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The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and also in the tumor invasion process. In addition, EMT also causes disruption of cell-cell adherence, loss of apico-basal polarity, matrix remodeling, increased motility and invasiveness in promoting tumor metastasis. The tumor microenvironment plays an important role in facilitating cancer metastasis and may induce the occurrence of EMT in tumor cells. A large number of inflammatory cells infiltrating the tumor site, as well as hypoxia existing in a large area of tumor, in addition many stem cells present in tumor microenvironment, such as cancer stem cells (CSCs), mesenchymal stem cells (MSCs), all of these may be the inducers of EMT in tumor cells. The signaling pathways involved in EMT are various, including TGF-β, NF-κB, Wnt, Notch, and others. In this review, we discuss the current knowledge about the role of the tumor microenvironment in EMT and the related signaling pathways as well as the interaction between them.

Osteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.

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STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity.

BackgroundThe endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated,MethodsFour HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristicsResultsThe in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-κB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-κB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients.ConclusionsOur results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.

Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In this review, we discussed the interaction between autophagy and the tumor microenvironment and the paradoxical roles of autophagy on tumor growth at different stages of tumor development.

Background/Aims: TGF-β plays a key role in the progression of various tumors. The main objective of our study was to investigate whether TGF-β is able to regulate N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) progression in a mouse model by inducing Treg cell polarization. Methods: HCC progression, TGF-β and Foxp3 expression levels, serum TGF-β, IL10 and GP73 levels as well as percentage of Treg cells were analyzed in healthy, HCC and HCC+SM-16 mouse groups. The effect of TGF-β on Treg cell polarization in vitro was measured by flow cytometric analysis. The expression of TGF-β and IL10 was identified by IHC in HCC patients and the correlation between TGF-β and IL10 was also assessed. Results: TGF-β expression is up-regulated in a DEN-induced HCC mouse model. TGF-β can promote the differentiation of Foxp3⁺CD4⁺ T cells (Treg cells) in vitro. However, blocking the TGF-β pathway with a specific TGF-β receptor inhibitor, SM-16, reduced HCC progression and the percentage of Treg cells in liver tissue. The correlation between TGF-β and Treg cells was also confirmed in HCC patients and the expression of both TGF-β and IL-10 was shown to be associated with HCC progression. Conclusion: TGF-β is necessary for HCC progression, acting by inducing Treg cell polarization.