BackgroundTGF-β promotes tumor invasion and metastasis through inducing epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in human cancers. However, whether and how circRNAs contribute to TGF-β-induced EMT and metastasis in NSCLC remain vague. Here, we investigated the regulation and function of Circular RNA hsa_circ_0008305 (circPTK2) in TGF-β-induced EMT and tumor metastasis, as well as a link between circPTK2 and transcriptional intermediary factor 1 γ (TIF1γ) in NSCLC.MethodsCircular RNAs were determined by human circRNA Array analysis, real-time quantitative reverse transcriptase PCR and northern blot. Luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were employed to test the interaction between circPTK2 and miR-429/miR-200b-3p. Ectopic overexpression and siRNA-mediated knockdown of circPTK2, TGF-β-induced EMT, Transwell migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPTK2. Transcription and prognosis analyses were done in public databases.ResultsCircPTK2 and TIF1γ were significantly down-regulated in NSCLC cells undergoing EMT induced by TGF-β. CircPTK2 overexpression augmented TIF1γ expression, inhibited TGF-β-induced EMT and NSCLC cell invasion, whereas circPTK2 knockdown had the opposite effects. CircPTK2 functions as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p promote TGF-β-induced EMT and NSCLC cell invasion by targeting TIF1γ. CircPTK2 overexpression inhibited the invasion-promoting phenotype of endogenous miR-429/miR-200b-3p in NSCLC cells in response to TGF-β. CircPTK2 overexpression significantly decreased the expression of Snail, an important downstream transcriptional activator of TGF-β/Smad signaling. In an in vivo experiment of metastasis, circPTK2 overexpression suppressed NSCLC cell metastasis. Moreover, circPTK2 expression was dramatically down-regulated and positively correlated with TIF1γ expression in human NSCLC tissues. Especially, circPTK2 was significantly lower in metastatic NSCLC tissues than non-metastatic counterparts.ConclusionOur findings show that circPTK2 (hsa_circ_0008305) inhibits TGF-β-induced EMT and metastasis by controlling TIF1γ in NSCLC, revealing a novel mechanism by which circRNA regulates TGF-β-induced EMT and tumor metastasis, and suggesting that circPTK2 overexpression could provide a therapeutic strategy for advanced NSCLC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0889-7) contains supplementary material, which is available to authorized users.

Epithelial to mesenchymal transition (EMT), and the reverse mesenchymal to epithelial transition (MET), are known examples of epithelial plasticity that are important in kidney development and cancer metastasis. Here we identify ASPP2, a haploinsufficient tumour suppressor, p53 activator and PAR3 binding partner, as a molecular switch of MET and EMT. ASPP2 contributes to MET in mouse kidney in vivo. Mechanistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin's N-terminal phosphorylation to stabilize the β-catenin-E-cadherin complex. ASPP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASPP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients. Hence, ASPP2 is a key regulator of epithelial plasticity that connects cell polarity to the suppression of WNT signalling, EMT and tumour metastasis.

Photoacoustic computed tomography (PACT) has generated increasing interest for uses in preclinical research and clinical translation. However, the imaging depth, speed, and quality of existing PACT systems have previously limited the potential applications of this technology. To overcome these issues, we developed a three-dimensional photoacoustic computed tomography (3D-PACT) system that features large imaging depth, scalable field of view with isotropic spatial resolution, high imaging speed, and superior image quality. 3D-PACT allows for multipurpose imaging to reveal detailed angiographic information in biological tissues ranging from the rodent brain to the human breast. In the rat brain, we visualize whole brain vasculatures and hemodynamics. In the human breast, an in vivo imaging depth of 4 cm is achieved by scanning the breast within a single breath hold of 10 s. Here, we introduce the 3D-PACT system to provide a unique tool for preclinical research and an appealing prototype for clinical translation.

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The HIV Tat-interacting protein (TIP30), also called CC3 or HTIP2, is encoded by Tip30, a putative tumorsuppressor gene located on human chromosome 11p15.1. In this study, we investigated the role of TIP30 in the progression and metastasis of lung cancer. TIP30 expression was analyzed in 206 paired lung cancers and adjacent non-tumor tissues, as well as in 70 matched lymph node metastases using a high-density tissue microarray. Results were compared with the clinicopathologic features of the patients from whom the tissues were taken. Low TIP30 expression levels were found in all 9 cases of small cell lung cancer and in 36.5% (72/197) of non-small cell lung cancer, which were correlated with lymph node metastasis in non-small cell lung cancer and with poor differentiation and advanced stage of tumor cells in squamous cell carcinoma. The immunostaining scores were significantly lower in the metastatic lesions than in the primary lesions. Down-regulation of TIP30 by a short hairpin RNA enhanced cell survival, migration, and invasion through Matrigel in vitro, and promoted lung metastasis and vascularization in nude mice. Further studies revealed that the downregulation of TIP30 enhanced the expression of osteopontin, as well as matrix metalloproteinase-2 and vascular endothelial growth factor. Our results suggest that the down-regulation of TIP30 promotes metastatic progression of lung cancer, hence it could serve as a potential target for the development of lung cancer therapies.