Background: Renal cell carcinoma (RCC) is a malignancy with a poor prognosis. We aimed to explore whether the expression of Long Non-Coding RNA (LncRNA) growth arrest-specific transcript 5 (GAS5) is associated with RCC genesis. Methods: We selected twelve clinical samples diagnosed for renal clear cell carcinoma and found that the LncRNA GAS5 transcript levels were significantly reduced relative to those in adjacent unaffected normal renal tissues. Results: In addition, expression of GAS5 was lower in the RCC cell line A498 than that in normal renal cell line HK-2. Furthermore, using functional expression cloning, we found that overexpression of GAS5 in A498 cells inhibited cell proliferation, induced cell apoptosis and arrested cell cycling. At the same time, the migration and invasion potential of A498 cells were inhibited compared to control groups. Conclusion: Our study provided the first evidence that a decrease in GAS5 expression is associated with RCC genesis and progression and overexpression of GAS5 can act as a tumor suppressor for RCC, providing a potential attractive therapeutic approach for this malignancy.
Dectin-1 is a C-type lectin that recognizes
Toll-like receptor 3 (TLR3) mediates antiviral response by recognizing double-stranded RNA. Its cytoplasmic domain is tyrosine phosphorylated upon ligand binding and initiates downstream signaling via the adapter TIR-containing adaptor inducing interferon-β (TRIF). However, the kinase responsible for TLR3 phosphorylation remains unknown. We show here that Bruton's tyrosine kinase (BTK)-deficient macrophages failed to secrete inflammatory cytokines and IFN-β upon TLR3 stimulation and were impaired in clearing intracellular dengue virus infection. Mutant mice were also less susceptible to D-galactosamine/p(I:C)-induced sepsis. In the absence of BTK, TLR3-induced phosphoinositide 3-kinase (PI3K), AKT and MAPK signaling and activation of NFκB, IRF3, and AP-1 transcription factors were all defective. We demonstrate that BTK directly phosphorylates TLR3 and in particular the critical Tyr759 residue. BTK point mutations that abrogate or led to constitutive kinase activity have opposite effects on TLR3 phosphorylation. Loss of BTK also compromises the formation of the downstream TRIF/receptor-interacting protein 1 (RIP1)/TBK1 complex. Thus, BTK plays a critical role in initiating TLR3 signaling. T oll-like receptors (TLRs) recognize pathogen-associated molecular patterns and activate signaling pathways that induce the expression of host immune and inflammatory genes (1). All TLRs contain extracellular leucine-rich domains for ligand recognition and a cytoplasmic Toll/IL-1R (TIR) domain for signaling. Most TLRs signal via the adapter myeloid differentiating factor 88 (MyD88) with the exception of TLR4, which also uses a few other adapters and TLR3, which uses solely TIRcontaining adaptor inducing interferon-β (TRIF) (2). Hence, TLR3 provides a unique system to study innate signaling.TLR3 is involved in antiviral response. Its engagement by viral double-stranded RNA (dsRNA) or the synthetic analog polyinsosinic: polyribocytidylic acid (p(I:C)) triggers the secretion of IFN-β and other inflammatory cytokines such as IL-6 and TNF-α. Mechanistically, TLR3 stimulation leads to the recruitment of TRIF and subsequent activation of the transcription factor IFN regulatory factor-3 (IRF3) (3). The N-terminal of TRIF binds tumor necrosis factor receptor-associated factor 3 (TRAF3)-TANK-binding kinase 1 (TBK1) complex that leads to IRF3 phosphorylation, dimerization, and translocation to nucleus to induce IFN-β expression (4). The C-terminal of TRIF binds receptor-interacting protein 1 (RIP1) and induces the ubiquitination of RIP1 (5). TLR3 signaling also activates ERK, JNK, p38 MAPKs, and phosphoinositide 3-kinase (PI3K) (6). MAPKs activate the AP-1 family of transcription factors, which induces proinflammatory cytokine genes (7). On the other hand, TLR3-induced PI3K signaling contributes to the full activation of IRF3 (8). TRIF signaling leading to TNF-α production also acts in a feed-forward manner to further and fully activate NFκB signaling (9, 10). Although the major signaling pathways associated with TLR3/TRIF activation have...
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