AGO2 is also known as Argonaute RISC catalytic component 2. The AGO2 gene is located in 8q24.3. Its protein contains four globular domains of N terminal (amino-terminal), PAZ, MID and PIWI, and two connecting domains of L1 and L2. The main function of the AGO2 protein is finally achieved by participating in the composition of the RISC (RNA-induced silencing complex) complex: a precise combination of the PAZ-MID-PIWI domain with the small RNA. AGO2 with endonuclease activity cleavage completely complementary siRNA or miRNA double strands. The incomplete complementary dsRNA (mostly seen in miRNA) is cut through a non endonuclease pathway. After a series of shear processes, the nonsense chain of small RNA falls off and activates RISC, thus giving play to the post transcriptional silence of the gene, degrading the target mRNA and preventing protein expression. Among them, the interactions between the four AGO2, the small RNA guide chain, the destination mRNA and the small RNA product are dynamically balanced. Other studies have found that there is a hydrophilic region at the junction of the AGO2 protein L2 junction and the MID domain, which can be combined with the mRNA sequence with a specific location of adenylate (T1), bypassing the complementary pairing of miRNA and mRNA and accelerating the translation inhibition.
The ways in which AGO2 participates in the formation of RISCs vary with miRNA-mediated gene silencing in two ways: one to inhibit protein expression and the other to promote mRNA degradation. Both mechanisms require the participation of GW182. GW182 in mammals is a member of the GW family of AGO-related proteins, which are named for their glycine-tryptophan (GW)-rich regions. In humans, this family member includes TNRC6A (GW182), TNRC6B and TNRC6C. Among the different GW proteins, tryptophan residues are always present in pairs and are separated by a flexible linker consisting of 8-14 amino acid residues. The GW protein typically interacts with the PIWI domain of the AGO2 protein, and tryptophan residues being critical to mediating this interaction. In addition, GW182 is an effective component of the RNA silencing pathway and is involved in the degradation of AGO2 protein and mRNA. It is a link between RNA silencing and mRNA degradation.
Figure 1. AGO2 could serve as initiator of target mRNAs degradation, stopper of target gene translation, regulator of miRNAs abundance, function, maturation and stability. (Ye, et al. 2015).
The Relationship between AGO2 Overexpression and Human Tumors
AGO2 protein is closely related to human tumors. It plays an important role in the development of systemic tumors such as digestion, urogenital and blood by self-overexpression or post-translational modification, participation in RISC complex, or interaction with other proteins. Cheng et al. found in the study of hepatocellular carcinoma that AGO2 is highly expressed in hepatocarcinoma tissues and promotes tumor cell proliferation and non-anchored colony formation, tumorigenesis and metastasis. In contrast, knocking out the AGO2 gene inhibits the aforementioned malignant biological behavior. The pathogenesis of colon cancer is also associated with AGO2, and AGO2 mRNA content and protein levels increase with increasing tumor staging. In addition, similar findings have been found in gastric cancer-related studies, showing that elevated levels of AGO2 protein and associated with tumor progression.
In breast cancer studies, AGO2 mRNA and protein levels were increased in ER-α(-) breast cancer cells, and elevated AGO2 to epidermal growth factor (EGF) receptor inhibitors and MAPK Signal pathway inhibitors are very insensitive. This suggests that there is another way to achieve the action of AGO2 protein. Further studies have found that AGO2 can promote breast cancer cell proliferation, reduce intercellular adhesion, and increase cell migration ability. And overexpression of AGO2 can reduce the levels of E-cadherin, β-catenin, and β-actin. However, AGO2 gene silencing leads to inhibition of cancer cell proliferation and active apoptosis. In a related study of patients with advanced ovarian cancer, AGO2 mRNA levels were elevated in primary tumors, metastatic cancer, and ascites. And the higher the level of AGO2 mRNA in the peritoneal effusion of patients before chemotherapy, the shorter the progression-free survival of the tumor. Yang et al have similar findings on bladder transitional cell carcinoma. AGO2 mRNA and protein levels are elevated in bladder tumor tissues and are associated with histopathological features such as histological grade, lymph node metastasis and distant metastasis. Survival curves also showed that increased AGO2 expression predicted poor overall survival.
In addition, AGO2 also has an abnormally high expression in head and neck squamous cell carcinoma, skin squamous cell carcinoma, and basal cell carcinoma. Studies at home and abroad have shown that AGO2 plays a role in the development of various tumors in human.It is related to the clinicopathological features and survival rate of tumors.
AGO2 Participates in Human Humor Development through RISC
AGO2 is the only protein in the human AGO family that has been characterized by endonuclease activity. It is closely related to tumors by participating in the RISC complex, regulating the binding of miRNA and siRNA and the cleavage of target mRNA. Carouge et al found that AGO2 can affect the development of germ cells through chromosome parental effects and promote the development of testicular germ cell tumors. By knocking out the maternal AGO2 gene, they found that the risk of male heterozygous offspring with testicular germ cell tumors was reduced but knocking out the paternal AGO2 gene did not. Further studies found that human germ cell tumors have low expression of the Let-7 family and overexpression of Lin28, while the level of Let-7 miRNA is regulated by AGO2, which indirectly proves the correlation between AGO2 and germ cell tumor. Guo et al.'s functional study of miR-346 found that the intermediate sequence is a GC-rich circular structure that binds to the 3'UTR region of AGO2, promoting AGO2 expression. This result can be found in a variety of tumors such as cervical cancer, colorectal cancer, and ovarian cancer. Over-expressed AGO2 can promote the development of cervical cancer to a malignant phenotype.
Further mechanistic studies have shown that miR-346-mediated increases in AGO2 protein expression and increased oncomiR abundance will activate oncomiRs. For example, miR-21 and miR-150 cause down-regulation of their targeting tumor suppressor proteins PTEN and p53. Shuang et al. modeled in chicken chorioallantoic membrane and found that AGO2 regulates angiogenesis-related miRNA expression levels by miRNA microarray, increasing expression of the pro-angiogenic let-7 family and miR-17/92 clusters, inhabiting the expression of miR-145, and promoting neovascularization of myeloma. Xu et al.'s study on the mechanism of action of AGO2 in myeloma showed that after interference with AGO2 expression, miRNAs expression was down-regulated, related protein synthesis was abnormal, cell growth was inhibited, and apoptosis occurred.
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