and RhoA, which leads to a decrease in the ability of cells to migrate and invade [163]. Stimulation of miRNA miR-34a expression occurs when the tumor repressor p53 is activated [184]. Activation of p53 also leads to an increase in the expression of another miRNA, miR-145-5p, which also controls the expression of the MYC gene [154] (Figure 3). These data demonstrate that the stimulation of the expression of miR-34a and miR-145-5p is significant in the antitumor activity of p53 in various types of cancer. Overexpression of miR-145-5p considerably suppresses the proliferation of breast and colon cancer cells [154], lung cancer cells [181], prostate cancer cells [193], gastric cancer [167], and oral squamous carcinoma cells [189].

miRNAs That Control the Expression of the MYC Gene in Breast Cancer Cells
The influence of miRNAs of other families on the expression of the MYC gene has been shown in certain types of tumors. Thus, for breast cancer, in addition to the previously described let-7, miR-34, miR-145-5p, and miR-24-3p, a contribution to the regulation of MYC expression was shown for several other miRNAs with more distinct tissue specificity ( Table 1). For example, in addition to let-7, two other miRNAs that control the expression of the MYC gene are involved in coordinating the response to estrogen in breast cancer cells: miR-21-5p and miR-98-5p [136]. The expression of miRNAs miR-17-5p and miR-20a-5p that suppress the MYC gene is activated in breast cancer cells by the c-Myc factor, which demonstrates their participation in the negative regulation of the expression of this factor [152] (Figure 3).
MiR-33b and miR-93 have been shown to reduce MYC expression in bowel cancer cells ( Table 1). Suppression of the activity of these miRNAs leads to an increase in the ability of the tumor to grow and form metastases [155]. Four other miRNAs that control MYC expression were also found in cells of this type of cancer: miR-200b-3p, miR-182-5p, miR-182a-5p, and miR-320b ( Figure 3). The expression of all these RNAs is reduced in tumor cells, and their overexpression suppresses the proliferation of rectal cancer cells [156][157][158].
Regulation of MYC gene expression by miRNAs of the miR-320 family has been shown for liver cancer cells. Increased expression of miR-320a inhibits the ability of hepatocellular carcinoma cells to grow invasively [177]. MiRNA let-7, miR-148a-5p, miR-363-3p, miR-744-5p, miR-599, miR-9, miR-185-5p, miR-526b, miR-17-5p, and miR-122-5 are also involved in regulating the expression of the MYC proto-oncogene in liver cancer cells (Table 1). Constitutive overexpression of these miRNA suppresses the proliferation of cancer cells and their ability to invade [127,133,140,[174][175][176][178][179][180]. For three of these RNAs, miR-148a-5p, miR-363-3p, and miR-122-5, negative feedback was shown with the expression of the MYC gene ( Figure 3). Thus, c-Myc has been shown to directly inhibit the activity of these RNA promoters in liver cancer cells [174,179]. It is worth noting that unlike miR-148a-5p and miR-122-5, which directly interacts with the mRNA of the MYC gene, miR-363-3p suppresses the expression of ubiquitin-specific protease 28, that stabilizes the c-Myc protein [174]. For miRNAs miR-17-5p, miR-9, and miR-185-5p, positive feedback was shown with MYC gene expression; transcription factor c-Myc stimulates transcription of these miRNAs in liver cancer cells [133,178] (Figure 3). Interestingly, in contrast to miR-17-5p, the expression levels of miR-9 and miR-185-5p in tumor cells are higher than in normal tissues [178]. A high level of miRNA suppressing MYC expression can be combined with a high level of transcription of this proto-oncogene in tumor cells due to ceRNA, which binds and inactivates certain miRNAs. Therefore, earlier in the liver cells, an increased level of RNA CCAT1, which binds to miRNA of the let-7 family, was detected [140]. A specific ceRNA, Linc00176, was also found for miRNAs miR-9 and miR-185-5p. Its enhanced expression level disrupts the reverse regulation of MYC gene expression in hepatocellular carcinoma cells, creating conditions for consistently high MYC expression. For this reason, this ceRNA can be considered as an important target for the development of therapy [178].

miRNAs That Control MYC Gene Expression in Lung Cancer Cells
An intriguing study was devoted to the negative effect of cigarette smoke on the expression of miR-487b-3p in lung cancer cells. This RNA suppresses the expression of a number of proto-oncogenes, including MYC, and its constitutive expression leads to a decrease in the proliferation and ability of lung cancer cells to invade [182]. In addition to the RNA families let-7, miR-34, and miR-145 mentioned in other sections, the expression of the MYC gene in lung cancer cells is also controlled by miR-199a-5p, miR-449c-5p, and miR-451a ( Table 1). As expected, the expression levels of these RNAs in tumor cells are lower than in normal tissue, and a constitutive increase in their expression level leads to impaired proliferation and mesenchymal-epithelial transition of tumor cells [146,183,185]. Some miRNAs affect the expression level of the MYC gene by affecting the mRNA of factors that regulate the transcription of this oncogene. Thus, miR-4302 interacts with ZNF121 mRNA, lowering the level of the factor that activates the transcription of the MYC gene. The binding of this RNA by circRNA-103809 in lung cancer cells leads to an increase in the ability of the tumor for invasive growth [88] (Figure 3).

miRNAs That Control the Expression of the MYC Gene in Prostate Cancer Cells
In addition to the RNA families let-7, miR-34, and miR-145 mentioned before, the expression of the MYC gene in prostate cancer cells is controlled by miR-3667-3p and miR-33b ( Table 1). The expression of the latter in tumor cells is suppressed by the cullin-4B protein, the mutation of which is characteristic of different cancer types [195,197] (Figure 3). Recently, it has also been found that the expression of miR-449a in prostate cancer cells increases in response to ionizing radiation at a dose of 4-8 Gy and, by suppressing the expression of the MYC gene, increases the sensitivity of these cells to radiation. Increasing the expression of such RNAs can be used to enhance the effectiveness of tumor radiotherapy [196]. In prostate cancer cells, dysregulation of MYC expression was also found due to an increased level of ceRNA MYU, which is able to bind to miRNA miR-184 [198] (Figure 3). The same miRNA is involved in the regulation of c-Myc levels in nasopharyngeal cancer cells. MiR-184 has been shown to inhibit MYC expression and tumor cell proliferation in response to increased levels of the tumor suppressor PDCD4 [188].

miRNAs That Control MYC Gene Expression in Blood Cancer Cells
Besides the RNA families let-7 and miR-34, the expression of the MYC gene in Burkitt lymphoma cells is controlled by miR-132-5p, miR-125b-1, miR-154, and mir-98 ( Table 1). The expression of these miRNAs is suppressed in tumor cells, and their constitutive expression inhibits the proliferation of lymphoma cells [120,121]. In other types of blood cancers, specific miRNAs involved in the regulation of MYC gene expression have also been discovered. For example, a low level of the miRNAs miR-451a and miR-709 has been shown to have an important role in the development of acute T-cell leukemia [200]. Suppression of the expression of two other miRNAs that control the level of the MYC protooncogene, miR-126-5p and miR-29a-3p, is necessary for the survival and reproduction of myeloma cells [187,205] (Table 1). The expression of miR-126-5p in myeloma cells is suppressed by histone methyltransferase MMSET, the level of which can be increased in tumor cells as a result of a translocation between chromosomes 4 and 14 [187] (Figure 3). Additionally, in acute myeloma cells, it has been revealed that the lncRNA CCAT1 binds to miR-155, which leads to an increase in the level of MYC expression [149]. The use of these miRNAs and their analogs for tumor therapy is not yet common practice, but the level of expression of some miRNAs can be regulated using low-molecular-weight substances. For example, PRIMA-1Met causes an increase in the expression of miR-29a-3p in multiple myeloma cells, which leads to a decrease in the level of c-Myc and reduces the survival rate of tumor cells [205] (Figure 3).

miRNAs That Control the Expression of the MYC Gene in the Cells of Tumors of the Nervous System
In glioma cells, the level of c-Myc is controlled by miR-29b-1, the expression of which is suppressed by neurotensin (Figure 3). Decreased expression of the neurotensin receptor restored the level of this miRNA and suppressed the proliferation of tumor cells [170]. In patients with glioma, there is an inverse correlation between survivability and the expression of another RNA, miR-135a-5p, which suppresses the expression of the MYC gene [172] (Table 1). In the cancers of the nervous system, glioma and medulloblastoma, miRNA miR-33b-5p disturbs the regulation of MYC expression [171,186]. When searching for small molecules as anti-cancer drugs, it was found that lovastatin can increase the expression of miR-33b-5p in medulloblastoma cells [186] (Figure 3).

miRNAs That Control the Expression of the MYC Gene in Thyroid Tumor Cells
Another RNA of the miR-33a family, miR-33a-5p, is involved in the regulation of MYC expression in thyroid cancer. Suppression of the expression of this miRNA may be associated with the activity of the XB130 protein, and inhibition of this factor led to stunted growth of tumor cells [202] (Figure 3).

lncRNA
Long non-coding RNAs can control the level of active factor c-Myc at different levels: (1) at the level of transcription, by attracting transcription factors to the MYC gene regulatory sequence; (2) at the level of mRNA stability of this gene, by recruiting specific miRNA; (3) at the level of protein stability and by regulating the efficiency of c-Myc binding to DNA regulatory sequences (Figure 4). Several lncRNAs have been shown to be involved in regulatory loops associated with MYC gene expression in different tumor types. For example, the lncRNA c-Myc inhibitory factor (MIF), found in B-cell lymphoma cells, is synthesized with the participation of c-Myc factor, but by binding miR-586 it activates the expression of ubiquitin ligase E3, which promotes the degradation of c-Myc factor. Increased expression of MIF lncRNA suppresses the proliferation of lung cancer and cervical cancer cells [59]. Another lncRNA involved in a regulatory loop with the MYC gene is the ovarian adenocarcinoma-amplified lncRNA OVAAL. This lncRNA stimulates the activity of the MAPK cascade, including ERK kinase, which stabilizes c-Myc factor by phosphorylating it at serine 62. OVAAL RNA expression, in turn, is stimulated by c-Myc factor. Increased levels of this lncRNA promote the survival and proliferation of melanoma and colon cancer cells [206]. The expression of an antisense lncRNA of glutaminase (GLS-AS) can be suppressed in some tumor types, and this correlates with high levels of glutaminase. This enzyme can interact with c-Myc, increasing its stability. Interestingly, c-Myc factor itself suppresses GLS-AS expression [207] (Figure 4).

lncRNAs Controlling MYC Gene Expression in Different Tumor Types
Several lncRNAs are currently known to regulate MYC gene expression in various tumor types (Table 2). Of these, the most studied is the ceRNA colon cancer-associated transcript-1 (CCAT1) whose increased expression was first detected in colon cancer cells in 2011 [208]. This lncRNA has been shown to stimulate tumor growth, vascularization, and metastatic activity [209]. Increased expression of CCAT1 was also found in leukemia,

lncRNAs Controlling MYC Gene Expression in Different Tumor Types
Several lncRNAs are currently known to regulate MYC gene expression in various tumor types (Table 2). Of these, the most studied is the ceRNA colon cancer-associated transcript-1 (CCAT1) whose increased expression was first detected in colon cancer cells in 2011 [208]. This lncRNA has been shown to stimulate tumor growth, vascularization, and metastatic activity [209]. Increased expression of CCAT1 was also found in leukemia, lung, gastric, liver, gallbladder, kidney, prostate, and ovarian cancer cells. CCAT1 lncRNA stimulated cell survival, proliferation, and migration in these tumors [149,208,[210][211][212][213][214][215]. Thus far, two main mechanisms of action of this RNA on MYC gene expression are known. Firstly, CCAT1 is involved in the spatial proximity of its locus (MYC-515), located 515 kb before the MYC promoter, and the enhancer (MYC-335), located 335 kb before the aforementioned promoter. This interaction enhances the transcription of this proto-oncogene in tumor cells [216]. Secondly, as mentioned in the previous section, CCAT1 protects the MYC gene mRNA by binding miRNAs let-7 and miR-155 [140,149] (Figure 4).   Uterine cervical cancer CCAT2 Up-regulated Progression of uterine cervical cancer [260] Another lncRNA from the same family, CCAT2, also increases c-Myc levels in colon cancer cells, but by recruiting the transcription factor TCF7L2 to the MYC gene promoter [226]. It was shown that the expression level of this lncRNA in ovarian cancer cells can be suppressed by vitamin D metabolites, which reduces the ability of tumor cells for invasive growth [253] (Figure 4). Additionally, high levels of CCAT2 lncRNA enhance the ability of osteosarcoma and hepatocellular carcinoma cells to invade and proliferate [241,250] and improve the resistance to radiotherapy of esophageal cancer cells [248]. The more common rs6983267(G) polymorphism variant of the CCAT2 gene has been shown to be associated with increased MYC gene expression levels and accelerated cervical cancer progression [260].
Another lncRNA affecting MYC expression in various tumor types is NEAT1, which forms specific nuclear structures called paraspeckles. These structures are involved in the maturation and retention of different types of RNA in the nucleus [261]. Elevated NEAT1 levels are associated with suppression of miR-34b activity and increased MYC gene expression in B-cell lymphoma cells [159]. In addition, NEAT1 is involved in the activation of histone acetylation in the MYC gene promoter region, activating its function [233]. It is worth noting that NEAT1 expression is in turn repressed by the c-Myc factor, which creates a negative regulatory loop [159] (Figure 4). Constitutive repression of NEAT1 lncRNA expression decreases proliferation capacity, reduces survival, and increases chemotherapeutic drug sensitivity in chronic myeloid leukemia [225], diffuse B-cell lymphoma [159], bladder cancer [219], uterine cancer [236], and rectal cancer [233,234].
Another lncRNA whose expression correlates positively with MYC expression is THOR. This lncRNA interacts with the insulin-like growth factor 2 mRNA-binding protein (IGF2BP1). The THOR-IGF2BP1 complex increases the mRNA stability of several proto-oncogenes, including the MYC gene [246] (Figure 4). Suppression of this lncRNA's expression leads to decreased proliferation and migration ability of colon cancer cells [228]. High THOR expression accelerates tumor transformation of retinoblastoma cells [258] and growth of osteosarcoma, nasopharyngeal, and renal tumors [247,251,257].
GHET1 lncRNA also increases the stability of MYC gene mRNA through interaction with IGF2BP1 protein (Figure 4). Suppression of this lncRNA expression in gastric and colorectal cancer cells leads to reduced c-Myc levels and suppression of tumor cell proliferation [230,262]. High levels of GHET1 lncRNA expression in tumor cells are associated with poor prognosis in patients with lung, breast, head and neck, nasopharyngeal, stomach, liver, pancreatic, bowel, bladder, and osteosarcoma cancers [218]. High levels of expression of LINRIS lncRNA have been detected in colon cancer cells. This lncRNA stabilizes IGF2BP2, another member of this family of proteins, that extend the lifespan of MYC mRNA [232] ( Figure 4).
Amplification of the locus containing the MYC gene has been observed in many tumor types. Moreover, the same locus contains several genes encoding lncRNAs. The expression of one such lncRNA, PVT1a, was shown to be up-regulated in 98% of tumors with amplification of the locus containing the MYC gene. Moreover, suppression of this lncRNA expression in such cells resulted in reduced MYC expression levels and suppressed proliferation [227]. It was found that PVT1a lncRNA can interact with the c-Myc factor, preventing its degradation. Suppression of this lncRNA's expression has been shown to reduce the ability of lung, colon, and bladder cancer cells to proliferate, migrate, and grow invasively [220,227,244,263]. Recently, it was also shown that PVT1a lncRNA stimulates invasive growth of hepatitis B virus-infected liver cancer cells through stimulation of MYC gene transcription; this lncRNA blocks histone methyltransferase EZH2, which inhibits MYC promoter activity through methylation of lysine 27 on histone H3 [240] (Figure 4).
While searching for potentially oncogenic lncRNAs, EPIC1 RNA was found. This lncRNA interacts directly with the c-Myc protein and stimulates binding of this transcription factor to the promoters of genes controlling the cell cycle. It has also been shown that lncRNA EPIC1 can moderately enhance the Myc-Max interaction [221] (Figure 4). In addition to binding to the c-Myc factor, EPIC1 lncRNA is a potential regulator of the AKT-mTORC1 signaling pathway. The mTOR-specific inhibitor rapamycin is used for the therapy of some types of cancer, but cases of resistance to this drug have been described [264]. EPIC1 knockdown makes resistant breast and ovarian cancer cells sensitive to rapamycin [252]. High expression of EPIC1 lncRNA accelerates proliferation of lung cancer cells [243] and cholangiocarcinoma cells [224] and enhances invasive growth of colon cancer cells [229].

lncRNAs Controlling MYC Gene Expression in Digestive Tumors
Several other lncRNAs controlling the level and stability of c-Myc factor in tumor cells were found for digestive system cancers ( Table 2). For example, Linc-RoR lncRNA stabilizes MYC gene mRNA in colon cancer cells by controlling its interaction with AU-rich element RNA-binding protein 1 (AUF1) and heterogeneous nuclear ribonucleoprotein I (hn-RNPI) [223]. The expression of this lncRNA was also elevated in esophageal tumors [249]. In oral squamous cell cancer cells, Linc-RoR lncRNA binds miRNA miR-145-5p, blocking its binding to MYC gene mRNA [190] (Figure 4). A similar mechanism has been described for other lncRNAs whose increased expression is associated with high levels of c-Myc in cancer cells of the digestive system. For example, in gastric cancer cells, the ceRNA HOXC-AS1 binds miR-590-3p [165], in colon cancer cells the ceRNA SNHG3 suppresses miR-182-5p activity [157], and ceRNA Linc00176 blocks the binding of miR-9 and miR-185-5p to MYC mRNA in hepatocellular carcinoma cells [178] (Figure 4). Enhanced expression of CMPK2 lncRNA, which stabilizes far upstream element (FUSE)-binding protein 3 (FUBP3) and promotes its binding to the MYC gene regulatory element, was also found in colon cancer cells, resulting in activation of transcription of the MYC proto-oncogene [235]. Under conditions of glucose deficiency in rectal cancer cells, GLCC1 lncRNA expression is activated, which activates the interaction of the transcription factor c-Myc with the heat shock protein Hsp90, which prevents ubiquitination and degradation of this factor [231] (Figure 4).

lncRNAs Controlling MYC Gene Expression in Urinary Tumor Cells
Increased expression of GClnc1 lncRNA is an indicator of lower survival chances in bladder cancer. High levels of GClnc1 significantly promoted cell proliferation, metastasis, and tumor invasiveness [217]. GClnc1 binds to LIN28B and activates this protein, and LIN28B, as described in the previous section, is involved in degrading the miRNA of the the miR-let-7 family that controls MYC gene expression (Figure 4).
For lncRNA FILNC1, the ability to bind to the previously mentioned AUF1 protein, which controls the stability of many cellular mRNAs, including MYC, was shown ( Figure 4). FILNC1 lncRNA expression in renal cancer cells is stimulated under conditions of ATP deficiency and leads to suppression of MYC expression and decreased tumor cell survival. Low levels of FILNC1 lncRNA in renal tumor cells are associated with a negative prognosis [256].

lncRNAs Controlling MYC Gene Expression in Prostate Cancer Cells
An interesting mechanism for regulating MYC oncogene expression was found in prostate cancer cell culture by switching the expression of three overlapping lncRNAs, NAT6531, NAT6558, and NAT7281. The scenario in the cell in this case is determined by the work of histone deacetylases. Their high activity promotes the transcription of only NAT6531 lncRNA. This lncRNA is a substrate for DICER nuclease, which slices it to form small RNAs that bind to MYC gene RNA and act as miRNA (Figure 4). Weak suppression of deacetylase activity increases the acetylation of histone H3 at the locus described, which blocks the transcription of NAT6531 and activates the transcription of lncRNA NAT6558. NAT6558 lncRNA does not form a loop that interacts with DICER nuclease and is not a source of small RNAs that decrease the half-life of MYC gene mRNA. When histone deacetylases are completely repressed, the longest lncRNA of this group, NAT7281, is synthesized and the transcription of NAT6531 and NAT6558 is blocked. Expression of NAT7281 leads to a strong suppression of MYC gene transcription [254] (Figure 4). Another lncRNA has been shown to be involved in the regulation of MYC gene expression in prostate cancer cells. PCGEM1 is a prostate-specific lncRNA that is up-regulated in various tumors of this organ and stimulated by androgens. This lncRNA interacts directly with the promoter region of the MYC gene, stimulating its transcription [255]. MYC expression was also found to be up-regulated in prostate cancer cells by elevated levels of ceRNA MYU which binds miR-184. Suppression of MYU RNA expression resulted in decreased levels of MYC expression and suppression of tumor cell proliferation [198]. Another ceRNA found in prostate tumors, PCAT-1, binds miR-3667-3p (Figure 4). Suppression of expression of this ceRNA results in reduced MYC expression and suppression of cancer cell proliferation [195].

lncRNAs That Control MYC Gene Expression in Breast Cancer Cells
Increased expression of LINC01638 lncRNA has been detected in breast cancer tissues compared to normal tissue. This lncRNA promotes the proliferation of breast cancer cells with a triple-negative phenotype. LINC01638 has been shown to interact with c-Myc and protect it from SPOP-mediated ubiquitination and degradation [97] (Figure 4). Reduced lncRNA levels of FGF13-AS1 have been detected in breast cancer cells and highly metastatic breast cancer cell lines. FGF13-AS1 inhibits tumor cell proliferation, migration, and invasion. This lncRNA binds specifically to the IGF2BP family of proteins and disrupts the interaction between IGF2BP and MYC mRNA. It leads to a decrease in the lifetime of MYC mRNA and, consequently, a lower level of the corresponding factor. Importantly, the c-Myc factor itself suppresses the expression of FGF13-AS1 [222] (Figure 4). Thus, any suppression of the expression or activity of this transcription factor can activate the FGF13-AS1 lncRNA-mediated regulatory mechanism, enhancing the suppression of MYC gene expression.

lncRNAs That Control MYC Gene Expression in Lung Cancer Cells
Several new lncRNAs affecting c-Myc factor expression have been found in lung cancer cells (Table 2). LINC01123 lncRNA in lung cancer cells forms a positive LINC01123/miR-199a-5p/MYC regulatory loop with c-Myc factor (Figure 4). Such regulatory loops may be a prospective target for therapeutic action, as suppression of the expression of this lncRNA inhibits the ability of cancer cells to proliferate [185]. An alternative isoform of the previously described PVT1 lncRNA, PVT1b, was also found in lung cancer cells. This isoform is synthesized under the influence of tumor suppressor p53 and, unlike the PVT1a isoform described above, suppresses the expression of the MYC gene (Figure 4). Increased expression of the PVT1b isoform in cancer cells slows down tumor growth [245].

lncRNAs Controlling MYC Gene Expression in Myeloma Cells
One important role of c-Myc factor in oncogenesis, as was mentioned earlier, is the formation of drug resistance in tumor cells. The role of PDIA3P lncRNA in this process has been demonstrated in multiple myeloma cells. This lncRNA interacts with the c-Myc factor and enhances its stimulatory effect on the glucose-6-phosphate dehydrogenase gene promoter (Figure 4), high levels of which allow for reducing the toxic effect of bortezomib on myeloma cells [56].

lncRNAs Controlling MYC Gene Expression in Medulloblastoma Cells
In nervous system tumors, gliomas and medulloblastomas, the regulation of MYC gene expression was found to be impaired by the binding of miR-33b-5p ceRNA DANCR (Figure 4). Suppression of this ceRNA's expression leads to decreased levels of c-Myc factor and slows down cancer cell proliferation [171].

Circular RNA
A new type of RNA, circular RNA (circRNA), has been discovered relatively recently. This RNA type is characterized by a closed-loop structure and is, therefore, more resistant against the action of nucleases than linear RNA molecules. CircRNA is formed by splicing, so the same gene can be transcribed to both linear and circular RNA molecules. Due to the absence of a 5'-end and hence no cap structure, most circRNAs in eukaryotes are non-coding. However, circRNAs can perform a number of functions described for lncRNAs: they bind miRNAs, interact with regulatory sequences of the genome, and bind to proteins, altering their functions [265,266].
The role of circRNA in the development of various types of tumors has not been studied as well as for lncRNA and miRNA (Tables 1-3). In this section, we focus on the variety of mechanisms by which they affect c-Myc factor formation, function, and degradation. Some circRNAs bind miRNAs in different types of tumors. For example, increased expression of the cyclic isoform of the aforementioned PVT1 RNA, circPVT1, has been observed in leukemia, gastric, and colon cancer cells. This circRNA can activate MYC gene expression by binding miR-125 and miR-145 ( Figure 5). Increased circPVT1 levels are associated with accelerated proliferation and increased tumor cell viability [267]. Similarly, circRNA_103809 enhances the ability of lung cancer cells to invasively grow by binding miR-4302, which suppresses ZNF121-dependent expression of the MYC gene [88] ( Figure 5). For another RNA, circCCDC66, the ability to up-regulate MYC gene expression in colon cancer cells through the binding of miR-33b and miR-93 was shown ( Figure 5). High levels of this circCCDC66 promote tumor growth and metastasis [155]. Additionally, high levels of this circRNA promote the development of gastric cancer [268]. Two other circRNAs, circLMTK2 and circ-PRMT5, have been shown to bind miR-150-5p, miR-145, and miR-1304 and increase MYC gene expression in gastric cancer cells ( Figure 5). Suppression of the expression of these circRNAs reduces the proliferation and migration of tumor cells [166,167] A circRNA, circ_0068307, was also found to stimulate MYC gene expression and bladder cancer cell proliferation by binding miR-147 [150]. Table 3. CircRNAs that control the expression of the MYC gene in tumors of various human organs.

Cancer circRNA Alteration in Cancer Mechanistically References
Glioblastoma circ-FBXW7 Down-regulated Suppresses cancer cell growth [274] Leukemia circPVT1 Up-regulated Promotes cancer cell proliferation [267] Liver cancer circ_0091581 Up-regulated Stimulates tumor growth [180] Lung cancer circRNA_103809 Up-regulated Stimulates cancer cell proliferation and invasion [88] Osteosarcoma CircECE1 Up-regulated Promotes cancer cell migration and proliferation [275] Squamous cell carcinoma circUHRF1 Up-regulated Promotes cancer cell proliferation [191] Thyroid cancer circ-ITCH Down-regulated Suppresses cancer cell migration and proliferation [276] circRNA_102171 Up-regulated Promotes cancer cell migration and proliferation [277] In some cases, circRNAs form regulatory loops with the MYC gene. For example, in gastric cancer cells, circ-NOTCH1 RNA is involved in the regulation of MYC gene expression. The expression of this circRNA is stimulated by c-Myc factor, while the RNA itself stabilizes MYC gene mRNA by binding miRNA miR-449c-5p [168] (Figure 5). Similarly, in oral squamous cell carcinoma cells, c-Myc factor activates the expression of circUHRF1 RNA, which in turn binds miR-526b, increasing the stability of this factor's mRNA [191].
Some studies are able to trace longer chains of interactions linking circRNA and c-Myc factor activity. Thus, in gastric cancer cells, it was shown that the RNA circHECTD1 binds miR-1256, thus activating expression of the USP5 gene which in turn leads to stabilization of β-catenin which activates expression of the MYC gene. Another RNA affecting βcatenin activity is circRNA_102171. This RNA binds to the β-catenin-interacting protein CTNNBIP1, resulting in increased β-catenin activity and MYC gene expression in thyroid cancer cells ( Figure 5). High levels of this circRNA stimulate tumor growth and the process of metastasis formation [277]. One more RNA which suppresses β-catenin activity in thyroid tumor cells is circ-ITCH. This circRNA binds miR-22-3p and increases the expression of CBL ubiquitin ligase, which suppresses β-catenin activity. Increased levels of circ-ITCH also suppress tumor growth and metastasis [276].
In addition to miRNA binding, circ-ITCH RNAs can influence MYC expression through direct interaction with the gene promoter. In colon cancer cells, circCTIC1 RNA binds BPTF and attracts it to the MYC gene promoter ( Figure 5). High levels of this circRNA enhance MYC gene transcription and cancer cell proliferation [272]. In contrast, another cir-cRNA, circNR3C1, inhibits the interaction of the BRD4 protein with the MYC gene promoter and suppresses the expression of this gene and bladder tumor cell proliferation [270].
CircRNA is also able to influence the stability and activity of the c-Myc factor itself. For example, the circRNA angiomotin-like1 (circ-Amotl1) binds to c-Myc factor and promotes its stabilization and transport to the nucleus. Increased expression of this RNA in breast cancer cells enhances tumor growth [271]. Another RNA, circECE1, also interacts with c-Myc protein and inhibits its ubiquitination and degradation ( Figure 5). Its increased level is associated with activation of osteosarcoma cell proliferation and migration processes, as well as increased oxygen-free metabolism [275]. CircRNAs have also been found to decrease the stability of the c-Myc factor. CircCDYL RNA does not affect the mRNA level of the MYC gene, but it decreases the level of the corresponding protein, apparently decreasing its stability. High levels of this circRNA suppress bladder cancer cell proliferation and migration [269]. In rare cases, circRNA can work by means of encoded polypeptides. For example, circ-FBXW7 encodes the FBXW7-185 protein that binds to ubiquitin-specific peptidase 28 (USP28 protein). This protein interaction causes accelerated degradation of the peptidase and disrupts the stabilization of the c-Myc factor by this enzyme (Figure 5). Increased expression of circ-FBXW7 in glioblastoma cells suppresses their proliferation [274].

Conclusions
Numerous data in this review demonstrate that с-Myc plays an important role in the development of a wide variety of cancers. According to current reports, MYC expression levels are elevated in approximately 70% of human tumors [278,279]. However, there are In rare cases, circRNA can work by means of encoded polypeptides. For example, circ-FBXW7 encodes the FBXW7-185 protein that binds to ubiquitin-specific peptidase 28 (USP28 protein). This protein interaction causes accelerated degradation of the peptidase and disrupts the stabilization of the c-Myc factor by this enzyme (Figure 5). Increased expression of circ-FBXW7 in glioblastoma cells suppresses their proliferation [274].

Conclusions
Numerous data in this review demonstrate that c-Myc plays an important role in the development of a wide variety of cancers. According to current reports, MYC expression levels are elevated in approximately 70% of human tumors [278,279]. However, there are still no drugs widely available in clinical practice which aim at suppressing the expression or activity of this oncogene [280]. Typically, low-molecular-weight compounds that specifically block the activity of the target protein are developed to block oncogene activity. However, the c-Myc molecule is not an enzyme and lacks the "pockets" to which low-molecular-weight inhibitors are usually matched [280,281]. To date, several molecules have been found that disrupt the binding of c-Myc and its partner Max, and stimulate c-Myc degradation by facilitating its phosphorylation by threonine 58 and subsequent ubiquitination [282]. A study of these molecules in animal models showed that the use of these inhibitors resulted in the enrichment of the tumor with cells with high PD-L1 expression, indicating the need for simultaneous use of c-Myc and PD-1 inhibitors [282]. Due to the high rate of change in c-Myc levels, prolonged and continuous exposure to these transcriptional factor inhibitors is required to effectively suppress its expression. The narrow therapeutic window of currently developed drugs makes it difficult to use them for tumor therapy [280].
An alternative approach to suppress c-Myc levels is the use of siRNA analogs. Two studies of such molecules currently exist, but both have been halted due to sponsor rejection (NCT02110563; NCT0231405). The use of RNA-and DNA-based drugs has been underdeveloped until recently due to low stability, difficulties in targeted delivery, and possible side effects [283]. However, the widespread use of RNA-and DNA-based vaccines against SARS-CoV2 could significantly advance the use of RNA-and DNA-containing drugs. The use of nuclease-protected siRNA analogs and single-stranded DNA complementary to target RNA may be an effective way to reduce the expression of certain genes in the long term [284]. However, in the case of the MYC gene, the question of the optimal sequence selection for the annealing therapeutic molecule arises. Known natural miRNAs that inhibit c-Myc synthesis may have additional targets, which may vary for different cell types. In addition, the set of lncRNAs and circRNAs capable of blocking certain miRNAs may differ in different cell types. When selecting a target, it is also important to consider positive and negative regulatory loops. As one of the solutions, a more long-lasting effect can be achieved by simultaneously blocking several RNAs involved in different regulatory loops.
This review describes different types of RNA that control MYC gene expression in different tissues and tumor types (Tables 1-3; Figure 6). Especially noteworthy is the diversity of different types of RNAs controlling the expression of this proto-oncogene in cells of digestive system cancers (Tables 1-3; Figure 7). Using tissue-specific regulatory RNAs rather than MYC gene mRNA as targets provides a potential opportunity to selectively influence c-Myc expression in cells of a particular tumor type. This may allow for creating a drug with a more selective effect and, consequently, a wider therapeutic window. It is worth noting that the studies on the role of different RNAs in the regulation of MYC expression in different cell types are not exhaustive, and some of the mentioned RNAs may function in a wider range of tissues and tumors than is currently known.
Thus, the information provided in this review indicates the possibility of developing a specific diagnosis and treatment for different tumor types. Since suppression of MYC expression can reduce cell resistance to chemotherapy and radiotherapy, the use of tumorspecific MYC inhibitors can be applied to create effective anti-tumor therapy options. ines 2021, 9, x FOR PEER REVIEW 26 of 39 Figure 6. Controlling MYC RNAs in different types of cancer except those of the digestive system. The fields indicate miRNAs, lncRNAs, and circRNAs that have altered expression compared to healthy tissues in a particular cancer. Arrows indicate an increased (green) or decreased (red) level of RNA in a particular type of cancer. The human body (the left part is a male, the right part is female) and the location of cancer tumors are presented schematically. The colored circles indicate a particular type of cancer: burgundy-multiple myeloma, orange-leukemia, pink-breast cancer, peach-uterine or endometrial cancer, yellow-sarcoma or bone cancer, lime green-non-Hodgkin lymphoma, teal-ovarian cancer, light blue-prostate cancer, black-skin cancer, gray-brain cancer, white-lung cancer, blue, yellow, and purple-bladder cancer, blue, pink, and teal-thyroid cancer, white and burgundy-head and neck cancer. The underlined RNAs are currently believed to be tissue specific but new roles can potentially be discovered. Controlling MYC RNAs in different types of cancer except those of the digestive system. The fields indicate miRNAs, lncRNAs, and circRNAs that have altered expression compared to healthy tissues in a particular cancer. Arrows indicate an increased (green) or decreased (red) level of RNA in a particular type of cancer. The human body (the left part is a male, the right part is female) and the location of cancer tumors are presented schematically. The colored circles indicate a particular type of cancer: burgundy-multiple myeloma, orange-leukemia, pink-breast cancer, peach-uterine or endometrial cancer, yellow-sarcoma or bone cancer, lime green-non-Hodgkin lymphoma, teal-ovarian cancer, light blue-prostate cancer, black-skin cancer, gray-brain cancer, white-lung cancer, blue, yellow, and purple-bladder cancer, blue, pink, and teal-thyroid cancer, white and burgundy-head and neck cancer. The underlined RNAs are currently believed to be tissue specific but new roles can potentially be discovered.