Background Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but its use is hampered by the secondary drug resistance. Yes-associated protein (YAP) is the crucial downstream effector of the Hippo signaling pathway, which is crucial for liver tumorigenesis. However, the underlying mechanism regarding YAP and sorafenib resistance remains unclear. Methods Western blotting, flow cytometry, and CCK-8 assay were used to confirm the role of YAP in HCC sorafenib resistance. RT-PCR and western blotting were then performed to identify survivin as

The dysfunction of the intestinal epithelial barrier contributes to local or systemic infection and inflammation. Some lactic acid bacteria (LAB) strains had been shown to improve the conditions of barrier function and, for this reason, are recognized as probiotics. Weissella cibaria, a species belonging to the LAB group, is known to promote several health benefits. However, the role of W. cibaria in regulating the integrity of the intestinal epithelial barrier has not yet been investigated. In this study, W. cibaria MW01 was isolated from Chinese sauerkraut and was selected based on its functional features, such as gastric juice and bile salt tolerance, besides antagonistic activity against pathogenic bacteria. In a cellular model of the intestinal barrier, it was observed that W. cibaria was able to adhere more efficiently than Lactobacillus rhamnosus GG in Caco-2 cells. Moreover, the LPS-induced inflammation in Caco-2 cells was attenuated by the treatment with W. cibaria MW01, which reduced the synthesis of TNF-α, IL-6, and IL-8. In addition, it was noted that the treatment with W. cibaria MW01 recovered the integrity of the Caco-2 cell monolayer exposed to LPS. Furthermore, W. cibaria MW01 significantly alleviated LPS-induced downregulation of tight junction proteins (TJP) (claudin, occludin, and tight junction protein-1). Mechanistically, W. cibaria MW01 inhibited the translocation of NF-κB to the nucleus and deactivated the MLCK-pMLC pathway during LPS exposure. Thus, W. cibaria MW01, as a potential probiotic, can protect intestinal epithelial barrier function by regulating inflammation and expression of TJP via the NF-κB-mediated MLCK-pMLC pathway.

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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

<p>Microbiome is ubiquitous in human and distributed in not only normal organs such as gut, but also in tumor tissues of the host. Numerous studies have proven that the extratumoral microbiota (mainly gut microbiota) has a close relationship with the local and systemic immune systems of the host. The bacteria, viruses and fungi in gut can influence the activity of innate and adaptive immune cells, affecting the outcomes of immunotherapy. In addition to microbiota in the gut, special microbiota (intratumoral microbiota) exists in the tumor microenvironment (TME), which provides a critical niche for anaerobic or facultative anaerobic bacteria to colonize and proliferate. Intratumoral microorganisms or their metabolites can substantially improve the immunosuppressive of the TME, reactivate immune cells, or recruit activated immune cells, indicating a potential effect on immunotherapy. Furthermore, with the development of synthetic biology, some tumor-targeting bacteria can be used as a biological chassis for the accurate delivery of different immunotherapeutic agents to tumor core through genetic programming technologies, enriching immunotherapy paradigms. In this review, we summarize the recent developments in effect of human microbiota, especially microorganisms in the TME, on immunoregulation, and discuss their potential application in the field of cancer immunotherapy. We also describe the ways to take advantage of genetically engineered bacteria targeting the TME to strengthen the efficacy of immunotherapy against cancer. Additionally, the remaining questions and further directions for microbiota application in immunotherapy are also discussed.</p>