Originally, research aimed at investigating miRNA expression profiles revealed differences in the expression of specific miRNAs in cancers. Recently, research has started to focus on the regulation and function of miRNAs. Several studies have investigated the specific influence of key inflammatory cytokines on miRNA expression. Overexpression of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1, IL-8, IL-10, IL-12, and TGF-β can either promote or inhibit cancer development [
18,
19]. Several miRNAs such as miR-155 and miR-21 have been implicated in cancer development and inflammation [
20], and they are controlled by inflammatory mediators, the most prominent being Toll-like receptors (TLRs), TNF, TGF-β, and other cytokines that link the functions of miRNAs with inflammatory events [
11,
20‐
24]. Table
1 describes the miRNAs implicated in both cancer and inflammation and their functions.
Table 1
Representative microRNAs implicated in both cancer and inflammation
miR-155 | Leukemias/lymphomas, breast, colon, lung, pancreatic, and gastric tumors | Promote the progression of inflammatory pathologies; targeting of key oncogenic suppressors or anti-inflammatory signal transduction pathways | TNF-a; IFN-γ/IL-12/IL-18 | |
miR-125b | Colorectal cancer (CRC), muscle-invasive bladder cancer (MIBC), ovarian cancer | A promising diagnostic biomarker for CRC and a promising prognostic parameter for MIBC; targeting proto-oncogene BCL3 | Peroxisome proliferator-activated receptor (PPAR)γ; interferon regulatory factor 4 (IRF4) | |
miR-21 | Almost all carcinomas and hematolgogical malignancies | Plays important roles in the oncogenic process by targeting PTEN, PDCD4, and BTG2 | TGF-β; STAT3; IFN | |
miR-196 | Pancreatic adenocarcinoma, breast cancer, ovarian cancer, oral cancer, Crohn’s disease | Promoting cell migration and invasion; promoting proliferation of and suppressing apoptosis | IFN-β; IκBα | |
miR-210 | Breast cancer, squamous cell carcinoma, renal cancer, sarcoma, bladder cancer, glioblastoma | Plays important roles in the regulation of cell growth, angiogenesis, and apoptosis | Hypoxia inducing factors (HIFs); IL-6; TNF | |
miR-126 | Inflammatory bowel disease (IBD); its expression is suppressed in cancers of the gastrointestinal tract, genital tract, breast, thyroid, and lung | Plays a key role in autoimmune and inflammatory diseases; can inhibit the progression of some cancers via negative control of proliferation, migration, invasion, and cell survival | NF-κB; vascular endothelial growth factor A (VEGF-A) | |
miR-132 | Upregulated during the inflammatory phase of wound repair; glioma | Critical regulator of skin wound healing; inhibits Smad7 expression | TGF-β1; TGF-β2 | |
miR-146 | Pancreatic carcinoma, papillary thyroid carcinoma, gastric cancer, breast cancer, non-small cell lung cancer | Control of the inflammatory response of cells of the innate immune system; plays a role in the development and maintenance of neoplastic processes | TNF; IL-1 | |
Aberrant miRNA expression leads to developmental abnormalities and diseases; however, the processes regulating miRNA biogenesis are largely unknown. miRNAs are transcribed as long and capped polyadenylated pri-miRNAs. The pri-miRNA is cropped into a hairpin-shaped pre-miRNA by the Drosha complex. Next, the pre-miRNA is translocated to the nucleus by exportin-5 and further processed by the Dicer complex. The resulting miRNA is dissociated and incorporated into the RNA-induced silencing complex (RISC), where it functions in gene silencing by promoting the degradation of target mRNAs or by translational inhibition. The identification of mechanisms of miRNA biogenesis regulation revealed that various factors or growth factor signaling pathways control every step of the miRNA biogenesis pathway [
52].
miR-155, which was the first miRNA shown to play an oncogenic role [
53], is overexpressed in a variety of tumors such as leukemia/lymphoma, breast, colon, lung, pancreatic, and gastric tumors [
25,
26]. Enhanced expression of miR-155 is often associated with increased cytokine expression, a prominent feature of inflammatory processes [
27,
54,
55]. For example, lipopolysaccharide (LPS)/TNF-α stimulation results in the upregulation of miR-155 and downregulation of miR-125b [
27]. miR-21 is upregulated in almost all carcinomas and hematological malignancies [
6] and is induced in macrophages and blood mononuclear cells upon lipopolysaccharide (LPS) challenge [
34] and in mammary epithelial cells by inflammatory signals [
35]. miR-210 links inflammatory signals with the hypoxic microenvironment, as it is induced in response to low oxygen and inhibited by the cytokines IL-6 and TNF [
42]. On the other hand, inflammatory cytokines can be modulated by miRNAs. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, are important transcriptional regulators of certain inflammation-related mediators [
8].