The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.

Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy.

Hydrogel-based platforms for site-specific doxorubicin release in cancer therapy.

Hydrogels are promising candidates for the delivery of therapeutics in the treatment of human cancers. Regarding to the biocomaptiiblity, high drug and encapsulation efficacy and adjustable physico-chemical features, the hydrogels have been widely utilized for the delivery of chemotherapy drugs. Doxorubicin (DOX) is one of the most common chemotherapy drugs used in cancer therapy through impairing topoisomerase II function and increasing oxidative damage. However, the tumor cells have developed resistance into DOX-mediated cytotoxic impacts, requiring the delivery systems to increase internalization and anti-cancer activity of this drug. The hydrogels can deliver DOX in a sustained manner to maximize its anti-cancer activity, improving cancer elimination and reduction in side effects and drug resistance. The natural-based hydrogels such as chitosan, alginate and gelatin hydrogels have shown favourable biocompatibility and degradability in DOX delivery for tumor suppression. The hydrogels are able to co-deliver DOX with other drugs or genes to enhance drug sensitivity and mediate polychemotherapy, synergistically suppressing cancer progression. The incorporation of nanoparticles in the structure of hydrogels can improve the sustained release of DOX and enhancing intracellular internalization, accelerating DOX's cytotoxicity. Furthermore, the stimuli-responsive hydrogels including pH-, redox- and thermo-sensitive platforms are able to improve the specific release of DOX at the tumor site. The DOX-loaded hydrogels can be further employed in the clinic for the treatment of cancer patients and improving efficacy of chemotherapy.

Biodegradable Piezoelectric-Conductive Integrated Hydrogel Scaffold for Repair of Osteochondral Defects.

Osteochondral injury is a prevalent condition for which no specific treatment is currently available. This study presents a piezoelectric-conductive scaffold composed of a piezoelectric cartilage-decellularized extracellular matrix (dECM) and piezoelectric-conductive modified gelatin (Gel-PC). The piezoelectricity of the scaffold is achieved through the modification of diphenylalanine (FF) assembly on the pore surface, while the conductive properties of scaffold are achieved by the incorporating poly(3,4-ethylenedioxythiophene). In vitro experiments demonstrate that bone marrow mesenchymal stem cells (BMSCs) undergo biphasic division during differentiation. In vivo studies using a Parma pig model of osteochondral defects demonstrate that the piezoelectric-conductive scaffold exhibits superior reparative efficacy. Notably, the generation of electrical stimulation is linked to joint movement. During joint activity, mechanical forces compress the scaffold, leading to deformation and the subsequent generation of an electric potential difference. The positive charges accumulated on the upper layer of the scaffold attract BMSCs, promoting their migration to the upper layer and chondrogenic differentiation. Meanwhile, the negative charges in the lower layer induce the osteogenic differentiation of BMSCs. Overall, this piezoelectric-conducive scaffold provides a promising platform for the effective repair of osteochondral defects.

[Breeding of L-tryptophan high-yield strain by ARTP mutagenesis and high-throughput screening].

L-tryptophan is an indispensable essential amino acid with a wide range of applications, which leads to a high demand. Accordingly, the production of L-tryptophan becomes a much-anticipated direction in research and industrial development. While irrational mutagenesis is an effective means to breed industrial strains, how to screen the strains with desirable phenotypes is still a major challenge. In order to improve the efficiency and accuracy of screening L-tryptophan high-yield strains, we used atmospheric and room temperature plasma mutagenesis to construct a random mutant library and then combined it with high-throughput screening in deep-well plates. Using a pseudo-fluorescent protein sensor capable of responding specifically to L-tryptophan, we successfully screened out a strain producing L-tryptophan at a high yield from a random mutagenesis library. The fermentation with the strain in shake flasks produced L-tryptophan at a yield of 1.99 g/L, which was 41.77% higher than that of the starting strain. Finally, the mechanism of high yield of the strain was deciphered by comparative genomics and transcriptomics. The above strategies provide a solid research foundation for further selection and development of high quality L-tryptophan producing strains.

Propolis Alleviates Acute Lung Injury Induced by Heat-Inactivated Methicillin-Resistant Staphylococcus aureus via Regulating Inflammatory Mediators, Gut Microbiota and Serum Metabolites.

Propolis has potential anti-inflammatory properties, but little is known about its efficacy against inflammatory reactions caused by drug-resistant bacteria, and the difference in efficacy between propolis and tree gum is also unclear. Here, an in vivo study was performed to study the effects of ethanol extract from poplar propolis (EEP) and poplar tree gum (EEG) against heat-inactivated methicillin-resistant Staphylococcus aureus (MRSA)-induced acute lung injury (ALI) in mice. Pre-treatment with EEP and EEG (100 mg/kg, p.o.) resulted in significant protective effects on ALI in mice, and EEP exerted stronger activity to alleviate lung tissue lesions and ALI scores compared with that of EEG. Furthermore, EEP significantly suppressed the levels of pro-inflammatory mediators in the lung, including TNF-α, IL-1ß, IL-6, and IFN-γ. Gut microbiota analysis revealed that both EEP and EEG could modulate the composition of the gut microbiota, enhance the abundance of beneficial microbiota and reduce the harmful ones, and partly restore the levels of short-chain fatty acids. EEP could modulate more serum metabolites and showed a more robust correlation between serum metabolites and gut microbiota. Overall, these results support the anti-inflammatory effects of propolis in the treatment of ALI, and the necessity of the quality control of propolis.

Choline Phosphate-Grafted Nanozymes as Universal Extracellular Vesicle Probes for Bladder Cancer Detection.

Urinary extracellular vesicles (uEVs) are regarded as highly promising liquid-biopsy biomarkers for the early diagnosis and prognosis of bladder cancer (BC). However, detection of uEVs remains technically challenging owing to their huge heterogeneity and ultralow abundance in real samples. We herein present a choline phosphate-grafted platinum nanozyme (Pt@CP) that acts as a universal EV probe for the construction of a high-throughput and high-sensitivity immunoassay, which allowed multiplex profiling of uEV protein markers for BC detection. With the Pt@CP-based immunoassays, three uEV protein markers (MUC-1, CCDC25, and GLUT1) were identified for BC, by which the BC cases (n = 48), cystitis patients (n = 27), and healthy donors (n = 24) were discriminated with high clinical sensitivity and specificity (area under curve = 98.3%). For the BC cases (n = 9) after surgery, the Pt@CP-based immunoassay could report the postoperative residual tumor that cannot be observed by cystoscopy, which is clinically significant for assessing BC recurrence. This work provides generally high sensitivity for EV detection, facilitating the discovery and clinical use of EV-based biomarkers.

Sodium chloride promotes macrophage pyroptosis and aggravates rheumatoid arthritis by activating SGK1 through GABA receptors Slc6a12.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and the production of autoantibodies. Previous studies have indicated an association between high-salt diets (HSD) and an increased risk of RA, yet the underlying mechanisms remain unclear. Macrophage pyroptosis, a pro-inflammatory form of cell death, plays a pivotal role in RA. In this study, we demonstrate that HSD exacerbates the severity of arthritis in collagen-induced arthritis (CIA) mice, correlating with macrophage infiltration and inflammatory lesions. Given the significant alterations observed in macrophages from CIA mice subjected to HSD, we specifically investigate the impact of HSD on macrophage responses in the inflammatory milieu of RA. In our in vitro experiments, pretreatment with NaCl enhances LPS-induced pyroptosis in RAW.264.7 and THP-1 cells through the p38 MAPK/NF-κB signaling pathway. Subsequent experiments reveal that Slc6a12 inhibitors and SGK1 silencing inhibit sodium-induced activation of macrophage pyroptosis and the p38 MAPK/NF-κB signaling pathway, whereas overexpression of the SGK1 gene counteracts the effect of sodium on macrophages. In conclusion, our findings verified that high salt intake promotes the progression of RA and provided a detailed elucidation of the activation of macrophage pyroptosis induced by sodium transportation through the Slc6a12 channel.

Association between blood ethylene oxide levels and the prevalence of periodontitis: evidence from NHANES 2013-2014.

BACKGROUND: The study aimed to establish a link between blood ethylene oxide (EO) levels and periodontitis, given the growing concern about EO's detrimental health effects. MATERIALS AND METHODS: The study included 1006 adults from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) dataset. We assessed periodontitis prevalence across groups, used weighted binary logistic regression and restricted cubic spline fitting for HbEO-periodontitis association, and employed Receiver Operating Characteristic (ROC) curves for prediction. RESULTS: In the periodontitis group, HbEO levels were significantly higher (40.57 vs. 28.87 pmol/g Hb, P < 0.001). The highest HbEO quartile showed increased periodontitis risk (OR = 2.88, 95% CI: 1.31, 6.31, P = 0.01). A "J"-shaped nonlinear HbEO-periodontitis relationship existed (NL-P value = 0.0116), with an inflection point at ln-HbEO = 2.96 (EO = 19.30 pmol/g Hb). Beyond this, ln-HbEO correlated with higher periodontitis risk. A predictive model incorporating sex, age, education, poverty income ratio, alcohol consumption, and HbEO had 69.9% sensitivity and 69.2% specificity. The model achieved an area under the ROC curve of 0.761. CONCLUSIONS: These findings suggest a correlation between HbEO levels and an increased susceptibility to periodontitis.

Platinum Prodrug Nanoparticles with COX-2 Inhibition Amplify Pyroptosis for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer.

Pyroptosis, an emerging mechanism of programmed cell death, holds great potential to trigger a robust antitumor immune response. Platinum-based chemotherapeutic agents can induce pyroptosis via caspase-3 activation. However, these agents also enhance cyclooxygenase-2 (COX-2) expression in tumor tissues, leading to drug resistance and immune evasion in pancreatic cancer and significantly limiting the effectiveness of chemotherapy-induced pyroptosis. Here, an amphiphilic polymer (denoted as PHDT-Pt-In) containing both indomethacin (In, a COX-2 inhibitor) and platinum(IV) prodrug (Pt(IV)) is developed, which is responsive to glutathione (GSH). This polymer self-assemble into nanoparticles (denoted as Pt-In NP) that can disintegrate in cancer cells due to the GSH responsiveness, releasing In to inhibit the COX-2 expression, hence overcoming the chemoresistance and amplifying cisplatin-induced pyroptosis. In a pancreatic cancer mouse model, Pt-In NP significantly inhibit tumor growth and elicit both innate and adaptive immune responses. Moreover, when combined with anti-programmed death ligand (α-PD-L1) treatment, Pt-In NP demonstrate the ability to completely suppress metastatic tumors, transforming "cold tumors" into "hot tumors". Overall, the sustained release of Pt(IV) and In from Pt-In NP amplifies platinum-drug-induced pyroptosis to elicit long-term immune responses, hence presenting a generalizable strategy for pancreatic cancer.

Spatiotemporal Modulated Scaffold for Endogenous Bone Regeneration via Harnessing Sequentially Released Guiding Signals.

The design of a scaffold that can regulate the sequential differentiation of bone marrow mesenchymal stromal cells (BMSCs) according to the endochondral ossification (ECO) mechanism is highly desirable for effective bone regeneration. In this study, we successfully fabricated a dual-networked composite hydrogel composed of gelatin and hyaluronic acid (termed GCDH-M), which can sequentially release chondroitin sulfate (CS) and magnesium/silicon (Mg/Si) ions to provide spatiotemporal guidance for chondrogenesis, angiogenesis, and osteogenesis. The fast release of CS is from the GCDH hydrogel, and the sustained releases of Mg/Si ions are from poly(lactide-co-glycolide) microspheres embedded in the hydrogel. There is a difference in the release rates between CS and ions, resulting in the ability for the fast release of CS and sustained release of ions. The dual networks between the modified gelatin and hyaluronic acid via covalent bonding and host-guest interactions render the hydrogel with some dynamic feature to meet the differentiation development of BMSCs laden inside the hydrogel, i.e., transforming into a chondrogenic phenotype, further to a hypertrophic phenotype and eventually to an osteogenic phenotype. As evidenced by the results of in vitro and in vivo evaluations, this GCDH-M composite hydrogel was proved to be able to create an optimal microenvironment for embedded BMSCs responding to the sequential guiding signals, which aligns with the rhythm of the ECO process and ultimately boosts bone regeneration. The promising outcome achieved with this innovative hydrogel system sheds light on novel scaffold design targeting bone tissue engineering.

Development and validation of real-time recombinase polymerase amplification-based assays for detecting HPV16 and HPV18 DNA.

IMPORTANCE: HPV DNA screening is an effective approach for the prevention of cervical cancer. The novel real-time recombinase polymerase amplification-based HPV detection systems we developed constitute an improvement over the HPV detection methods currently used in clinical practice and should help to extend cervical cancer screening in the future, particularly in point-of-care test settings.

Stimuli-responsive ultra-small vanadate prodrug nanoparticles with NIR photothermal properties to precisely inhibit Na/K-ATPase for enhanced cancer therapy.

Inhibition of Na/K-ATPase is a promising cancer treatment owing to the essential role of Na/K-ATPase in maintaining various cellular functions. The potent Na/K-ATPase inhibitor, vanadate(V) (termed as V(V)), has exhibited efficient anticancer effects. However, nonspecific inhibition using V(V) results in serious side effects, which hinder its clinical application. Here, bovine serum albumin (BSA)-modified ultra-small vanadate prodrug nanoparticles (V(IV) NPs) were synthesized via a combined reduction-coordination strategy with a natural polyphenol tannic acid (TA). A lower systemic toxicity of V(IV) NPs is achieved by strong metal-polyphenol coordination interactions. An efficient V(V) activation is realized by reactive oxygen species (ROS) at the tumor site. Furthermore, V(IV) NPs show excellent photothermal properties in the near-infrared (NIR) region. By NIR irradiation at the tumor site for mild hyperthermia, selective enhancement of the interactions between V(V) and Na/K-ATPase achieves stronger inhibition of Na/K-ATPase for robust cell killing effect. Altogether, V(IV) NPs specifically inhibit Na/K-ATPase in cancer cells with negligible toxicity to normal tissues, thus making them a promising candidate for clinical applications of Na/K-ATPase inhibition.

CRYSTAF, DSC and SAXS Study of the Co-Crystallization, Phase Separation and Lamellar Packing of the Blends with Different Polyethylenes.

The crystallization of polyethylene (PE) blends is a highly complex process, owing to the significant differences in crystallizability of the various PE components and the varying PE sequence distributions resulting from short- or long-chain branching. In this study, we examined both the resins and their blends through crystallization analysis fractionation (CRYSTAF) to understand the PE sequence distribution and differential scanning calorimetry (DSC) to investigate the non-isothermal crystallization behavior of the bulk materials. Small-angle X-ray scattering (SAXS) was utilized to study the crystal packing structure. The results showed that the PE molecules in the blends crystallize at different rates during cooling, resulting in a complicated crystallization behavior characterized by nucleation, co-crystallization, and fractionation. We compared these behaviors to those of reference immiscible blends and found that the extent of the differences is related to the disparity in crystallizability between components. Furthermore, the lamellar packing of the blends is closely associated with their crystallization behaviors, and the crystalline structure varies significantly depending on the components' compositions. Specifically, the lamellar packing of the HDPE/LLDPE and HDPE/LDPE blends is similar to that of the HDPE component owing to its strong crystallizability, while the lamellar packing of the LLDPE/LDPE blend is approximately an average of the two neat components.

A biomimetic piezoelectric scaffold with sustained Mg2+ release promotes neurogenic and angiogenic differentiation for enhanced bone regeneration.

Natural bone is a composite tissue made of organic and inorganic components, showing piezoelectricity. Whitlockite (WH), which is a natural magnesium-containing calcium phosphate, has attracted great attention in bone formation recently due to its unique piezoelectric property after sintering treatment and sustained release of magnesium ion (Mg2+). Herein, a composite scaffold (denoted as PWH scaffold) composed of piezoelectric WH (PWH) and poly(ε-caprolactone) (PCL) was 3D printed to meet the physiological demands for the regeneration of neuro-vascularized bone tissue, namely, providing endogenous electric field at the defect site. The sustained release of Mg2+ from the PWH scaffold, displaying multiple biological activities, and thus exhibits a strong synergistic effect with the piezoelectricity on inhibiting osteoclast activation, promoting the neurogenic, angiogenic, and osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) in vitro. In a rat calvarial defect model, this PWH scaffold is remarkably conducive to efficient neo-bone formation with rich neurogenic and angiogenic expressions. Overall, this study presents the first example of biomimetic piezoelectric scaffold with sustained Mg2+ release for promoting the regeneration of neuro-vascularized bone tissue in vivo, which offers new insights for regenerative medicine.

Fibrous dressing containing bioactive glass with combined chemotherapy and wound healing promotion for post-surgical treatment of melanoma.

Surgery is the mainstream treatment for melanoma. However, inappropriate post-surgical treatment could result in the tumor recurrence and sever tissue damage, which ultimately leads to the failure of therapy and significantly compromises the therapeutic outcome of surgery. Herein, taking advantages of the co-axial electrospinning technology, we construct a dual-function nanofibrous wound dressing for the post-surgical treatment of melanoma. Si-Ca-P-based mesoporous bioactive glass (MBG) was prepared by the template-sol-gel process, with the compositions being set as 60 SiO2: 36 CaO: 4 P2O5 in mol%. Through rational design, 5-fluorouracil (5-FU)-loaded MBG nanoparticles (MBG-U) are successfully incorporated into the fiber core with biodegradable poly(lactic-co-glycolic acid) (PLGA) as the cladding layer to form the core-shell nanofibers (MBG-U CSF), which achieves sustained releases of chemotherapeutic drug (i.e.,5-FU) and wound healing promotion function. Thereafter, the post-surgical melanoma model was established to evaluate the in-situ anti-cancer and wound healing effect of MBG-U CSF. Thereafter, the post-surgical melanoma model was established to evaluate the anti-cancer and wound healing effect. The results demonstrated that the core-shell nanofibrous dressing almost complete suppressed tumor growth, and simultaneously promoted skin regeneration, which provides a promising strategy for the post-surgical treatment for melanoma.

Preparing Biosurfactant Glucolipids from Crude Sophorolipids via Chemical Modifications and Their Potential Application in the Food Industry.

This investigation developed a novel strategy for efficiently preparing glucolipids (GLs) by chemically modifying crude sophorolipids. Running this strategy, crude sophorolipids were effectively transformed into GLs through deglycosylation and de-esterification, with a yield of 54.1%. The acquired GLs were then purified via stepwise extractions, and 66.2% of GLs with 95% purity was recovered. GLs are more hydrophobic and present a stronger surface activity than acidic sophorolipids (ASLs). More importantly, these GLs displayed a superior antimicrobial activity to that of ASLs against the tested Gram-positive food pathogens, with a minimum inhibitory concentration of 32-64 mg/L, except against E. coli . This activity of GLs is pH-dependent and especially more powerful under acidic conditions. The mechanism involved is possibly associated with the more efficient adsorption of GLs, as demonstrated by the hydrophobicity of the cell membrane. These GLs could be used as antimicrobial agents for food preservation and health in the food industry.

The synergistic effect of polytetrafluoroethylene in-situ fibrillation and dibenzoyl sebacate hydrazide on the crystallization and foaming behavior of poly (lactic acid).

The fully degradable poly (lactic acid) foam with green environmental protection characteristics can alleviate the shortage of petroleum resources caused by the application of plastics. However, due to the inherent low melt strength and slow crystallization rate of linear PLA. It is difficult to obtain PLA microcellular foam with good morphology. In order to obtain PLA microcellular foam with ultra-high expansion ratio and small cell size, PTFE (polytetrafluoroethylene) nanofibers with excellent CO2 adsorption rate were introduced. Self-assembled nucleator TMC-300(dibenzoyl sebacate hydrazide) was also introduced to blend with PLA to obtain small-sized cells. The results show that the PTFE entanglement network as a self-assembled template can effectively improve the early crystallization nucleation efficiency and increase the crystallinity of branched PLA (CBPLA)/TMC by 7 %. The microcellular foam with PTFE content of 0.5 wt% (CBPLA/TMC/PTFE 0.5) was successfully prepared by physical foaming agent, which had the lowest cell size (8.7 µm) And high expansion ratio (1200 %).

LncRNA-Profile-Based Screening of Extracellular Vesicles Released from Brain Endothelial Cells after Oxygen-Glucose Deprivation.

Brain microvascular endothelial cells (BMECs) linked by tight junctions play important roles in cerebral ischemia. Intercellular signaling via extracellular vesicles (EVs) is an underappreciated mode of cell-cell crosstalk. This study aims to explore the potential function of long noncoding RNAs (lncRNAs) in BMECs' secreted EVs. We subjected primary human and rat BMECs to oxygen and glucose deprivation (OGD). EVs were enriched for RNA sequencing. A comparison of the sequencing results revealed 146 upregulated lncRNAs and 331 downregulated lncRNAs in human cells and 1215 upregulated lncRNAs and 1200 downregulated lncRNAs in rat cells. Next, we analyzed the genes that were coexpressed with the differentially expressed (DE) lncRNAs on chromosomes and performed Gene Ontology (GO) and signaling pathway enrichment analyses. The results showed that the lncRNAs may play roles in apoptosis, the TNF signaling pathway, and leukocyte transendothelial migration. Next, three conserved lncRNAs between humans and rats were analyzed and confirmed using PCR. The binding proteins of these three lncRNAs in human astrocytes were identified via RNA pulldown and mass spectrometry. These proteins could regulate mRNA stability and translation. Additionally, the lentivirus was used to upregulate them in human microglial HMC3 cells. The results showed NR_002323.2 induced microglial M1 activation. Therefore, these results suggest that BMECs' EVs carry the lncRNAs, which may regulate gliocyte function after cerebral ischemia.

Abundance and fractional solubility of phosphorus and trace metals in combustion ash and desert dust: Implications for bioavailability and reactivity.

Aerosol phosphorus (P) and trace metals derived from natural processes and anthropogenic emissions have considerable impacts on ocean ecosystems, human health, and atmospheric processes. However, the abundance and fractional solubility of P and trace metals in combustion ash and desert dust, which are two of the largest emission sources of aerosols, are still not well understood. In this study, the abundance and fractional solubility of P and trace metals in seven coal fly ash samples, two municipal waste fly ash samples, and three desert dust samples were experimentally examined. It was found that the abundance of aluminum (Al) in combustion ash was comparable or even higher than that in desert dust, and, therefore, care should be taken when using Al as a tracer of desert dust. The abundance and fractional solubility of P were higher in combustion ash, with a soluble P content ~4-6 times higher than that of the desert dust, indicating that combustion ash could be an important source of bioavailable P in the atmosphere. Except for Mn, the abundance and fractional solubility of other heavy metals were higher in the combustion ash compared to the desert dust, indicating the potential importance of combustion ash in ocean ecosystems, human health, and atmospheric processes. In contrast, both the abundance and solubility of Mn were highest in the desert dust, indicating a potentially important source of soluble Mn in the atmosphere. The fractional solubilities of P and trace metals are significantly affected by acidity and ions in the extraction solutions, and it is suggested that a buffer solution can better represent the acidity of the aqueous system in the true atmospheric environment. The results of this study improve our understanding of the sources of bioavailable and reactive P and trace metals in ambient aerosols.

Exosomal microRNA-25 released from cancer cells targets SIK1 to promote hepatocellular carcinoma tumorigenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) is recognized as a leading cause of cancer-associated fatality worldwide. Our study here aimed to probe the mechanism by which exosomes secreted by CSQT-2, an HCC cell line, affected the progression of HCC. METHODS: Exosomes were extracted from CSQT-2 cells. Colony formation, Transwell, sphere formation and flow cytometric analyses were applied to assess cell biological activities. Microarray analysis detected the change of microRNA (miRNA) expression after exosome treatment, followed by RT-qPCR validation. Luciferase reporter was applied to detect the binding between SIK1 and miR-25. Xenograft studies in nude mice manifested tumor growth and metastatic ability of miR-25 and SIK1. RESULTS: The exosome treatment enhanced cell malignant phenotype in vitro and tumor growth and liver and lung metastases in vivo. The exosomes elevated miR-25 expression in HCC cells. miR-25 targeted SIK1 which was decreased in the exosomes-treated cells. miR-25 inhibitor reduced cell malignant phenotype and attenuated tumorigenesis and metastasis in vivo. SIK1 silencing reversed the effect of miR-25 inhibitor. The exosome treatment potentiated the Wnt/ß-catenin pathway in cells, whereas miR-25 inhibitor blunted the pathway activity. CONCLUSION: MiR-25 shuttled through CSQT-2-derived exosomes promoted the development of HCC by reducing SIK1 expression and potentiating the Wnt/ß-catenin pathway.