From inflammatory bowel disease to colorectal cancer: what’s the role of miRNAs?

Immune system plays a central role in the pathogenesis of IBD. In fact, this is an inappropriate response of the immune system to some intestinal microorganisms, which, in addition to the genetic predisposition, leads to the onset of IBD. Inflammation has no harmful nature and is an immune response to infection or damage with a beneficial nature led to the removal of aggressive agents, repairing structures and restoring tissue function. Acute phase of inflammation is associated with the rapid flow of immune cells, especially neutrophils and inflammatory macrophages to the affected tissue. Inflammatory macrophages have effect on the performance of tissue macrophages. In addition, several cytokines are produced by neutrophils and macrophages that play a very important role in immune response. These interactions cause common symptoms of inflammation such as heat, pain and swelling. When the harmful stimulus disappears, the inflammatory reaction is subsided, and the immune cells are returned to the phenotype and the number before the inflammatory reaction. In fact, acute inflammation is resolved and the tissue is restored, but if there is a disturbance in the resolving of acute inflammation, chronic inflammation will be developed resulted an increased tissue damage just as in IBD [23]. In intestine, a mucosal barrier prevents microbes from penetrating into lamina propria. The stability of this mucosal barrier depends on the existence of tight junctions between epithelial cells. In IBD, these tight junctions are loosened, so the mucosal barrier is weakened and the bacterial penetration increased to lamina propria which is followed by neutrophils, then macrophages enter to the lamina propria to eliminate these bacteria and an inflammatory reaction begins. In IBD, CD4⁺ T cells and innate immune cells such as neutrophils and macrophages interact closely with each other. Thus the inflammatory signaling pathways such as NFκB and STAT3, as well as inflammatory cytokines, mediate these interactions in a way that Innate immune cells secrete cytokines such as TNF-α, IL-6, IL-1, IL-12, IL-21, IL-22 and IL-23 resulted an increasing of pro-inflammatory CD4⁺ T cells recruitment to lamina propria. These cells also secrete cytokines that increase the number of innate immune cells which is resulted in the continued cycle of inflammatory response and chronic inflammation [13, 24, 25]. Some of these cytokines can directly affect the epithelial cells and stimulate signaling pathways which are involved in tumorigenesis.

T cells, based on their glycoprotein co-receptor that they have in their surface, are divided into two major CD4⁺ and CD8⁺ groups. CD4⁺ T cells play an important role in the pathogenesis of IBD and CAC and divided into two groups under the names of effector cells and regulatory cells [13]. Th1, Th2 and Th17 are three main categories of T-effector cells and secrete very important cytokines. Interferon γ is the most important cytokine produced by Th1 cells, while Th2 cells secreting IL-4 significantly. IL-17, IL-22 and IL-21 are also secreted by Th17 cells. Regulatory T cells play a role in regulating the activity of T-effector cells and immune tolerance, and secrete cytokines such as TGF-β usually play anti-inflammatory activity role. CD8⁺ T cells which are known as killer cells are closely interacting with T-effector cells. In fact, the function of CD8⁺ T cells that is very important in the fight against cancer cells is dependent on receiving signals from CD4⁺ T cells [13]. Th1 and Th2 cells appear to have opposing roles in CAC so that Th1 cells play a protective role; however, Th2 cells interfere with tumor stimulation [26, 27]. Despite the high similarities in the immune-pathogenesis of Crohn’s disease and Ulcerative colitis, there are some differences in the adaptive immune response between the two diseases. Th2 has been shown to be more involved in the pathogenesis of Ulcerative colitis, but, Th1 and Th17 are more involved in the pathogenesis of Crohn’s disease [13, 28]. Some of the phenotypic differences between Crohn’s disease and Ulcerative colitis mentioned in the introduction may be related to these differences in the adaptive immune response. For example, transmural inflammation in Crohn’s disease may be due to the predominant immune response of Th1 and Th17 cells, whereas mucosal inflammation in Ulcerative colitis is probably due to a more pronounced Th2 immune response [28]. Granuloma formation in Crohn's disease also appears to be associated with Th1 immune response and interferon γ [29, 30]. Granuloma formation begins following an inflammatory stimulus. As mentioned above, macrophages are recruited to the site of inflammation, as an important part of the innate immune response. Due to the events mentioned above and the chronic inflammation in Crohn's disease, this recruitment can occur continuously. Macrophages, in turn, by secreting cytokines such as TNF-α, IL-1, IL-6 and IL-12 can enhance leukocyte infiltration and T cell activation. Th1 cells can also further enhance the recruitment of macrophages to the area of inflammation by secreting chemokines and cytokines such as TNF-α, interferon γ, and IL-6. In a study of colon tissue granulomas of patients with Crohn's disease significant immunoreactivity was reported for IL-12 and interferon γ.

The secretion of interferon γ by Th1 cells is also involved in shifting the polarization of macrophages to the pro-inflammatory phenotype (M1), which will be discussed below [30‐32]. Continuation of successive cycles of inflammation and secretion of TNF-α and interferon γ by macrophages and Th1 cells leads to further maturation of macrophages [33]. This maturation of macrophages causes the formation of structures called epithelioid cells that are similar to epithelial cells. These epithelioid cells fuse together to form multinucleated giant cells, and eventually a structure called a granuloma can form [31]. In fact, granuloma is an organized structure consisting of activated macrophages aggregate (epithelioid and multinucleated giant cells), which are surrounded by lymphocytes [34]. As mentioned in the introduction, granuloma can be an endoscopic feature of Crohn’s disease that can help to distinguish Crohn's disease from Ulcerative colitis. Neutrophils and macrophages role are also inevitable in the progression of IBD to cancer. Neutrophils, in addition to the role played by inflammatory cytokines, play an important role in increasing the risk of colorectal cancer in patients with IBD by production of free radicals and carcinogenic compounds such as N-nitroso [35, 36]. Macrophages also play an important role in IBD and cancer. These cells are divided into two types of inflammatory M1 and anti-inflammatory M2. Inflammatory macrophages mainly inhibit cell proliferation, while M2 macrophages play a role in stimulating cell proliferation. Inflammatory macrophages release high levels of free radicals as well as IL-6, which play an important role in tumorigenesis. M2 macrophages play a role in neutralizing the destructive effects of these compounds, as well as repairing tissue damage. In fact, there is a balance between these two macrophages. Studies have shown that this balance is changed in progress of Dysplasia toward colorectal carcinoma in favor of M2 macrophages [13, 37]. In fact, M1 macrophages seem to play a role in cellular damage and initiate the process of tumorigenesis, while these are M2 macrophages that play a major role in progressing towards colorectal carcinoma. Another group of immune cells that appear to be involved in the pathogenesis of IBD are innate lymphoid cells (ILCs). These cells are originated from common lymphoid progenitors (CLPs) and divided into three groups, which are named from 1 to 3. NK cells and ILC1s are in group 1, ILC2s are in group 2 and ILC3s are in group 3 of these cells [38]. The number of NK cells in the lamina propria of patients with IBD (both Ulcerative colitis and Crohn's disease) appears to be increased [39].

These cells may be involved in the pathogenesis of IBD by secreting interferon γ and enhancing the differentiation of Th1 cells from naive CD4⁺ T cells. In addition, excessive amount of interferon γ has destructive effects on the tight junctions of the intestinal mucosal barrier [40], which is an important event in strengthening chronic inflammation in IBD. However, some studies in animal models of colitis have shown that NK cells, through NKG2A inhibitory receptors and direct cell–cell contact, attenuate the pro-inflammatory functions of neutrophils, including cytokine and ROS secretion, and have protective effects against colitis [41]. ILC1 cells have the ability to secrete interferon γ and express T-bet, which is a transcription factor. These cells can be developed from ILC3 cells [RORγt (+) ILC3] under the effect of IL-12. It seems that the frequency of ILC1 cells in the inflamed intestine of patients with Crohn’s disease increases [42]. Increased frequency of ILC1 in inflamed intestinal tissue of patients with established Ulcerative colitis has also been reported [43]. These findings suggest the role of ILC1 in chronic bowel inflammation. However, the exact mechanism of function of these cells in the pathogenesis of IBD is not yet clear and needs to be further studied. Increased ILC2 cell populations have also been reported in inflamed tissues of patients with newly diagnosed Ulcerative colitis, and patients with established Crohn's disease and Ulcerative colitis [43]. These cells have the ability to secrete IL-13 and IL-5, and in fact provide a primary source of Th2 cytokines [40]. ILC2 cells appear to be involved in maintaining the integrity of the intestinal mucosal barrier In addition, IL-13 derived from these cells may be involved in enhancing the differentiation of intestinal stem cells into Goblet and Turf cells and repairing intestinal damage [44]. IL-33, which can be released from damaged epithelial cells [45], appears to have an effect on ILC2 cells and this effect is involved in the pathogenesis of IBD, but contradictory results have been published in this regard. One study found that IL-33 deficiency impaired the differentiation of ILC2 and Th17 cells, and reduced levels of cytokines such as IL-6 and IL-1, which protected mice against DSS-induced colitis. The results of this study also showed that exogenous IL-33 causes exacerbation of colitis [46]. However, the results of another study showed that IL-33 had a protective effect against DSS-induced colitis by enhancing the expansion of ILC2 and Treg cells [47]. Therefore, further studies are needed to determine the exact mechanism of action of ILC2 cells in the pathogenesis of IBD. Besides, given that IL-33 appears to be involved in the progression of colorectal adenoma to colorectal cancer [48], it is necessary to study the role of ILC2 cells in the development of CAC.

ILC3 cells are another group of innate lymphoid cells that appear to be involved in the pathogenesis of IBD and CAC. Continuous expression of RORγt and aryl hydrocarbon receptor (AHR) is necessary for the differentiation and survival of these cells [38].Lymphoid tissue inducer (LTi) cells, NKp44⁺ ILC3s and NKp44⁻ ILC3s are subgroups of ILC3 cells. The majority of the populations of ILC cells in the intestinal lamina propria are NKp44⁺ ILC3s cells [40]. Interestingly, one study showed that the frequency of these cells in the inflamed tissue of IBD patients (both Ulcerative colitis and Crohn’s disease) was reduced [43]. These cells have the ability to produce IL-22 [40]. This cytokine has protective effects on IBD and can enhance the integrity of the intestinal mucosal barrier and induce antimicrobial compounds [49]. However, IL-22 can enhance STAT3 signaling in epithelial cells, increase proliferation, and play a role in colorectal cancer development [50]. NKp44⁺ ILC3s present in the inflamed intestinal tissue of patients with Crohn's disease appear to secrete less IL-22 but are capable of secreting interferon γ. NKp44⁺ ILC3s present in the inflamed intestinal tissue of patients with Crohn's disease appear to secrete less IL-22 but are capable of secreting interferon γ. These cells also enhance the accumulation of inflammatory monocytes by secreting GM-CSF, leading to promotion of intestinal inflammation [40]. Therefore, these cells seem to be involved in the pathogenesis of IBD and CAC, but their exact role is not yet clear and requires further study. Another group of immune cells that appear to be involved in the pathogenesis of IBD are NKT cells. The development of these cells depends on the thymus and most of them branch from CD4⁺ CD8⁺ double-positive (DP) thymocytes. In fact, majority of NKT cells branch out from the conventional development of T cells in the CD4⁺ CD8⁺ DP step [51]. These cells express surface molecules of both T cells (such as TCR and CD3) and NK cells (such as NKG2D and CD161), are divided into two types based on differences in TCR [52]. The population of NKT type 1 cells in the intestinal tissue and peripheral blood of IBD patients (both Crohn's disease and Ulcerative colitis) appears to decrease, but a significant accumulation of NKT type 2 cells in the intestinal tissue of patients with Ulcerative colitis has been reported [53]. It seems that the pathogenic role of NKT type 2 cells in Ulcerative colitis is exerted by the secretion of IL-13 and this cytokine can cause apoptosis of intestinal epithelial cells and play a role in the destruction of intestinal mucosal barrier. NKT type 1 cells from the lamina propria of patients with Crohn's disease also have the ability to secrete pro-inflammatory cytokines, such as TNF-α,IFN-γ, and IL-13, and are involved in the destruction of the intestinal mucosal barrier [54, 55].

Some studies have also shown that NKT type 1 cells have protective effects against colitis in mice by secreting IL-9 [56].In overall, type1 NKT cells appear to have both a protective and a pathogenic role in IBD but type2 NKT cells may enhance intestinal inflammation [52]. All of immune cells and cytokines produced by them involved in bowel chronic inflammation have an important role in developing CAC. As previously mentioned, the risk of CAC induced colorectal cancer among IBD patients. In recent years, extensive studies have been conducted to find out how IBD increases the risk of colorectal cancer. These studies have shown that chronic inflammation (a major characteristic of IBD) has harmful effects on intestinal epithelial cells. Free radicals and inflammatory mediators can cause DNA damage and mutation in important genes such as TP53 tumor suppressant gene. Additionally, chronic inflammation causes the epithelial cells to acquire the characteristics of stem cells which is called epithelial–mesenchymal transition (EMT) and eventually become a tumor cell [57]. Studies also provide significant information on cytokines produced by immune cells, key signaling pathways in developing CAC and also the role of miRNAs in all of these interactions (Fig. 2). Inflammation that is induced by microorganism leads to the removal of mucinous layer and penetration of bacteria in lamina propria and stimulate immune cell. The production of cytokine and inflammatory factors lead to the progression of IBD to colorectal cancer.

DNA damage and mutation can be the starting point for cancer development. Of course, cell has mechanisms to repair these injuries. If these mechanisms fail to resolve the damage, cell destroys itself with apoptosis process. However, if the apoptosis has not happened, some of these catastrophic mutations such as mutations in TP53 tumor suppressant gene push the cell into malignancy. In IBD patients, beside antioxidant defense impairment, the presence of oxidative and nitrosative stress and the production of free radicals of oxygen and nitrogen in high amounts by neutrophils, macrophages and epithelial cells have been observed [58‐61]. Free radicals not only damage DNA, but also appear to disrupt some repair mechanisms including mismatch repair [62]. Some inflammatory cytokines such as IL-6 and IL-22 also activate the signaling pathways of NFκB and STAT6 in epithelial cells.

These signaling pathways stimulate the expression of anti-apoptotic genes, so chronic inflammation not only causes DNA damage and impaired some restorative processes like mismatch repair, but also eliminates the cell from apoptosis, raising the risk of colorectal cancer in patients with IBD. Oxidative stress occurs when the balance between the production of free radicals and their clearing by antioxidant system is interrupted. In IBD, immune cells including macrophages and neutrophils, in addition to produce a high level of free radicals themselves by inducing enzymes such as NADPH oxidase and nitric oxide synthase (NOS) in colon cells could produce a high level of ROS and RNS [61]. The role of nitric oxide in pathogenesis of IBD and creation of DNA damage is very interesting. Nitric oxide can react with anion superoxide (a highly reactive free radical) and generates radical peroxynitrite (ONOO⁻) which is a very destructive oxidant factor in causing DNA fragmentation [61]. In addition, nitric oxide stimulates the production of TNF-α which is playing significant role in the pathogenesis of IBD and causing mutation and progressing to CAC. Accordingly, downregulation of nitric oxide synthase reduces the severity of colitis in mouse models [63, 64]. Furthermore, it has been shown that mesalazine (commonly used drug for IBD treatment) has antioxidant properties [65]. Some studies have also shown that some antioxidant compounds can be effective in protecting against DNA damage, as well as reducing colitis severity or even inhibiting the signaling pathway of WNT/β-Catenin, which is very important in colorectal cancer development and invasion [66‐68]. Although the role of free radicals in IBD and the early stages of tumorigenesis is a destructive role, it seems that these highly reactive compounds are useful in preventing invasion and in colorectal cancer treatment [69, 70], while antioxidants may play a destructive role in the end stages. It seems that, superoxide dismutase (an antioxidant enzyme) has been involved in EMT and tumor cell invasion in colorectal cancer [71]. In addition, strengthening the antioxidant system seems to be one of the mechanisms of resistance to chemotherapy in colorectal cancer cells [12]. The relationship between miRNAs and oxidant and antioxidant compounds is very interesting topic addressed recently. For example, it has been shown that miR-212 by targeting superoxide dismutase mRNA neutralizes the role of this enzyme in invasion of tumor cells [71]. MiR-143 is also another miRNA whose effects have been shown to induce apoptosis and inhibit the proliferation of colorectal cancer cells [72].

By exacerbating the oxidative stress, this miRNA reduces the resistance of colorectal cancer cells to treatment, thus it seems that the useful role of free radicals in colorectal cancer treatment appears to interact with miRNAs such as miR-143 [69] (Table 1). Adding that the harmful roles of free radicals as important factors in IBD and in the early stages of tumorigenesis are also likely to interact with miRNAs. For example, free radicals can activate miR-21 as important oncogenic microRNA and more interestingly this miRNA increases the production of free radicals by targeting antioxidant enzyme superoxide dismutase, suggesting a close relationship between this oncomiR and free radicals [73, 74]. MiR-21 also plays a very active role in the pathogenesis of IBD and is probably one of the miRNAs that play a very important role in colorectal cancer development in patients with IBD [13]. Some miRNAs such as miR-23a-3p play a protective role against oxidative stress. This miRNA increases the expression of superoxide dismutase enzyme, requiring more studies on IBD and colorectal cancer [75]. Identifying the mechanism of action and the use of these miRNAs or inhibiting miRNAs such as miR-21 may have a protective effect against oxidative stress and subsequent oxidative DNA damage in IBD patients and prevent the onset of tumorigenesis and progression towards colorectal adenocarcinoma. Chronic inflammation can also cause damage to DNA and mutation without free radical involvement. TNF-α increases the expression of activation induced cytidine deaminase (AID) in colon epithelial cells by activating NFκB and IL-4/STAT6 signaling pathways [76, 77]. This enzyme causes deamination and conversion of cytosine base to uracil in DNA structure, and it seems to play an important role in creating and development of CAC [77‐79]. Also, activation of this enzyme in the following of inflammation reaction is associated with an increase in the mutation of TP53 gene in colon cells [76]. Interestingly, it has been shown that in IL-10 (−/−) AID (−/−) mouse models, despite chronic inflammation, colon cancer does not occur and mutations in the Tp53 gene is significantly lower [80]. According to these findings, AID inhibition can be an effective approach to prevent CAC in IBD patients, and this inhibition can be done by miRNAs such as miR-93, miR-155 and miR-16 [81, 82] (Fig. 3A and B).

TP53 is the most important tumor suppressant gene in the body's cells, which encodes p53. In the presence of damage in DNA, p53 is phosphorylated and activated by ATM and ATR protein kinases. Activated p53 increases the P21 production in the cell, and by preventing phosphorylation of retinoblastoma protein activates P21, subsequently, stops the cell cycle in G1 phase so that repairing systems can repair DNA damage. In addition, P53 through increasing the transcription of apoptotic proteins plays a key role in induction of apoptosis [83], so mostly the mutation of genes of this tumor suppressor leads to cancer development. In many cancers including colorectal cancer, mutation occurs in TP53 gene. As previously mentioned, contrary to sporadic type in CAC, mutation occurs in TP53 gene in the first stages of Dysplasia. In fact, the early start of IBD progression towards Dysplasia is caused by the harmful effects of free radicals and inflammatory interactions on DNA. Subsequently, the impairment of repair and mutation processes in TP53 gene along with chronic inflammation resulted in the continuous production of inflammatory cytokines and high activity of STAT3 and NFκB signaling pathways have anti-apoptosis properties running Dysplasia towards colorectal adenocarcinoma. Alternatively, more mutations in TP53 gene of colon tissue with Ulcerative colitis compared to healthy people as another reason for high risk of colorectal cancer developing have been studied [84]. p53 seems to apply some of its anti-tumor effects by miRNAs. For example, p53 inhibits hypoxia-inducible factor 1 (HIF1) which is an angiogenesis stimulator transcription factor by stimulating the production of miR-107 and inhibiting angiogenesis (a vital process for cancer cells) [85] (Table 1). p53 also has an inhibitory effect on EMT via miR-15-a and miR-16-1 [86]. In addition, with increasing the levels of miR-16, p53 targets an important survival protein called Survivin and also inhibits proliferation of colon tumor cells [87]. Some miRNAs also apply their tumorigenic effect by targeting p53, and some other miRNAs enhance the antitumor function of p53. For example, miR-19b with targeting p53 can increase tumor growth, inhibit apoptosis, and increase invasion and metastasis, so it is suggested to inhibit this miRNA by using appropriate antagomiR as an appropriate therapeutic approach [88].

In contrast, miR-766 can inhibit the cell cycle by enhancing the function of p53 [89]. In addition, some studies have shown that increasing the expression of miR-203 and miR-22 in colon cancer cells with a mutation in TP53 can cause induction of apoptosis, inhibition of proliferation, decrease in survival and also increasing sensitivity to chemotherapy [90, 91] (Fig. 3C).

DNA methylation in CpG Island regions of promoter of genes is one of the ways to silence some genes and is a highly regulated process. Disruptions in this setting like hyper methylation of tumor suppressor genes can have catastrophic consequences. DNA methylation is performed by DNA methyl transferase enzymes (DNMT) and up to now three DNMT enzymes have been identified: DNMT1, DNMT3A and DNMT3B [92]. One of the destructive events that occur in IBD appears to be the increased expression of DNMT1 and DNMT3B in colon epithelial cells and hypermethylation of some important genes in inflammation and cancer such as some tumor suppressor genes, which is observed in active phase of disease [93, 94]. In pre-tumor cells as well as CAC tumor cells, the increased expression of DNMT1 has been reported compared to the sporadic type [95]. During chronic inflammation, cytokines such as IL-6 stimulate the expression of DNMT1 enzymes, and IL-6 possibly by inhibiting miR-148a and miR-152 plays an incite role because these miRNAs reduce the expression of DNMT1 enzyme [96, 97]. Hyper methylation of some miRNAs in colorectal tumor cells has been observed compared to healthy cells, which seem to play a role in weakening proliferation and inhibition of metastasis [98‐101]. In addition, increased miR-124a methylation raises the risk of colorectal cancer development in IBD patients, and likely the level of this methylation is directly related to the duration of IBD [102]. Considering the significance of this finding, the evaluation of methylation level of some miRNAs including miR-124, miR-16, miR-9 and especially miR-137 as a prognostic marker has been suggested to identify high-risk individuals for colorectal cancer development among IBD patients [103]. Some miRNAs play an antitumor role with targeting DNMT enzymes. For example, miR-506 and miR-124 inhibiting colorectal cancer progression and increasing sensitivity to chemotherapy by targeting DNMT1 and DNMT3B [104]. miR-342 is involved in inhibiting of proliferation and invasion of colorectal tumor cells by targeting DNMT1 [105] (Table 1). miR-143 also plays its tumor suppressor role by targeting DNMT3A [106] (Fig. 4A).

As previously mentioned, some of the signaling pathways such as NFκB, STAT3 and AKT/PI3K pathways play a very important role in the development and progression of CAC. NFκB is a transcription factor that has a great importance in the inflammation process. NFκB has two subunits called p50 and p65, which form a heterodimer complex. NFκB is in the cytoplasm and under the Inhibition of IKB in normal state is inactive for transcription. Pro-inflammatory cytokines and free radicals activate the enzyme called IKB kinase. This enzyme with IKB phosphorylation causes IKB ubiquitination and degradation. Subsequently, NFκB is released and goes to the cell's nucleus, where it increases the transcription of the genes involved in inflammatory response [107]. STAT3 is also a transcription factor involved in inflammation, cell growth and is also very important in controlling apoptosis. STAT3 is also present in cytoplasm and in response to inflammatory cytokines, especially IL-6 and IL-22 under the influence of JAK that is phosphorylated and comes in the form of dimer and goes to the nucleus [108, 109]. It seems that STAT3 has a twofold role in the pathophysiology of IBD. Though its important role in differentiating of Th17-effector has been specified, it affects Treg cells. Indeed, it affects the process of inflammation both stimulatory and inhibitory [110, 111]. The activation of STAT3 signaling pathway in IL-22-induced epithelial cells increases the cell survival and inhibits apoptosis, which is indicative of the importance of this signaling pathway in progressing IBD to cancer [112]. In addition to STAT3, NFκB signaling pathway is also very important in inhibition of apoptosis in epithelial cells, as some studies have shown that inactivation of NFκB pathway inhibits the expression of anti-apoptotic genes and reduces tumor size in animal models of CAC [113]. In human studies, an increase in the expression of NFκB in colon and peripheral blood has been also reported in patients with colorectal carcinoma [114, 115]. There is an interesting association between PI3K/AKT and NFκB signaling pathways. AKT/PI3K signaling pathway can also play an important role in the pathogenesis of CAC. This signaling pathway is started by the attachment of an extracellular ligand such as IL-6 to the cell surface receptors leading to phosphorylation and activation of PI3K. Active PI3K activates a secondary messenger called PIP3 with phosphorylation of membrane lipids, and this is PIP3 that activates AKT. AKT enhances cell survival, inhibits apoptosis and also increases cell proliferation [116, 117].

AKT can decompose IKB and release NFκB by phosphorylation of IKB kinase leading to enhancement of NFκB signaling [118]. Additionally, AKT is also associated with WNT/β-Catenin signaling pathway. Some studies have shown that activation of WNT/β-Catenin signaling pathway in T-effector cells, especially Th17 and Treg cells is involved in development of CAC [119, 120]. The above-mentioned signals are the most important signaling pathways involved in CAC development and progression. However, transcription factors and other signaling pathways are also related to CAC, among which SMAD proteins and aryl hydrocarbon receptors can be mentioned [121, 122] (Fig. 4B).

The activation of the NFκB and STAT3 signaling pathways in intestinal epithelial cells plays a major role in resistance to apoptosis and tumorigenesis. Some cytokines produced by immune cells have a receptor on the epithelial cells of intestine and can activate these signaling pathways in epithelial cells and enhance tumorigenesis. Therefore, one of the reasons for high risk of colorectal cancer in IBD patients is continuous production of these cytokines due to chronic inflammation. In this section, we review the most important role of these cytokines in the progression of chronic bowel inflammation to colorectal cancer, and discuss the association of miRNAs with these cytokines and their dependent signaling pathways.