MicroRNA-206 suppresses TGF-beta signalling to limit tumor growth and metastasis in lung adenocarcinoma
CELLULAR SIGNALLING
Authors: Watt, Kathleen; Newsted, Daniel; Voorand, Elena; Gooding, Robert J.; Majewski, Adrianna; Truesdell, Peter; Yao, Binchen; Tuschl, Thomas; Renwick, Neil; Craig, Andrew W.
Abstract
MicroRNA-206 (miR-206) has demonstrated tumor suppressive effects in a variety of cancers. Numerous studies have identified aberrantly expressed targets of miR-206 that contribute to tumor progression and metastasis, however, the broader gene-networks and pathways regulated by miR-206 remain poorly defined. Here, we have ectopically expressed miR-206 in lung adenocarcinoma cell lines and tumors to identify differentially expressed genes, and study the effects on tumor growth and metastasis. In H1299 tumor xenograft assays, stable expression of miR-206 suppressed both tumor growth and metastasis in mice. Profiling of xenograft tumors using small RNA sequencing and a targeted panel of tumor progression and metastasis-related genes revealed a network of genes involved in TGF-beta signalling that were regulated by miR-206. Among these were the TGFB1 ligand, as well as direct transcriptional targets of Smad3. Other differentially expressed genes included components of the extracellular matrix involved in TGF-beta activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-beta in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-beta, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-beta target genes linked to epithelial-mesenchymal transition. This was due at least in part to the suppression of Smad3 protein levels in lung adenocarcinoma cells with ectopic miR-206 expression. Together, these findings indicate that miR-206 can suppress tumor progression and metastasis by limiting autocrine production of TGF-beta, and highlight the potential utility of TGF-beta inhibitors for the treatment of lung adenocarcinomas.
Toll-like receptor 2 mediates the immune response of the bovine oviductal ampulla to sperm binding
MOLECULAR REPRODUCTION AND DEVELOPMENT
Authors: Morillo, Vernadyn A.; Akthar, Ihshan; Fiorenza, Mariani F.; Takahashi, Ken-ichi; Sasaki, Motoki; Marey, Mohamed A.; Suarez, Susan S.; Miyamoto, Akio
Abstract
We previously reported that sperm binding to cultured bovine oviduct epithelial cells induces an anti-inflammatory immune response. Now we have developed a differentiated explant model to focus on the oviductal ampulla, where fertilization occurs, and to study the effect of sperm capacitation on the immune response. We used heparin to stimulate bovine sperm capacitation. Fluorescence imaging showed that 5,5MODIFIER LETTER PRIME,6,6MODIFIER LETTER PRIME-tetrachloro-1,1MODIFIER LETTER PRIME,3,3MODIFIER LETTER PRIME-tetraethylbenzimidazolyl-carbocyanine iodide-labeled sperm pretreated with (Hep((+))) or without (Hep(()(-))) heparin rapidly attached to the explant ciliated epithelium in similar numbers. However, only Hep((+))sperm upregulated explant messenger RNA (mRNA) transcription ofTLR2, IL8, TGFB1, andPGES, without changes inTNFAandIL-10expression, while Hep(()(-))sperm only upregulatedPGES. The responses were primarily anti-inflammatory, with a greater response produced by Hep((+))sperm, which also produced a substantial increase in TLR2 protein expression in the epithelium. The addition of TLR1/2 (toll-like receptor 1/2) antagonist to the Hep((+))and (Hep(()(-))) sperm-explant coincubations reduced sperm attachment to the epithelium and inhibited TLR2 protein expression and some of the Hep((+))sperm-induced mRNA transcription. Our observations suggest that the ampullar epithelium immunologically reacts more strongly to sperm that have undergone heparin stimulation of capacitation. This anti-inflammatory response could serve to protect capacitated sperm as they approach the oocyte in the ampulla.
COA
Publication 
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