The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia

The insulin-like growth factors (IGFs) are polypeptides with similar sequences with insulin. These factors regulate cell growth, development, maturation, and aging via different processes including the interplay with MAPK, Akt, and PI3K. IGF signaling participates in the pathogenesis of neoplasia, insulin resistance, diabetes mellitus, polycystic ovarian syndrome, cerebral ischemic injury, fatty liver disease, and several other conditions. Recent investigations have demonstrated the interplay between non-coding RNAs and IGF signaling. This interplay has fundamental roles in the development of the mentioned disorders. We designed the current study to search the available data about the role of IGF-associated non-coding RNAs in the evolution of neoplasia and other conditions. As novel therapeutic strategies have been designed for modification of IGF signaling, identification of the impact of non-coding RNAs in this pathway is necessary for the prediction of response to these modalities.


BACKGROUND
The insulin-like growth factors (IGFs) are involved in growth and developmental processes and are evolutionarily conserved among several species (Rosenzweig, 2020). The functions of IGFs are mediated through two receptor tyrosine kinases and receptors for IGF1 and insulin. Besides, several IGF binding proteins selectively inhibit IGF1 or IGF2. IGF1 receptors have been shown to be up-regulated in tumors, thus participating in the tumorigenesis, resistance to therapies, and facilitation of metastasis in various cancer kinds (Rosenzweig, 2020). IGF1 receptors are known inducers of the Akt and mitogen-activated protein kinase (MAPK) (Pollak, 2008). Besides, IGF signaling is involved in the pathogenesis of insulin resistance and other disorders (Rosenzweig, 2020). The contribution of IGF in the pathogenesis of a wide assortment of human disorders including neoplasia and other disorders is explained by its influence on energy metabolism and cell growth (Pollak, 2008). IGF1 acts downstream of the growth hormone and through activation of MAPK and PI3K pathways and anabolism, it promotes growth and maturation of almost all tissues. Therefore, it is also involved in the aging process (Wrigley et al., 2017). Figure 1 depicts an overview of Insulin-like growth factor (IGF) signal transduction and two downstream signaling pathways: PI3K/AKT and MAPK/ERK. The IGF signaling network is composed of three receptor tyrosine kinases (IGF1R, IGF2R, and INSR), three ligands (insulin, IGF1, and IGF2), and six serum insulin-like growth factor binding proteins (IGFBP). Figure 1 shows the IGF signal transduction and its downstream effectors.
Recent investigations have verified the influence of regulatory non-coding RNAs on IGF signaling . Most investigations in this regard have focused on long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) . LncRNAs are transcripts with sizes of more than 200 nucleotides which are principally produced by RNA polymerase II. These transcripts have various functions in the modulation of genomic structure, chromatin configuration, mRNA stability, alternative splicing, and enhancement or inhibition of transcription. The other types of regulatory noncoding RNAs, i.e., miRNAs mainly influence gene expression at the post-transcriptional phase via binding with the 3 UTR of their specific targets. Both classes of non-coding RNAs participate in the pathogenesis of human diseases. We designed the current study to search the available data about the role of IGFassociated non-coding RNAs in the evolution of neoplasia and other conditions.

IGF-ASSOCIATED miRNAs IN HUMAN DISORDERS
Several IGF-associated miRNAs have been dysregulated in neoplastic conditions. For instance, experiments in ovarian cancer cells have shown that miR−19a−3p suppresses the levels of IGF binding protein−3 (IGFBP−3), thus promoting the growth and migration of these cells. Notably, the expression of this miRNA can be modulated by NF−κB (Bai et al., 2019). Shastri et al. have demonstrated the inhibitory effects of the miR-29 family on IGF-1. Members of the miR-30 family can inhibit both IGF-1 and IGF-1R. Notably, calorie restriction has resulted in the over-expression of miR-29 and miR-30 in the normal liver and the liver being metastasized by breast cancer cells, indicating a possible role for dietary modifications in the management of liver metastases (Shastri et al., 2020). In nasopharyngeal squamous cell carcinoma cells, miR-30a inhibitor could reverse IGF-I-associated epithelial-mesenchymal transition (EMT). The IGF-1R/Src/miR-30a/E-cadherin axis has been identified as an important pathway in the regulation of EMT in these cells . miR-99a is another miRNA that can inhibit proliferation, migration, and invasion of breast carcinoma via suppression of IGF-1R (Xia et al., 2016). Being up-regulated in hepatocellular carcinoma cells, miR-155 can increase expression of IGF-II and IGF-1R, while decreasing IGFBP-3 expression. Through these pathways, miR-155 can increase proliferation, migration, and clonogenicity of hepatocellular carcinoma cells . In the same type of cancer, miR-342-3p can inhibit cell proliferation through the suppression of the IGF-1R-associated Warburg effect (Liu et al., 2018d). In colorectal cancer cells, the oncogenic protein IGF2BP2 has a functional interaction with miR-195 through which it regulates RAF1 expression and participates in the carcinogenic process (Ye S. et al., 2016). Meanwhile, can inhibit the expression of IGFBP3 through binding with its 3 -UTR, hence enhancing cell migratory potential and invasion of colorectal cancer cells . Supplementary Table 1 reviews the results of studies that displayed the role of IGF-associated miRNAs in the neoplastic conditions.
The interaction between IGF-related proteins and miRNAs has been also assessed in non-neoplastic conditions. For instance, IGF-1 is targeted by miR-17. This miRNA has been over-expressed in ox-LDL treated human umbilical vascular endothelial cells (HUVECs) in association with down-regulation of IGF-1. Up-regulation of miR-17 has enhanced cell viability and suppressed the apoptosis of ox-LDL exposed cells. Such effects have been accompanied by down-regulation of Bax and Caspase3 expressions, while up-regulation of Bcl-2, suggesting a role for miR-17 as a biomarker for coronary heart disease . Expression of miR-30a-3p has been elevated in the placenta samples of women with preeclampsia. This miRNA has been shown to regulate the expression of IGF-1, therefore influencing the invasive capacity and apoptosis of trophoblasts (Niu et al., 2018). Over-expression of miR-129 has suppressed proliferation and migration of Schwan cells and axonal outgrowth of dorsal root ganglion neurons through modulation of several targets including IGF-1 (Zhu H. et al., 2018).  in synovial tissues of patients with rheumatoid arthritis compared with those affected with osteoarthritis. Down-regulation of miR-143-3p has inhibited cell proliferation, enhanced apoptosis, and reduced production of inflammatory cytokines. miR-143-3p has been shown to target IGF1R and IGFBP5 and regulate the Ras/p38 MAPK axis (Liu et al., 2018c). In colonic smooth muscle cells, miR-155 has been shown to down-regulate IGF-1 FIGURE 1 | A schematic diagram of the insulin-like growth factor (IGF) signal transduction and main downstream effects. Both IGF-1 and IGF-2 could bind with plasma membrane IGF-1R and IGF-1/Insulin hybrid receptor leading to autophosphorylation of this target receptor in the intracellular β-subunits and thus triggering the catalytic function of the IGF-1R, while insulin binds only to the Insulin-R. IGFBPs could regulate the bioavailability of both IGF-1 and IGF-2 signaling cascades. The bioavailability of IGF-2 could also be regulated via binding to the IGF-2R which results in receptor-triggered internalization and endosomal degradation of IGF-2 in the lysosomes. Phosphorylated β-subunits could in turn create docking sites for the adaptor proteins IRS-1/2, and Shc that modulate the activation of two signaling pathways: PI3K/AKT and MAPK/ERK. Activation of the PI3K and AKT pathway leads to modulation of a variety of cell signaling cascades, such as regulation of TSC1/2 to suppress mTORC1 complex and modulation of 4EB-P1 and S6K1/2 phosphorylation, promoting cell survival via activation or suppression of major effectors like the Foxo transcription factors, BCL-2, BAD, and P27, upregulation of transformation of glucose to glycogen through suppression of GSK-3β, increasing protein synthesis, as well as suppressing apoptosis and autophagy. Activation of AKT family of kinases via PDK1 and mTORC2 leads to the phosphorylation at Thr308 and Ser473, respectively. Besides, docking of Grb2 to the phosphorylated IGF-1R β subunits could trigger the Ras/Raf/MEK/ERK axis. Shc binding to activated IGF-1R leads to stimulation of the MAPK/ERK cascade which regulates a kinase signaling pathway and eventually results in promoting cellular proliferation via enhancing transcription factors activities including ELK1. levels. Up-regulation of miR-155 has increased apoptosis of these cells and reduced the thickness of the related tissue in the diabetic mice, suggesting the role of this miRNA in the aggravation of colonic dysmotility . Figure 2 illustrates the IGF signaling cascade modulating by dysregulated miRNAs in various human diseases as well as cancers. Table 1 reviews the role of IGF-associated miRNAs in non-neoplastic conditions.

IGF-ASSOCIATED lncRNAs IN HUMAN DISORDERS
Several lncRNAs have functional links with IGF-related proteins. Wang et al. have demonstrated over-expression of circ_0014130 in Non-Small Cell Lung Carcinoma tissues and cells. Downregulation of this cirCRNA has suppressed cell proliferation and enhanced cell apoptosis in these cells. Circ_0014130 has functional interactions with miR-142-5p and IGF-1. Small interfering RNA-mediated circ_0014130 silencing has enhanced IGF-1 levels through up-regulation of miR-142-5p . Another study in this kind of cancer has shown up-regulation of HOXA-AS2 in the tumor samples. HOXA-AS2 silencing has decreased the expression of IGF2. Therefore, HOXA-AS2 promotes the migratory and invasive capacities of lung cancer cells by enhancing IGF2 expression . In cervical cancer cells, the expression of linc00319 has been increased. Linc00319 silencing has suppressed cell proliferation, invasion, and migration of cervical cancer cells. This lncRNA interacts with miR-147a to modulate the expression of IGF1R . DBH-AS1 is another oncogenic lncRNA in hepatocellular carcinoma. Up-regulation of this lncRNA has been associated with the down-regulation of miR-138. DBH-AS1 knockdown and miR-138 up-regulation have decreased cell viability, repressed colony formation, and increased cell apoptosis. DBH-AS1 enhanced tumor growth and activated FAK/Src/ERK axis by modulating the expression of miR-138 . H19 is another up-regulated lncRNA in melanoma. H19 silencing has increased the sensitivity of melanoma cells to cisplatin, suppressed colony formation, and enhanced apoptosis of cisplatin-resistant melanoma cells. This lncRNA regulates IGF-1 expression through modulation of miR-18b expression . Honda et al. have assessed the methylation pattern of the H19 differentially methylated region (DMR), loss of heterozygosity, and allelic expression of IGF2 in hepatoblastoma. They reported associations between biallelic IGF2 expression and hypermethylation of H19 DMR. On the other hand, the monoallelic expression of IGF2 has been correlated with normal methylation of this region. They Frontiers in Cell and Developmental Biology | www.frontiersin.org also reported over-expression of IGF2 and predominance of the embryonic P3 transcript in most hepatoblastoma with retention of imprinting (Honda et al., 2008). Table 2 summarizes the role of IGF-associated lncRNAs in cancers. Via regulation of the IGF−1 signaling pathway, H19 can modulate proliferation and apoptosis of male germline stem cells. H19 silencing has reduced the cell quantities in the seminiferous tubule (Lei et al., 2019). Expression of the lncRNA 150Rik has been enhanced in renal tissue of animal models of diabetic nephropathy and in mesangial cells cultured in hyperglycemic media. This lncRNA regulates mesangial cell proliferation through interacting with miR-451, thus regulating the IGF1R/p38MAPK axis . LncIRS1 has been shown to act as a molecular sponge for miR−15a, miR−15b−5p, and miR−15c−5p to modulate the expression of IRS1 a downstream target of the IGF1-R. Up-regulation of lncIRS1 has enhanced IRS1 expression and increased phosphorylation of AKT as an important element in the IGF-1 pathway. LncIRS1 can also regulate the expression of atrophy−associated genes and affect muscle atrophy . TUG1 is an up-regulated lncRNA in ox-LDL-exposed vascular smooth muscle cell (VSMC) and HUVEC. Its silencing has suppressed proliferation and enhanced apoptosis in ox-LDL-exposed VSMC but has exerted opposite effects in HUVEC. miR-148b has been identified as a target of TUG1 in these cells. In turn, miR-148b has been shown to target IGF2. Therefore, TUG1 enhances IGF2 levels by sequestering miR-148b . HCP5 is a lncRNA that is involved in the pathogenesis of polycystic ovarian syndrome (PCOS). Down-regulation of this lncRNA inhibits cell proliferation via inducing cell cycle arrest at the G1 phase and stimulating the mitochondrial apoptotic route. miR-27a-3p has been recognized as a direct target of HCP5. This miRNA can bind with IGF-1. Therefore, HCP5 can be involved in the development of PCOS via modulating the miR-27a-3p/IGF-1 axis (Luo L.-H. et al., 2020). Figure 3 represents the dysregulation of various types of lncRNAs which have a remarkable role in negatively modulating IGF1, IGF2, IGFBP2, and IGF-1R through the IGF signaling pathway in different human cancers. Table 3 summarizes the information about the role of IGF-associated lncRNAs in non-neoplastic conditions.

DIAGNOSTIC/PROGNOSTIC VALUES OF IGF-ASSOCIATED miRNAs/lncRNAs IN CANCERS
A number of miRNAs and lncRNAs which are functionally linked with IGF signaling have potential applications as diagnostic/prognostic markers in cancers. Zhuang et al. have demonstrated high accuracy of NEAT1 levels in distinguishing colon cancer tissues from normal ones (area under the receiver operating curve = 0.89) (Zhuang et al., 2020). Expression levels of the IGF-associated miRNAs miR-485-5p and miR-155-5p have been associated with the survival of patients with lung cancer and Wilms tumor, respectively . Also, Linc00319, H19, AFAP1-AS1, SNHG7, HOTTIP, linc01023, DLEU1, and NEAT1 have been identified as prognostic markers in diverse kinds of cancer ( Table 4).

IMPORTANCE OF IGF-ASSOCIATED PATHWAYS IN RESPONSE TO CHEMOTHERAPY
IGF-associated molecules have been involved in the resistance of cancer cells to chemotherapeutic agents. In some cases, miRNAs or lncRNAs have been identified as molecules that mediate this phenotype. For instance, H19 silencing has enhanced the sensitivity of cancer cells to cisplatin and increased apoptosis of cisplatin-resistant melanoma cells through modulation of IGF1 expression . In a number of ovarian cancer cell lines, IGF-2 expression has been higher in Taxol-resistant cells compared with chemosensitive cell lines. Transient IGF2 silencing has enhanced Taxol sensitivity in these cells. However, IGF1R blocking did not affect the chemosensitivity of these cells. These results have supported the role of IGF-2 as a possible therapeutic target in drug-resistant ovarian cancer (Brouwer-Visser et al., 2014). IGF-1 has been shown to confer resistance to docetaxel in prostate cancer cells. IGF-I treatment has reduced expression of miR-143 expression, while enhanced expression IGF-1R and IRS1, direct targets of this miRNA. Up-regulation of miR-143 has stopped IGF-I-associated resistance to docetaxel, reduced expressions of IGF-I, IRS1, and VEGF in these cells (Niu et al., 2017). Table 5 reviews the importance of IGF-related pathways in response to chemotherapy.

IGF SIGNALING PATHWAY IN TUMORIGENESIS AND PROGRESSION OF CHEMOTHERAPEUTIC DRUG RESISTANCE PROVIDING THE NEW CONCEPTS IN CANCER THERAPY
One of the major impediments to current cancer remedy endeavors is the induction of drug resistance by tumors. Despite recent improvements in diagnostic methods and surgical interventions, many aggressive tumors have a poor response to adjuvant or neoadjuvant chemotherapy and radiation. The   IGF signaling axis has been detected to have a pivotal role in the progression and development of a variety of tumors (Denduluri et al., 2015). The IGF-1R is involved in various human cancers, such as ovarian, breast, pancreatic, glioma, hepatocellular, lymphoma, and non-small lung cancers. In some cases, its anti-apoptotic attributes strengthen cancerous cells to resist the cytotoxic characteristics of chemotherapeutic agents or radiotherapy (Beauchamp et al., 2009;Dool et al., 2011;Awasthi et al., 2012;Zhou, 2015). Zhou et al. demonstrated that the IGF-1R kinase inhibitor nVp-ADW742 combined with temozolomide could trigger inhibition of P38, GSK3β, and AKT phosphorylation along with a considerable reduction in the intracellular expression levels of Bcl-2, P38, and GSK3β, thereby resulting in promoting response to chemotherapeutic drug temozolomide in medulloblastoma to a large extent (Zhou et al., 2011). Also, Vewinger et al. have illustrated that the IGF signaling pathway has an important role in HGNET-BCOR brain tumor since IGF-1R could be a significant target to improve the sensitivity of vinca alkaloids, vinblastine, doxorubicin, ceritinib, and actinomycin D as efficient drugs in patients affected with this kind of brain tumor. As a consequence, utilizing the offtarget IGF1R suppressor ceritinib may pave the way for the remedy of tumor cells driven by IGF1R and IGF2 (Vewinger et al., 2019). In another study, Valerie et al. have indicated that the activity of histone deacetylase inhibitors (HDACi) has reduced in Ewing sarcoma patients. Drug combinations of temozolomide with the dual ALK and IGF-1R inhibitor, AZD3463 could suppress AKT and STAT3 to promote the cytotoxic impacts of temozolomide, and thereby decreasing cell proliferation and enhancing apoptosis via cleavage of PARP and caspase-3 indicating that AKT and STAT3 activation could be modulated by ALK and IGF-1R signaling pathway (Sampson et al., 2015). Additionally, Refolo et al. have figured out that the combined treatment with regorafenib, vitamin K1, and two IGF-1R tyrosine kinase inhibitors GSK1838705A or OSI-906 could strengthen antitumor effects of the target drug, improving their actions and decreasing their toxicity to a large extent. Therefore, both IGF1-R inhibitors could enhance the pro-apoptotic and antiproliferative impacts of regorafenib and VK1 in hepatocellular carcinoma downregulating both MAPK and PI3K/AKT signaling pathways (Refolo et al., 2017). Supplementary   which cause cancerous cells to resist the cytotoxicproperties of chemotherapeutic drugs or radiotherapy.

EPIGENETIC REGULATION OF IGF-I, IGF-II, IGF-1R, AND IGFBPS OF IGF AXIS IN A VARIETY OF HUMAN CANCERS
Accumulating evidence indicates that dysregulation of epigenetic systems has an important role in cancer pathogenesis resulting in overexpression of altered target genes as well as malignant cellular transformation. Since the IGF axis could contribute to cancer progression and invasion, it is now widely accepted that aberrant methylation of IGFBP7, IGFBP-4, IGFBP-3, IGF-1R, IGF-1, and IGF-II promoters could be a potential factor in various common human cancers (Qian et al., 2011;Sato et al., 2011;Bolomsky et al., 2015;Ye P. et al., 2016). Beeghly et.al have demonstrated that differential promoter P2 and P3 methylation patterns of the IGF-II gene could be remarkably related to promoting the risk of disease progression in epithelial ovarian cancer, especially hypermethylation of P2 could be associated with unpleasant symptoms of this serious disease (Beeghly et al., 2007). Additionally, another research indicated that epigenetic alterations in the IGF signaling pathway could play an effective role in the emergence of hepatocellular carcinoma. Therefore, considerable demethylation and upregulation of IGFBP3 via employing 5-Aza-2 -deoxycytidine and trichostatin A therapy results in attenuating cell proliferation and decreasing colony formation in HCC cells (Han et al., 2015). Chang et al. have illustrated that hypermethylation of the IGFBP-3 promoter which dramatically suppressed the expression level of this target gene could be substantially related to poor prognosis among Non-Small Cell Lung Carcinoma patients. Therefore, utilizing demethylation agents to upregulate the expression of IGFBP-3 could pave the way for providing a pivotal remedial procedure for these patients (Chang et al., 2002 Frontiers in Cell and Developmental Biology | www.frontiersin.org  Doxorubicin via inhibiting IGF-1R and upregulating IGFBP-3 through p53 could lead to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Fabbi et al., 2015 cell death, decrease colony formation and invasion, inducing expression of the pro-apoptotic genes containing PUMA, p21, and BAX as well as caspase 3 cleavage and downregulating phosphorylation of AKT (Dar et al., 2010). Furthermore, Schayek et al. have indicated that hypermethylation of AR promoter in metastatic prostate cancer cells results in downregulation of IGF1R expression levels which indicates the fact that the IGF1R gene has been detected s a downstream target for AR action. Employing 5-Aza treatment could trigger demethylation of AR promoter and as a consequence the expression level of IGF1R could increase significantly which may consider as a promising therapy in human prostate cancer (Schayek et al., 2010). An overview of promoter methylation and epigenetic modulation of various genes relevant to the IGF signaling pathway in different human cancers is represented in Supplementary Table 3.

APPLYING REMEDIAL CRISPR AND siRNA STATE-OF-THE-ART GENOME EDITING SYSTEMS TO MANIPULATE THE IGF SIGNALING PATHWAY IN VARIOUS HUMAN CANCERS
It is now accepted that gene silencing via CRISPR-Cas9 and small interfering RNA (siRNA) is becoming an inevitable geneediting tool in biological research, especially to repair genetic defects via editing or knock out various genes related to the IGF signaling pathway. Via applying a CRISPR/Cas9 or siRNA genome editing tool, it could be possible to knock out or edit ectopic expression of various genes related to IGF signaling cascade through which we could be able to improve response to chemotherapeutic agents as well as attenuating tumor cell survival, proliferation, invasion, angiogenesis, and metastasis of different kinds to a large extent (Singh et al., 2008;Brouwer-Visser et al., 2014;Hussmann et al., 2017;Strub et al., 2018). Liu et al. have detected that knockdown of IGF2BP1 expression level through applying a CRISPR/Cas9 genome editing system could play a crucial role in repressing the expression levels of IGF2, Gli1, CD44, and Myc in skin SCC cells through which tumor cell proliferation and survival were suppressed considerably. Likewise, via utilizing siRNA-mediated knockout of IGF2BP1-bound lncRNA THOR, skin SCC cell growth could be suppressed dramatically (Liu et al., 2018e). In addition, another research demonstrated that silencing IGF1R expression through employing a CRISPR/Cas9 genome editing system leads to functional endpoint mechanism for TKI resistance in a targetable direction MET-amplification, and thereby resulting in improving response to treatment via suppressing resistance to Erlotinib in Non-Small Cell Lung Carcinoma cells and inhibiting epithelial-mesenchymal transition in tumor cells (Hussmann et al., 2017). Besides, Strub et al. have demonstrated that via applying a CRISPR-Cas9 screen targeting chromatin regulators the histone deacetylase SIRT6 haploinsufficiency could play an effective role in upregulating IGFBP2 expression level through promoting chromatin availability, H3K56 acetylation at the Frontiers in Cell and Developmental Biology | www.frontiersin.org  (Strub et al., 2018). Besides, another research indicated that POU2F3 can be expressed particularly in variant SCLC cancers that have the insufficient expression of neuroendocrine markers and markers of a chemosensory lineage. They applied domain-focused CRISPR screening as a suitable procedure to identify POU2F3 as a significant transcription factor in a subset of SCLC cells and to display other important associations in POU2F3-expressing SCLC lines, containing the lineage TFs SOX9 and ASCL2 and IGF1R. Besides, this strategy shed light on the fact that upregulation of IGFBP5 through employing lentivirus in POU2F3high SCLC lines could suppress tumor cell growth remarkably . Baade Rø et al. have illustrated that there are an extreme intricacy and interaction between the chemokine and cytokine network triggering migration. They have detected the positive relevance among the degree of cytokine-induced migration and phosphorylation of PAK. PAK phosphorylation was considerably elevated when tumor cells were triggered by combinations of SDF-1a, IGF-1, and HGF which could play an effective role in promoting myeloma cell migration to the large extent. Therefore, via utilizing small interfering RNA, the expression of PAK was downregulated leading to attenuating cytokine-driven migration (Rø et al., 2013). Another study detected that silencing expression of IGFBP-6 or IGF-I or IGF-II through applying siRNA mechanism as well as knockdown IGF-1R activity on fibroblasts could lead to altering fibroblast mobilization, attenuating tumor invasion and TME remodeling through the IGFs/IGF-1R axis in breast epithelial cells which can be considered as a helpful tool for pivotal therapeutic of breast cancer related to dysregulation of IGF signaling pathway (De Vincenzo et al., 2019

DISCUSSION
IGFs and the related signal transduction networks partake in the pathogenesis of cancers, diabetes complications, atherosclerosis, PCOS, and other disorders. Meanwhile, these signaling pathways are regulated by hundreds of miRNAs and lncRNAs. Several members of IGF signaling including IGF-I, IGF-II, IGF-1R, and    Bie et al., 2016 Frontiers in Cell and Developmental Biology | www.frontiersin.org IGFBP-3 are targets of regulation by miRNAs and lncRNAs. Therefore, understanding the complex interplay between these factors is a necessary step in the design of appropriate therapeutic options for these conditions. The importance of this task has been further underscored by the availability of several IGF-modifying modalities including receptor-specific antibodies, inhibitors of receptor kinases, and activators of AMP-activated protein kinases (Pollak, 2008). In addition to these types of therapeutics, a number of alternative medicines act by affecting the expression of IGF-related non-coding RNAs. For instance, bufothionine induces gastric cancer cell apoptosis via up-regulating miR-133a-3p which sponges IGF1R and regulates PI3K/Akt associated production of reactive oxygen species (Hu Z. H. et al., 2020). The data presented above indicate that most of the IGFassociated lncRNAs exert their roles via modulation of miRNAs. Examples of lncRNA/miRNA interactions in the IGF-related pathways are circ_0014130/miR-142-5p, Linc00319/miR-147a, TUG1/miR-148b, H19/miR-18b, HCP5/miR-27a-3p and DBH-AS1/miR-138. The association between lncRNAs/miRNAs and the IGF system has importance in regenerative medicine as well. IGF1R signaling has been shown to partake in the preservation of stem cell features and improvement of efficiency of stem cell therapy, as IGF1R-expressing stem cells exhibit strong pluripotent or multipotent features (Teng et al., 2018). Therefore, the lncRNA/miRNA-mediated regulation of IGF1R signaling might offer putative modalities for maintaining stem cell features and enhancing the effects of these therapeutics in clinical settings.
IGF-related miRNAs and lncRNAs can be used as potential markers for forecasting the prognosis of cancer. Moreover, expression levels of these transcripts can be used as diagnostic markers for neoplastic conditions. The importance of IGF signaling in the modulation of response of melanoma, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, colorectal cancer, and several other cancers to chemotherapeutic agents has been validated. Some lncRNAs and miRNAs such as H19, LUCAT1, miR-143, miR-497, and miR-223 are involved in this process. However, the role of other transcripts should be assessed in the upcoming researches. Based on the role of IGFrelated miRNAs and lncRNAs in the modulation of response o chemotherapeutic agents, these transcripts are putative targets for the improvement of the response of cancer cells to these agents.
Besides, promoter methylation of IGF-1R, IGF-1, IGF-II, and especially IGFBP-3 in various regions could be associated with cancer prognosis (Supplementary Table 3). Methylation patterns of these promoters are important for the regulation of their expression and could have pivotal clinical implications in various cancers. Re-expression of IGFBP-3 will be really helpful in curing the majority of aggressive tumors and can solve the problem of intratumoral heterogeneity.
Furthermore, employing CRISPR-Cas9 or siRNAs gene editing tools with the aim of knockdown of ectopic expression of target genes including IGF1R, IGF1, IGF2, IGFBP3, and IGFBP-6 can play an important role in attenuating the tumorigenesis characteristics as well as improving response to treatment in various human cancer cells. Utilizing this effective method will pave the way for future clinical advancement.

CONCLUSION
The advent of novel genome editing modalities and clarification of the role of epigenetic factors including both genomic marks and non-coding RNAs have raised the possibility of management of human cancers particularly neoplastic disorders with novel therapeutics. Meanwhile, concomitant assessment of expression profile and genomic marks of IGF-related genes using high throughput methods would facilitate appropriate stratification of patients with regards to possible response to each therapeutic option. Further investigations are needed to appraise the clinical application of novel therapeutic modalities that target IGF signaling and related lncRNAs.

Availability of Data and Materials
The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

AUTHOR CONTRIBUTIONS
MT and SG-F supervised the study, wrote the draft, and edited the submission. HS, AA, and MM performed the data collection, designed the tables and figures. All of the authors are contributed equally and fully aware of submission.