Considerable evidences have shown that autophagy has an important role in tumor chemoresistance. However, it is still unknown whether the lncRNA HULC (highly upregulated in liver cancer) is involved in autophagy and chemoresistance of hepatocellular carcinoma (HCC). In this study, we for the first time demonstrated that treatment with antitumor reagents such as oxaliplatin, 5-fluorouracil and pirarubicin (THP) dramatically induced HULC expression and protective autophagy. Silencing of HULC sensitized HCC cells to the three antitumor reagents via inhibiting protective autophagy. Ectopic expression of HULC elicited the autophagy of HCC cells through stabilizing silent information regulator 1 (Sirt1) protein. The investigation for the corresponding mechanism by which HULC stabilized Sirt1 revealed that HULC upregulated ubiquitin-specific peptidase 22 (USP22), leading to the decrease of ubiquitin-mediated degradation of Sirt1 protein by removing the conjugated polyubiquitin chains from Sirt1. Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. In addition, we showed that the level of HULC was positively correlated with that of Sirt1 protein in human HCC tissues. Collectively, our data reveals that the pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents, suggesting that this pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.

Background In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. Methods Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes. Results Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy. Conclusions The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Graphical abstract

Immunotherapy has become an emerging strategy for the treatment of cancer. Immunotherapeutic drugs have been increasing for clinical treatment. Despite significant advances in immunotherapy, the clinical application of immunotherapy for cancer patients has some challenges associated with safety and efficacy, including autoimmune reactions, cytokine release syndrome, and vascular leak syndrome. Novel strategies, particularly improved delivery strategies, including nanoparticles, scaffolds, and hydrogels, are able to effectively target tumors and/or immune cells of interest, increase the accumulation of immunotherapies within the lesion, and reduce off-target effects. Here, we briefly describe five major types of cancer immunotherapy, including their clinical status, strengths, and weaknesses. Then, we introduce novel delivery strategies, such as nanoparticle-based delivery of immunotherapy, implantable scaffolds, injectable biomaterials for immunotherapy, and matrix-binding molecular conjugates, which can improve the efficacy and safety of immunotherapies. Also, the limitations of novel delivery strategies and challenges of clinical translation are discussed.