Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, which arises from insufficient insulin secretion, insulin resistance, or augmented glucagon production. The world’s two most common diseases, cancer and type II diabetes (T2DM), share many overlapping risk factors and predisposing pathological conditions, with obesity as the most prominent. This suggests that a potential connection may exist between them. Recent epidemiological and clinical studies have shown a direct association between the incidence of diabetes and various types of malignancies, particularly hormone-associated cancer originating from pancreatic, breast, endometrial, or colorectal epithelium [1
]. Meta-analyses of both case-control and prospective cohort studies further confirmed that T2DM supports the development of these cancers with risk ratios ranging from 1.20 (95% CI, 1.11–1.30) for breast cancer to 2.6 (95% CI, 1.6–4.1) for pancreatic cancer [5
]. Some pancreatic cancer patients with DM were found to have a shorter history of diabetes (generally < 2 years) at the moment of cancer diagnosis, indicating that diabetes may not be the pre-existing disease, but that it may in fact be caused by pancreatic cancer [9
]. However, this situation has been recorded only in pancreatic cancer and may be explained by the fact that both DM and pancreatic cancer alter the biological functions of the same organ, the pancreas.
There are also cancer types for which epidemiological studies have revealed an inverse correlation for T2DM co-morbidity. For instance, a pooled analysis of 44 studies showed that T2DM reduces the risk of developing prostate cancer by 17%, suggesting that the interaction between diabetes and cancer is multifactorial and can be highly dependent on the tissue type as well as on the factors initiating the malignant transformation [10
]. Nevertheless, based on experimental, clinical, and epidemiological data, cancer is now considered as one of the most severe complications of T2DM.
Although the T2DM-cancer epidemiological relationship has been known for many decades, the exact mechanisms linking these conditions are yet to be fully understood. Considering obesity is a cause of the vast majority of T2DM diabetes, one underlying pathogenic mechanism could involve inflammation within adipose tissue with production of cytokines that interfere with insulin signaling, leading to resistance to insulin and decreased glucose clearing. The latter stimulates the pancreas to generate insulin, which leads to relative hyperinsulinemia [11
]. Thus, insulin and insulin-like growth factor type 1 (IGF-1) signaling pathways represent master regulators of pathophysiological processes directing obesity, DM, and cancer.
Non-coding RNAs (ncRNAs) refer to a large category of RNAs that commonly do not have protein encoding ability, but have a wide repertoire of biological functions through regulation of protein expression and functions [13
]. Among the different species of ncRNAs, the two most investigated classes are microRNAs (miRNAs) and the long non-coding RNAs (lncRNAs). The clustered miRNAs, miR-15a/16-1, located at chromosome position 13q14, are the first miRNAs identified in abnormally expressed in cancer (specifically down-regulated in B-cell chronic lymphocytic leukemia) [14
]. Since then, studies on the roles of miRNAs and lncRNAs in cancer biology have burst into the scene. Specific expression of various ncRNAs associated with tumor phenotypes have been identified, indicating their importance as predictive biomarkers for cancer diagnosis and prognosis, as well as prospective therapeutic targets [16
]. LncRNAs also impact gene regulatory networks and influence the essential pathological processes of cancer, such as metabolism [20
]. The insulin receptor (IR) and the IGF-1R, prevalently dysregulated signaling pathways in cancer and DM, have been reported to regulate or be regulated at different levels by ncRNAs [13
]. This integrative loop finely tunes multiple biological processes. By reviewing current literature, we aim to discuss the interaction between ncRNAs and the IGF-1R in the regulation of the carcinogenic process in patients with DM.
2. Role of IGF-1R Signaling in the Pathogenesis of DM and Cancer
The insulin and IGF family includes ligands, receptors, and proteins that modulate ligand bioavailability, also known as IGF-binding-proteins (IGFBPs). Currently, there are three recognized ligands (insulin, IGF-I, and IGF-II), along with three cell surface receptors, including the insulin receptor (IR), IGF-1R, and IGF-2R, and seven IGFBPs [22
]. During evolution in mammals, the IR gene has acquired an additional exon 11 that can be alternatively spliced generating two distinct isoforms: the full-length (exon 11+) IR-B, well known for its major role in controlling the glucose uptake and the shortest (exon 11−) IR-A also known as the “fetal” isoform for its recognized growth and anti-apoptotic roles during embryonic development [22
]. Nevertheless, the IR-A is also expressed in various adult tissues under physiological conditions (e.g., brain) or pathological circumstances (e.g., insulin-target tissues in type 2 diabetes or cancer cells) [22
The complexity of the system is further increased by the fact that cells expressing both IGF-1R and IR could generate IGF1R/IR hybrids, containing a half-IGF-1R linked to an insulin half-receptor. IGF-1R is activated mainly by IGF-I and IGF-II, while both IR-isoforms display almost the same high affinity for insulin [25
]. Yet, IR-A has a high affinity for IGF-II and low affinity for IGF-I, with the IR-B displaying low affinity for the IGF-II and much lower for the IGF-1. Therefore, hybrid receptors have different affinities for IGF-I, IGF-II, or insulin depending on whether the IR-B or IR-A is recruited to such hybrid receptors (for an extensive review of various ligand-receptor affinities please see [25
In addition to these classical members of the IGF-1R family, several other ligands (i.e., the antimicrobial peptide LL-37) [26
], and receptors (i.e., the orphan insulin-receptor-related receptor and the IR/IGF-1R hybrid receptor), could also be considered as members of the IGF-1R family [27
The IR, IGF-1R, and IR/IGF-1R hybrids are the only receptor tyrosine kinases (RTKs) expressed as preformed dimers. Each part of the dimer is comprised of extracellular α subunits and transmembrane β subunits, with the latter including the tyrosine kinase domain within the intracellular region [27
]. Binding of the ligand (IGF-I, IGF-II, or insulin) to the extracellular part of their cognate receptor leads to the autophosphorylation of three key tyrosine residues in the kinase domain, leading to increased kinase activity and subsequent phosphorylation of several other tyrosine and serine residues outside the kinase domain of IGF-1R or IR [22
]. This process, also known as canonical kinase signaling (Figure 1
), creates docking sites for downstream signaling molecules. These include insulin receptor substrates 1–4 (IRS1–4), and Src homology and collagen domain protein (Shc), which further activate several signaling pathways, including two of the most common dysregulated signaling pathways in cancer and DM: phosphoinositide 3-kinase (PI3K)-AKT and RAS-RAF-MAPK/ERK [22
]. Phosphorylation of extracellular signal-regulated kinases (ERK) and protein kinase B (PKB) are critical for the control of most biological processes that are associated with DM/cancer comorbidity, including cell proliferation, migration, and survival, as well as glucose metabolism through the activation of GLUT4-dependent glucose uptake [29
]. Some components of these kinase-activated pathways (e.g., mTOR complex 1, ERK1/2, and JNK) also trigger feedback control loops, by desensitizing the kinase signaling cascades [27
]. The IGF-1R, as many other RTKs, is able to initiate downstream signaling completely independently of ligand-binding through means of transactivation by other plasma-membrane receptors such as other RTKs, G-protein-coupled receptors (GPCRs), or integrins [30
]. Likewise, the IGF-1R could activate downstream non-kinase signaling pathways in a kinase-independent manner by employing the signal transduction machinery traditionally known to be used by the GPCR (e.g., the GRK/β-arrestin system and G-proteins) [32
]. Equally important, components of these non-canonical, kinase-independent pathways orchestrate feedback mechanisms controlling the IGF-1R expression, trafficking, and signaling [34
As critical initiators of these pathways, IGF-1R coordinates a complex downstream network and, thus plays essential roles in the regulation of cell growth, proliferation, survival, and cell motility, as well as on energy metabolism and glucose homeostasis. The role of IGF-1R in DM pathogenesis is complex, depending on different stages of DM. In the pre-diabetes stage, the interruption of IGF-1R signaling in the muscles and fat tissue, the primary tissues involved in the glucose metabolism will lead to insulin resistance and progression to DM [37
]. However, during development of DM, IGF-1R was found overexpressed or activated in other organs and tissues in response to hyperglycemia and hyperinsulinemia, thereby causing deterioration of DM. For example, IGF-1R was found to be overexpressed in the vascular smooth muscle cells and brain of a DM mouse model, causing atherosclerosis and diabetic encephalopathy, two common DM complications [39
]. Research has also shown that the IGF-1R ligand, IGF-II, is a key regulator of this feedback loop. Relatively elevated concentrations of insulin induced by insulin resistance boosts hepatic IGF-I synthesis and increases circulating IGF-I activity, which then also binds to IR, IGF-1R, and IR/IGF-1R to enhance the signaling [41
]. In conclusion, hyperinsulinemia in DM activates IGF1-R and triggers downstream target effectors. This review focuses on the IGF-1R due to its central role in the above presented signaling network. However, the importance of IGF-II, the most abundant peptide from the IGF family in human circulation, should also be highlighted, and was comprehensively reviewed by Holly et al. within this special focus issue [42
IGF-1R signaling also has crosstalk with molecules involved in inflammation, which is also a common biological process of DM and cancer. The overproduction of inflammation cytokines, in particular tumor necrosis factor-α (TNF-α) and interleukin-6, have been found to be associated with insulin resistance and the initiation and development of DM and cancer [43
]. These inflammatory reactions are partly influenced by the activation of intracellular mechanisms, the kinase-β/NF-κB axis, which has also been closely linked to IGF-1R signaling by AKT and its kinase function. In lung carcinoma, overexpression of IGF-1R induces the activation of AKT/MEKK3, and then promotes the response of NF-κB signaling to TNF-α. This effect could be abolished by the inhibition of PI3K or ERK [44
6. Concluding Remarks
The roles of the IR and IR/IGF-IR were reviewed, along with their association with ncRNAs in regulating DM and cancer [25
]. We discussed a number of well-known miRNAs and lncRNAs that regulate IGF-1R signaling in DM and cancer, and further highlight the potential underlying molecular pathogenesis of their comorbidity. Hence, miRNAs and lncRNAs are regarded as attractive potential biomarkers for diagnosis and therapeutic targets in DMs and cancer through the regulation of IGF-1R. Many studies have validated their role in diagnosing and monitoring the occurrence and development of DMs and cancer, some of them being currently explored in clinical trials to evaluate the diagnostic test sensitivity and efficiency. In addition, circulating miRNAs are more stable and can be detected in plasma, therefore they have been very promising as minimally aggressive biomarkers. Overall, ncRNAs have substantial potential as biomarkers in DMs and cancer. However, ncRNAs that regulate non-kinase signaling and the ncRNAs controlled by the activated IGF-1R warrant further investigation.
The principal therapeutic approach is to restore miRNAs that target and downregulate the IGF-1R expression and/or signaling during the development of DM, which is extensively discussed in previous reviews [116
]. Delivering miRNA directly or using exogenous recombinant viral vectors are two common therapeutic approaches under development. Although numerous in vitro and in vivo studies have proven that the strategy is feasible in the treatment of DM as well as in cancer, there are still challenging issues that need to be addressed for targeting the IGF-1R, especially in clinical settings [118
]. As discussed above, some ncRNAs have a complicated role in regulation, which makes the choice of intervention timing complicated. Collectively, this review demonstrates that ncRNAs involved in IGF-1R signaling, directly or indirectly, plays an important role in linking insulin resistance to DM and cancer.