The emerging role of Arid5a in cancer: A new target for tumors.

AT-rich interactive domain 5a (Arid5a) is a member of the arid family of proteins, which contain a helix-turn-helix domain and an ability to bind to nucleic acids. Current evidence suggests that Arid5a performs dual functions as a transcription factor and an RNA-binding protein in immune, nonimmune, and/ or tumor cells depending on its cellular localization. The contribution of Arid5a to the development of inflammation, autoimmunity, and obesity through its transcriptional and posttranscriptional regulatory functions has broadly been reviewed. Recent studies have indeed revealed an association of Arid5a with cancers, including breast, pancreatic, colorectal, and lung cancers and glioma. Notably, Arid5a affects various aspects of cellular homeostasis, including invasion, metastasis, epithelial-to-mesenchymal transition, immune evasion, adipogenesis and M1-like tumor-associated macrophage (TAM)-to-M2-like TAM transition. This review aims to summarize current knowledge of Arid5a from a cancer perspective and highlights recent advances in Arid5a-related cancer research. This review may improve the understanding of Arid5a-mediated molecular mechanisms and their relevance to cancers.

The novel long noncoding RNA AU021063, induced by IL-6/Arid5a signaling, exacerbates breast cancer invasion and metastasis by stabilizing Trib3 and activating the Mek/Erk pathway.

Interleukin (IL-6) is a pleotropic cytokine with both tumor-promoting and -inhibitory effects on breast cancer growth. However, the mechanisms governing the outcome of IL-6 on cancer progression remain to be clarified. Our study unraveled a novel long noncoding RNA (lncRNA) AU021063 downstream of IL-6 signaling. We found that IL-6 induced the expression of AU021063 predominantly in breast cancer compared to other cancer types. Mechanistically, IL-6 induced AT-rich interactive domain 5a (Arid5a) expression, which promotes the transcription of AU021063. In turn, AU021063 promotes breast cancer metastasis through stabilizing tribbles homolog 3 (Trib3) and activating Mek/Erk signaling pathway. Genetic ablation of either Arid5a, AU021063 or Trib3 abolished breast cancer metastasis in vitro and in vivo. Overall, our study highlights the importance of IL-6-Arid5a-AU021063 axis in regulating breast cancer invasiveness and metastasis, which may provide potential novel therapeutics for breast cancer.

Recent Advances in the Role of Arid5a in Immune Diseases and Cancer.

AT-rich interactive domain 5a (Arid5a) is a nucleic acid binding protein. In this review, we highlight recent advances in the association of Arid5a with inflammation and human diseases. Arid5a is known as a protein that performs dual functions. In in vitro and in vivo studies, it was found that an inflammation-dependent increase in Arid5a expression mediates both transcriptional and post-transcriptional regulatory effects that are implicated in immune regulation and cellular homeostasis. A series of publications demonstrated that inhibiting Arid5a augmented several processes, such as preventing septic shock, experimental autoimmune encephalomyelitis, acute lung injury, invasion and metastasis, immune evasion, epithelial-to-mesenchymal transition, and the M1-like tumor-associated macrophage (TAM) to M2-like TAM transition. In addition, Arid5a controls adipogenesis and obesity in mice to maintain metabolic homeostasis. Taken together, recent progress indicates that Arid5a exhibits multifaceted, both beneficial and detrimental, roles in health and disease and suggest the relevance of Arid5a as a potential therapeutic target.

Arid5a, an RNA-Binding Protein in Immune Regulation: RNA Stability, Inflammation, and Autoimmunity.

AT-rich interactive domain 5A (ARID5A/Arid5a) is a known cofactor of transcription factors (TFs) that contributes to cell growth and differentiation. It has recently been recognized for its unique function in the stabilization of mRNA, which is associated with inflammatory autoimmune diseases. Studies have revolutionized our understanding of the post-transcriptional regulation of inflammatory genes by revealing the fundamental events underpinning novel functions and activities of Arid5a. We review current research on Arid5a, which has focused our attention towards the therapeutic potential of this factor in the putative treatment of inflammatory and autoimmune disorders, including experimental autoimmune encephalomyelitis and sepsis in mice.

Arid5a Regulation and the Roles of Arid5a in the Inflammatory Response and Disease.

Abnormal gene expression patterns underlie many diseases that represent major public health concerns and robust therapeutic challenges. Posttranscriptional gene regulation by RNA-binding proteins (RBPs) is well-recognized, and the biological functions of RBPs have been implicated in many diseases, such as autoimmune diseases, inflammatory diseases, and cancer. However, a complete understanding of the regulation mediated by several RBPs is lacking. During the past few years, a novel role of AT-rich interactive domain-containing protein 5a (Arid5a) as an RBP is being investigated in the field of immunology owing to binding of Arid5a protein to the 3' untranslated region (UTR) of Il-6 mRNA. Indeed, Arid5a is a dynamic molecule because upon inflammation, it translocates to the cytoplasm and stabilizes a variety of inflammatory mRNA transcripts, including Il-6, Stat3, Ox40, T-bet, and IL-17-induced targets, and contributes to the inflammatory response and a variety of diseases. TLR4-activated NF-κB and MAPK pathways are involved in regulating Arid5a expression from synthesis to degradation, and even a slight alteration in these pathways can lead to intense production of inflammatory molecules, such as IL-6, which may further contribute to the development of inflammatory diseases such as sepsis and experimental autoimmune encephalomyelitis. This review highlights the regulation of the Arid5a expression and function. Additionally, recent findings on Arid5a are discussed to further our understanding of this molecule, which may be a promising therapeutic target for inflammatory diseases.

microRNAs in Mycobacterial Infection: Modulation of Host Immune Response and Apoptotic Pathways.

Our current knowledge of mycobacterial infections in humans has progressively increased over the past few decades. The infection of Mycobacterium tuberculosis causes tuberculosis (TB) disease, which has reasoned for excessive morbidity and mortality worldwide, and has become a foremost issue of health problem globally. Mycobacterium leprae, another member of the family Mycobacteriaceae, is responsible for causing a chronic disease known as leprosy that mainly affects mucosa of the upper respiratory tract, skin, peripheral nerves, and eyes. Ample amount of existing data suggests that pathogenic mycobacteria have skilled in utilizing different mechanisms to escape or offset the host immune responses. They hijack the machinery of immune cells through the modulation of microRNAs (miRs), which regulate gene expression and immune responses of the host. Evidence shows that miRs have now gained considerable attention in the research, owing to their involvement in a broad range of inflammatory processes that are further implicated in the pathogenesis of several diseases. However, the knowledge of functions of miRs during mycobacterial infections remains limited. This review summarises recent findings of differential expression of miRs, which are used to good advantage by mycobacteria in offsetting host immune responses generated against them.

Japanese encephalitis virus: Associated immune response and recent progress in vaccine development.

Japanese encephalitis (JE) has emerged as one of the most important form of viral encephalitis, which accounts for an estimated 70,000 cases each year with approximately 10,000 fatalities. The clinical presentations and outcome of the infection is dependent upon both virulence of viral determinants and host immune responses. The causative pathogen of JE is a virus known as Japanese encephalitis virus (JEV), which penetrates into the CNS from blood and triggers rapid humoral and cell-mediated immune response. Humoral response is crucial for the control of dissemination of JEV infection and the cytokines produced by cell-mediated immunity during JEV infections serve as potent immune mediators. Till date, JE is only vaccine preventable and no complete antiviral treatment is available so far. Further, vaccine-mediated prevention also has certain limitations. Therefore, an understanding of the pathogenesis of JEV infection can enable the researchers to presume the depth of treatment regime. This review highlights the importance of understanding of the immune mechanisms that are operated in the host during JEV infection and would be helpful in improving future vaccination strategy against JEV.

Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis.

Immune cells infiltrate adipose tissues and provide a framework to regulate energy homeostasis. However, the precise underlying mechanisms and signaling by which the immune system regulates energy homeostasis in metabolic tissues remain poorly understood. Here, we show that the AT-rich interactive domain 5A (Arid5a), a cytokine-induced nucleic acid binding protein, is important for the maintenance of adipose tissue homeostasis. Long-term deficiency of Arid5a in mice results in adult-onset severe obesity. In contrast, transgenic mice overexpressing Arid5a are highly resistant to high-fat diet-induced obesity. Inhibition of Arid5a facilitates the in vitro differentiation of 3T3-L1 cells and fibroblasts to adipocytes, whereas its induction substantially inhibits their differentiation. Molecular studies reveal that Arid5a represses the transcription of peroxisome proliferator activated receptor gamma 2 (Ppar-γ2) due to which, in the absence of Arid5a, Ppar-γ2 is persistently expressed in fibroblasts. This phenomenon is accompanied by enhanced fatty acid uptake in Arid5a-deficient cells, which shifts metabolic homeostasis toward prolipid metabolism. Furthermore, we show that Arid5a and Ppar-γ2 are dynamically counterregulated by each other, hence maintaining adipogenic homeostasis. Thus, we show that Arid5a is an important negative regulator of energy metabolism and can be a potential target for metabolic disorders.

Matrix metalloproteinases-2 and -9 in Campylobacter jejuni-induced paralytic neuropathy resembling Guillain-Barré syndrome in chickens.

Inflammation in Guillain-Barré syndrome (GBS) is manifested by changes in matrix metalloproteinase (MMP) and pro-inflammatory cytokine expression. We investigated the expression of MMP-2, -9 and TNF-α and correlated it with pathological changes in sciatic nerve tissue from Campylobacter jejuni-induced chicken model for GBS. Campylobacter jejuni and placebo were fed to chickens and assessed for disease symptoms. Sciatic nerves were examined by histopathology and immunohistochemistry. Expressions of MMPs and TNF-α, were determined by real-time PCR, and activities of MMPs by zymography. Diarrhea developed in 73.3% chickens after infection and 60.0% of them developed GBS like neuropathy. Pathology in sciatic nerves showed perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration and myelin swelling on 10th- 20th post infection day (PID). MMP-2, -9 and TNF-α were up-regulated in progressive phase of the disease. Enhanced MMP-2, -9 and TNF-α production in progressive phase correlated with sciatic nerve pathology in C. jejuni-induced GBS chicken model.

Arid5a-deficient mice are highly resistant to bleomycin-induced lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the major causes of death worldwide due to acute inflammation in the lung. AT-rich interactive domain-containing 5a (Arid5a) is an RNA-binding protein involved in inflammatory autoimmune disease through post-transcriptional control of Il6, Stat3 and Tbx21 gene expression. We found that Arid5a-deficient mice were highly refractory to bleomycin (BLM)-induced lethality. Arid5a deficiency suppressed lung pathology, cytokine production (especially, IL-6), and clinical symptoms in BLM-treated mice. Production of reactive oxygen species (ROS) in response to BLM-induced cellular damage was inhibited in Arid5a-deficient mice, potentially affecting the level of oxidized 1-palmitoyl-2-arachidonoyl-phosphaticylcholine (OxPAPC) production. OxPAPC, which is supposed to be a TLR4/TLR2 ligand, stimulated expression of the Arid5a and Il6 genes. Thus, reduction of ROS production in Arid5a-deficient mice could mitigate OxPAPC production, which in turn decreases IL-6 production in vivo due to dysregulated post-transcriptional regulation by loss of Arid5a. Therefore, the control of Arid5a expression represents a potential therapeutic target for treatment of ALI and ARDS.