O-GlcNAcylated RALY Contributes to Hepatocellular Carcinoma Cells Proliferation by Regulating USP22 mRNA Nuclear Export.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly tumors; however, its pathogenic mechanism remains largely elusive. In-depth researches are needed to reveal the expression regulatory mechanisms and functions of the RNA-binding protein RALY in HCC. Here, we identify RALY as a highly expressed oncogenic factor that affects HCC cells proliferation both in vitro and in vivo. O-GlcNAcylation of RALY at Ser176 enhances its stability by protecting RALY from TRIM27-mediated ubiquitination, thus maintaining hyper-expression of the RALY protein. Mechanistically, RALY interacts with USP22 messenger RNA, as revealed by RNA immunoprecipitation, to increase their cytoplasmic localization and protein expression, thereby promoting the proliferation of HCC cells. Furthermore, we develop a novel RALY protein degrader based on peptide proteolysis-targeting chimeras, named RALY-PROTAC, which we chemically synthesize by linking a RALY-targeting peptide with the E3 ubiquitin ligase recruitment ligand pomalidomide. In conclusion, our findings demonstrate a novel mechanism by which O-GlcNAcylation/RALY/USP22 mRNA axis aggravates HCC cells proliferation. RALY-PROTACs as degraders of the RALY protein exhibit potential as therapeutic drugs for RALY-overexpressing HCC.

Carrier-Free Self-Assembled Nanomedicines for Promoting Apoptosis and Inhibiting Proliferation in Hepatocellular Carcinoma.

In order to improve the effectiveness of tumor treatment and reduce the toxic side effects of drugs, we formed carrier-free multifunctional nanoparticles (BI NPs) by noncovalent interaction of berberine hydrochloride and IR780. BI NPs possessed the synergistic effects of promoting apoptosis, inhibiting proliferation and metastasis of tumors, and phototherapeutic treatment. Dispersive and passive targeting ability retention (EPR) effects of BI NPs on tumor sites in vivo could be monitored by fluorescence imaging. In addition, BI NPs exhibited effective reactive oxygen species (ROS) generation and photothermal conversion capabilities, photodynamic therapy (PDT), and photothermal therapy (PTT). Importantly, BI NPs inhibit tumor suppression through the AMPK/PI3K/AKT signaling pathway to inhibit tumor proliferation and metastasis. BI NPs not only have efficient in vivo multimodal therapeutic effects but also have good biosafety and potential clinical applications.

Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer.

Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it. The tumor microenvironment (TME) in pancreatic cancer, distinguished by fibrosis and the existence of cancer-associated fibroblasts (CAFs), exerts a pivotal influence on both tumor advancement and resistance to therapy. Recent advancements in the field of engineered extracellular vesicles (EVs) offer novel avenues for targeted therapy in pancreatic cancer. This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer. EVs obtained from bone marrow mesenchymal stem cells (BMSCs) were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone (PFD) and subjected to surface modification with integrin α5-targeting peptides (named IEVs-PFD/138) to reprogram CAFs and suppress their pro-tumorigenic effects. Integrin α5-targeting peptide modification enhanced the CAF-targeting ability of EVs. miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex, inhibiting TGF-ß signaling pathway activation. In addition, miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex. The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs. Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results. In particular, IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME, which resulted in decreased tumor pressure, enhanced gemcitabine perfusion, tumor hypoxia amelioration, and greater sensitivity of cancer cells to chemotherapy. Thus, the strategy developed in this study can improve chemotherapy outcomes. Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.

An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness.

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC.

Tumor microenvironment responsive nano-platform for overcoming sorafenib resistance of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously jeopardizes human health. The 5-year relative survival rate of HCC is only about 18%. Sorafenib, a small molecule multi-targeted tyrosine kinase inhibitor (MTKI), has been classified as the first-line treatment scheme for HCC and has significantly extended the median survival time for patients with advanced HCC. Nevertheless, the emergence of sorafenib resistance has substantially hampered its further clinical application. Herein, the nano-platform based on phototherapy and small molecular targeted therapy (SMTT) was devised to overcome the sorafenib resistance and reduce the adverse effects. Hollow mesoporous manganese dioxide (H-MnO2) was prepared by hard template method, and the prepared H-MnO2 was used to load sorafenib and Chlorin e6 (Ce6). Subsequently, the nanoparticle (NPs) were modified with dopamine to optimize biocompatibility. The final prepared NPs (MCS NPs) exhibit regular spherical shape with a hydrated particle size of approximately 97.02 nm. MCS NPs can not only possess tumor microenvironment (TME) stimuli-responsive drug release performance but also can enhance the efficacy of photodynamic therapy and reverse sorafenib resistance by alleviating tumor hypoxia. Under the action of phototherapy (Ce6) combined with molecular targeted therapy (sorafenib), MCS NPs manifest a satisfactory antitumor effect for sorafenib-sensitive or sorafenib-resistant HCC cells, and retain the antiangiogenic properties of sorafenib. In the nude mouse subcutaneous tumor model constructed with sorafenib-resistant cells, MCS NPs demonstrated superior tumor imaging ability and excellent biocompatibility. The tumor inhibition rate of the MCS NPs group without laser irradiation was 53.4 %, while the MCS NPs group with laser irradiation was as high as 100 %. The novel smart TME-responsive nano-platform shows great potential for overcoming sorafenib resistance and realizes multimodality imaging and therapy of HCC.

pH-Responsive and Actively Targeted Metal-Organic Framework Structures for Multimodal Antitumor Therapy and Inhibition of Tumor Invasion and Metastasis.

Multimodal treatment is an important tool to overcome tumor drug resistance. The reactive oxygen species (ROS) generated by photodynamic therapy (PDT) can directly play a killing role on tumor cells, which has the advantages of repeatable treatment and no drug resistance. However, its therapeutic oxygen consumption and destruction of tumor microvessels lead to hypoxia in tumor tissues, and hypoxia leads to overexpression of the receptor tyrosine kinase (c-MET) and vascular endothelial growth factor receptor (VEGFR). Overexpression of these two receptors leads to increased tumor invasiveness and metastasis. The molecularly targeted drug cabozantinib (CAB) has multiple targets, including anti-c-MET and VEGFR, to inhibit the development of hepatocellular carcinoma (HCC). In this study, our team designed a pH-sensitive nanoparticle CAB/Ce6@ZIF-8@PEG-FA (CCZP) loaded with CAB and Ce6, which exerted a multimodal therapeutic effect of PDT and molecularly targeted therapy by laser irradiation, and the PDT-induced overexpression of MET and VEGFR could also be inhibited by the target of CAB, thus reducing the invasive tumor cells metastasis. In summary, CCZP gives full play to the advantages of both drugs, exerting multimodal treatment while reducing HCC invasion and metastasis, providing a safe, potential approach to clinical treatment.

Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a common malignancy threatening human health, and existing diagnostic and therapeutic techniques are facing great challenges. In the last decade or so, nanotechnology has been developed and improved for tumor diagnosis and treatment. For example, nano-intravenous injections have been approved for malignant perivascular epithelioid cell tumors. This article provides a comprehensive review of the applications of nanotechnology in HCC in recent years: (I) in radiological imaging, magnetic resonance imaging (MRI), fluorescence imaging (FMI) and multimodality imaging. (II) For diagnostic applications in HCC serum markers. (III) As embolic agents in transarterial chemoembolization (TACE) or directly as therapeutic drugs. (IV) For application in photothermal therapy and photodynamic therapy. (V) As carriers of chemotherapeutic drugs, targeted drugs, and natural plant drugs. (VI) For application in gene and immunotherapy. Compared with the traditional methods for diagnosis and treatment of HCC, nanoparticles have high sensitivity, reduce drug toxicity and have a long duration of action, and can also be combined with photothermal and photodynamic multimodal combination therapy. These summaries provide insights for the further development of nanotechnology applications in HCC.

Nanomaterials based on phase change materials for antibacterial application.

Bacterial infections seriously threaten human health. Although antibiotics can significantly treat infectious diseases, antibiotics abuse has brought a series of serious problems, such as multidrug-resistant bacteria, adverse effects, and so on. Therefore, it is indispensable to develop alternative therapies with superior efficacy and minor toxicity to enhance the anti-infective outcome, overcome drug resistance and reduce adverse effects. The phase change material (PCM) is a substance that changes its physical properties with elevated temperatures. Nanoparticles based on PCM have been widely used in biomedical research due to their excellent biocompatibility, sustained release, and outstanding targeting properties. In this manuscript, the applications of PCM-based nanoparticles in the treatment of bacterial infections were summarized. Firstly, the composition and biotoxicity of PCM nanocarriers were described. Secondly, various antibacterial strategies based on PCM nanoparticles for combination therapy were highlighted. Finally, the prospects for antibacterial therapy of PCM nanomaterials were summarized.

Application of nanotechnology in the diagnosis and treatment of acute pancreatitis.

Acute pancreatitis (AP) is a common digestive system disease. The severity of AP ranges from mild edema in the pancreas to severe systemic inflammatory responses leading to peripancreatic/pancreatic necrosis, multi-organ failure and death. Improving the sensitivity of AP diagnosis and developing alternatives to traditional methods to treat AP have gained the attention of researchers. With the continuous rise of nanotechnology, it is being widely used in daily life, biomedicine, chemical energy and many other fields. Studies have demonstrated the effectiveness of nanotechnology in the diagnosis and treatment of AP. Nanotechnology has the advantages of simplicity, rapidity and sensitivity in detecting biomarkers of AP, as well as enhancing imaging, which helps in the early diagnosis of AP. On the other hand, nanoparticles (NPs) have oxidative stress inhibiting and anti-inflammatory effects, and can also be loaded with drugs as well as being used in anti-infection therapy, providing a new approach for the treatment of AP. In this article, we elaborate and summarize on the potential of nanoparticles for diagnostic and therapeutic applications in AP from the current reported literature and experimental results to provide useful guidelines for further research on the application of nanotechnology.

NOP14 regulates the growth, migration, and invasion of colorectal cancer cells by modulating the NRIP1/GSK-3ß/ß-catenin signaling pathway.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide. Recently, nucleolar complex protein 14 (NOP14) has been discovered to play a critical role in cancer development and progression, but the mechanisms of action of NOP14 in colorectal cancer remain to be elucidated. In this study, we used collected colorectal cancer tissues and cultured colorectal cancer cell lines (SW480, HT29, HCT116, DLD1, Lovo), and measured the mRNA and protein expression levels of NOP14 in colorectal cancer cells using qPCR and western blotting. GFP-NOP14 was constructed and siRNA fragments against NOP14 were synthesized to investigate the importance of NOP14 for the development of colorectal cells. Transwell migration assays were used to measure cell invasion and migration, CCK-8 kits were used to measure cell activity, and flow cytometry was applied to the observation of apoptosis. We found that both the mRNA and protein levels of NOP14 were significantly upregulated in CRC tissues and cell lines. Overexpression of GFP-NOP14 markedly promoted the growth, migration, and invasion of the CRC cells HT19 and SW480, while genetic knockdown of NOP14 inhibited these behaviors. Overexpression of NOP14 promoted the expression of NRIP1 and phosphorylated inactivation of GSK-3ß, leading to the upregulation of ß-catenin. Genetic knockdown of NOP14 had the opposite effect on NRIP1/GSK-3/ß-catenin signals. NOP14 therefore appears to be overexpressed in clinical samples and cell lines of colorectal cancer, and promotes the proliferation, growth, and metastasis of colorectal cancer cells by modulating the NRIP1/GSK-3ß/ß-catenin signaling pathway.