NIR and magnetism dual-response multi-core magnetic vortex nanoflowers for boosting magneto-photothermal cancer therapy.

Due to the relatively low efficiency of magnetic hyperthermia and photothermal conversion, it is rather challenging for magneto-photothermal nanoagents to be used as an effective treatment during tumor hyperthermal therapy. The advancement of magnetic nanoparticles exhibiting a vortex-domain structure holds great promise as a viable strategy to enhance the application performance of conventional magnetic nanoparticles while retaining their inherent biocompatibility. Here, we report the development of Mn0.5Zn0.5Fe2O4 nanoflowers with ellipsoidal magnetic cores, and show them as effective nanoagents for magneto-photothermal synergistic therapy. Comparative studies were conducted on the heating performance of anisometric Mn0.5Zn0.5Fe2O4 (MZF) nanoparticles, including nanocubes (MZF-C), hollow spheres (MZF-HS), nanoflowers consisting of ellipsoidal magnetic cores (MZF-NFE), and nanoflowers consisting of needle-like magnetic cores (MZF-NFN). MZF-NFE exhibits an intrinsic loss parameter (ILP) of up to 15.3 N h m2 kg-1, which is better than that of commercial equivalents. Micromagnetic simulations reveal the magnetization configurations and reversal characteristics of the various MZF shapes. Additionally, all nanostructures displayed a considerable photothermal conversion efficiency rate of more than 18%. Our results demonstrated that by combining the dual exposure of MHT and PTT for hyperthermia treatments induced by MZF-NFE, BT549, MCF-7, and 4T1 cell viability can be significantly decreased by ∼95.7% in vitro.

Hollow spherical Mn0.5Zn0.5Fe2O4 nanoparticles with a magnetic vortex configuration for enhanced magnetic hyperthermia efficacy.

Conventional magnetic nanoagents in cancer hyperthermia therapy suffer from a low magnetic heating efficiency. To address this issue, researchers have pursued magnetic nanoparticles with topological magnetic domain structures, such as the vortex-domain structure, to enhance the magnetic heating performance of conventional nanoparticles while maintaining excellent biocompatibility. In this study, we synthesized hollow spherical Mn0.5Zn0.5Fe2O4 (MZF-HS) nanoparticles using a straightforward solvothermal method, yielding samples with an average outer diameter of approximately 350 nm and an average inner diameter of about 220 nm. The heating efficiency of the nanoparticles was experimentally verified, and the specific absorption rate (SAR) value of the hollow MZF was found to be approximately 1.5 times that of solid MZF. The enhanced heating performance is attributed to the vortex states in the hollow MZF structure as validated with micromagnetic simulation studies. In vitro studies demonstrated the lower cell viability of breast cancer cells (MCF-7, BT549, and 4T1) after MHT in the presence of MZF-HS. The synthesized MZF caused 51% cell death after MHT, while samples of MZF-HS resulted in 77% cell death. Our findings reveal that magnetic particles with a vortex state demonstrate superior heating efficiency, highlighting the potential of hollow spherical particles as effective heat generators for MHT applications.

Combination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as associated with the extreme complexity of cancer-immunity interactions remain a major challenge to be resolved. Owing to the epigenome plasticity of cancer and immune cells, a growing body of evidence has been presented indicating that epigenetic treatments have the potential to overcome current limitations of immunotherapy, thus providing a rationalefor the combination of ICIs with epigenetic agents (epidrugs). In this review, we first make an overview about the epigenetic regulations in tumor biology and immunodevelopment. Subsequently, a diverse array of inhibitory agents under investigations targeted epigenetic modulators (Azacitidine, Decitabine, Vorinostat, Romidepsin, Belinostat, Panobinostat, Tazemetostat, Enasidenib and Ivosidenib, etc.) and immune checkpoints (Atezolizmab, Avelumab, Cemiplimab, Durvalumb, Ipilimumab, Nivolumab and Pembrolizmab, etc.) to increase anticancer responses were described and the potential mechanisms were further discussed. Finally, we summarize the findings of clinical trials and provide a perspective for future clinical studies directed at investigating the combination of epidrugs with ICIs as a treatment for cancer.

NDRG3 regulates imatinib resistance by promoting ß­catenin accumulation in the nucleus in chronic myelogenous leukemia.

Imatinib resistance in chronic myelogenous leukemia (CML) is a clinical problem. The present study examined the role of N­Myc downstream regulatory gene 3 (NDRG3) in imatinib resistance in CML. Quantitative PCR demonstrated that NDRG3 was highly expressed in patients with CML. Cell Counting Kit (CCK)­8 experiments proved that NDRG3 promoted the proliferation of K562 CML cells and enhanced imatinib resistance. Dual­luciferase assay showed that microRNA (miR)­204­5p inhibited expression of NDRG3 and immunofluorescence experiments showed that NDRG3 promoted accumulation of ß­catenin in the nucleus, thereby increasing the expression of downstream drug resistance­ and cell cycle­associated factors (c­Myc and MDR1). At the same time, cell proliferation experiments showed that ß­catenin played a role in cell proliferation and drug resistance. Co­transfection with small interfering (si)­ß­catenin partially reversed the effect of NDRG3. This finding indicated that NDRG3 plays an important role in imatinib resistance and miR­204­5p and ß­catenin are involved in the biological behavior of NDRG3. The present results provide theoretical support for overcoming drug resistance in CML.

Delivery of miR-3529-3p using MnO2 -SiO2 -APTES nanoparticles combined with phototherapy suppresses lung adenocarcinoma progression by targeting HIGD1A.

BACKGROUND: The present study aimed to investigate the function of miR-3529-3p in lung adenocarcinoma and MnO2 -SiO2 -APTES (MSA) as a promising multifunctional delivery agent for lung adenocarcinoma therapy. METHODS: Expression levels of miR-3529-3p were evaluated in lung carcinoma cells and tissues by qRT-PCR. The effects of miR-3529-3p on apoptosis, proliferation, metastasis and neovascularization were assessed by CCK-8, FACS, transwell and wound healing assays, tube formation and xenografts experiments. Luciferase reporter assays, western blot, qRT-PCR and mitochondrial complex assay were used to determine the targeting relationship between miR-3529-3p and hypoxia-inducible gene domain family member 1A (HIGD1A). MSA was fabricated using MnO2 nanoflowers, and its heating curves, temperature curves, IC50, and delivery efficiency were examined. The hypoxia and reactive oxygen species (ROS) production was investigated by nitro reductase probing, DCFH-DA staining and FACS. RESULTS: MiR-3529-3p expression was reduced in lung carcinoma tissues and cells. Transfection of miR-3529-3p could promote apoptosis and suppress cell proliferation, migration and angiogenesis. As a target of miR-3529-3p, HIGD1A expression was downregulated, through which miR-3529-3p could disrupt the activities of complexes III and IV of the respiratory chain. The multifunctional nanoparticle MSA could not only efficiently deliver miR-3529-3p into cells, but also enhance the antitumor function of miR-3529-3p. The underlying mechanism may be that MSA alleviates hypoxia and has synergistic effects in cellular ROS promotion with miR-3529-3p. CONCLUSIONS: Our results establish the antioncogenic role of miR-3529-3p, and demonstrate that miR-3529-3p delivered by MSA has enhanced tumor suppressive effects, probably through elevating ROS production and thermogenesis.

Dynamic QoS Prediction Algorithm Based on Kalman Filter Modification.

With the widespread adoption of service-oriented architectures (SOA), services with the same functionality but the different Quality of Service (QoS) are proliferating, which is challenging the ability of users to build high-quality services. It is often costly for users to evaluate the QoS of all feasible services; therefore, it is necessary to investigate QoS prediction algorithms to help users find services that meet their needs. In this paper, we propose a QoS prediction algorithm called the MFDK model, which is able to fill in historical sparse QoS values by a non-negative matrix decomposition algorithm and predict future QoS values by a deep neural network. In addition, this model uses a Kalman filter algorithm to correct the model prediction values with real-time QoS observations to reduce its prediction error. Through extensive simulation experiments on the WS-DREAM dataset, we analytically validate that the MFDK model has better prediction accuracy compared to the baseline model, and it can maintain good prediction results under different tensor densities and observation densities. We further demonstrate the rationality of our proposed model and its prediction performance through model ablation experiments and parameter tuning experiments.

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession.

PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 is considered as a "pseudokinase", contributing to different kinds of cancer. However, the detailed roles of TRIB2 in regulating cancer metabolism by PKM2 remain unclear. This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. The elevated pSer37-PKM2 would subsequently promote the PKM2 dimers to enter into nucleus and increase the expression of LDHA, GLUT1, and PTBP1. The aerobic glycolysis is then elevated to promote cancer cell proliferation and migration in TRIB2- or PKM2-overexpressed cultures. The glucose uptake and lactate production increased, but the ATP content decreased in TRIB2- or PKM2-treated cultures. Experiments of TRIB2-/- mice further supported that TRIB2 could regulate aerobic glycolysis by PKM2. Thus, these results reveal the new kinase activity of TRIB2 and its mechanism in cancer metabolism may be related to regulating PKM2 to promote lung cancer cell proliferation in vitro and in vivo, suggesting promising therapeutic targets for cancer therapy by controlling cancer metabolism.

TRIB2 regulates the expression of miR­33a­5p through the ERK/c­Fos pathway to affect the imatinib resistance of chronic myeloid leukemia cells.

Chronic myeloid leukemia (CML) is a hematological disease, and imatinib (IM) resistance represents a major problem for its clinical treatment. In the present study, the role of tribbles pseudokinase 2 (TRIB2) in IM resistance of CML and the possible mechanism were investigated. It was found that TRIB2 was highly expressed in IM­resistant patients with CML through the Oncomine database and this conclusion was confirmed using reverse transcription­quantitative PCR and western blot experiments. Knockdown of TRIB2 was found to increase the drug sensitivity of KG cells to IM using Cell­Counting Kit­8 (CCK­8) assays, and the low­expression TRIB2 mice were further found to be more sensitive to the IM and have a higher survival rate in leukemia model mice. Moreover, using western blot and luciferase experiments, it was found that TRIB2 could regulate c­Fos through the ERK signaling pathway, and c­Fos suppressed the transcriptional activity and the expression of miR­33a­5p. Further investigation identified that the binding site for c­Fos to function on miR­33a­5p was the ­958­965 region. Finally, CCK­8 assays and western blot experiments demonstrated that miR­33a­5p could inhibit the proliferation of KG cells and reduce IM resistance by suppressing the expression of HMGA2. In conclusion, it was demonstrated that TRIB2 regulates miR­33a­5p to reverse IM resistance in CML, which may help identify novel targets and therapeutic strategies for the clinical treatment of IM resistance.

Anticancer roles of let-7f-1-3p in non-small cell lung cancer via direct targeting of integrin ß1.

Lung cancer is one of the most common types of cancer, with the highest mortality rate worldwide. MicroRNAs play notable roles in the chemotherapeutic effects of anticancer drugs. The present study used reverse transcription-quantitative PCR, western blotting and cell migration and invasion assays to reveal the role of let-7f-1-3p in non-small cell lung cancer (NSCLC) and explore the effect of let-7f-1-3p on doxorubicin (DOX) treatment. It was demonstrated that the levels of let-7f-1-3p in carcinoma tissues were lower compared with those in paracarcinoma tissues. Thus, let-7f-1-3p may act as a suppressor gene. The present study also explored the role of let-7f-1-3p in A549 and NCI-H1975 cells. Results revealed that let-7f-1-3p could inhibit the viability, migration and invasion of NSCLC cells and induce their apoptosis. Integrin ß1 acted as a target gene regulated by let-7f-1-3p. This suggested that let-7f-1-3p could enhance DOX-inhibited cell viability, migration and invasion in vitro. Overall, the present study demonstrated that let-7f-1-3p may act as a target for drug design and lung cancer therapy.

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c-Myc/ATG10 axis.

Gastric cancer (GC) is a malignancy for which effective therapeutic drugs are limited. Podofilox exhibits antitumor effects in various types of cancer; however, whether it may inhibit GC growth remains unknown. The aim of the present study was to investigate the role of podofilox in GC. Cell Counting Kit-8, colony formation and cell cycle assays were used to detect the role of podofilox on cellular proliferation and the cell cycle, respectively. A microarray was used to detect the transcriptional changes induced by podofilox in GC cells. The results of the present study demonstrated that podofilox inhibited GC cell proliferation and colony formation. The half maximal inhibitory concentration of podofilox in AGS and HGC-27 cells was 2.327 and 1.981 nM, respectively. In addition, treatment with podofilox induced G0/G1 cell cycle arrest. Molecular analysis based on microarray data demonstrated that podofilox altered the expression levels of genes involved in the cell cycle, c-Myc and p53 signaling. Autophagy-related 10 (ATG10), which was highly expressed in GC tissues, was also downregulated by podofilox, as demonstrated by the results of the microarray analysis and immunoblotting. To determine the involvement of ATG10 in GC, ATG10 was knocked down in GC cells by small interfering RNA, which suppressed the proliferation and colony formation of GC cells compared with those observed in the control-transfected cells. Taken together, the results of the present study suggested that podofilox may inhibit GC cell proliferation by preventing the cell cycle progression and regulating the c-Myc/ATG10 signaling pathway.

miR-4293 upregulates lncRNA WFDC21P by suppressing mRNA-decapping enzyme 2 to promote lung carcinoma proliferation.

Non-coding RNAs (ncRNAs) involve in diverse biological processes by post-transcriptional regulation of gene expression. Emerging evidence shows that miRNA-4293 plays a significant role in the development of non-small cell lung cancer. However, the oncogenic functions of miR-4293 have not been studied. Our results demonstrated that miR-4293 expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, miR-4293 promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified mRNA-decapping enzyme 2 (DCP2) as a target of miR-4293 and its expression is suppressed by miR-4293. DCP2 can directly or indirectly bind to WFDC21P and downregulates its expression. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With a positive correlation to miR-4293 expression, WFDC21P also plays an oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both miR-4293 and WFDC21P. Overall, our results establish oncogenic roles for both miR-4293 and WFDC21P and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in the regulation of carcinoma pathogenesis. These results provided a valuable theoretical basis for the discovery of lung carcinoma therapeutic targets and diagnostic markers based on miR-4293 and WFDC21P.

Musk ketone induces apoptosis of gastric cancer cells via downregulation of sorbin and SH3 domain containing 2.

Musk ketone exerts antiproliferative effects on several types of cancer, such as lung and breast cancer. However, the effects and underlying mechanisms of action of musk ketone in gastric cancer (GC) are poorly understood. The present study aimed to investigate the effects of musk ketone in GC cells. The present study indicated that musk ketone exerted significant anticancer effects on GC cells. The IC50 values of musk ketone were 4.2 and 10.06 µM in AGS and HGC­27 cells, respectively. Low dosage of musk ketone significantly suppressed the proliferation and colony formation of AGS and HGC­27 cells. Cell cycle arrest and apoptosis were induced by musk ketone. Furthermore, microarray data indicated that musk ketone treatment led to downregulation of various genes, including sorbin and SH3 domain containing 2 (SORBS2). Reverse transcription­quantitative PCR and immunoblotting results indicated that musk ketone repressed mRNA and protein expression levels of SORBS2. It was also shown that knockdown of SORBS2 inhibited the proliferation and colony formation of HGC­27 cells. The antiproliferative effects of musk ketone were decreased in HGC­27 cells with SORBS2 silencing. In summary, the present study indicated that musk ketone suppressed the proliferation and growth of GC partly by downregulating SORBS2 expression.

Predictive value of the Delphian lymph node in cervical lymph node metastasis of papillary thyroid carcinoma.

INTRODUCTION: Delphian lymph node metastasis (DLNM) has proven to be a risk factor for a poor prognosis in head and neck malignancies. This study aimed to reveal the clinical features and evaluate the predictive value of the Delphian lymph node (DLN) in papillary thyroid carcinoma (PTC) to guide the extent of surgery. METHODS: Tianjin Medical University Cancer Institute and Hospital pathology database was reviewed from 2017 to 2020, and 516 PTC patients with DLN detection were enrolled. Retrospective analysis was performed, while multivariate analysis was performed to identify the risk factors for DLNM. RESULTS: Among the 516 PTC patients with DLN detection, the DLN metastasis rate was 25.39% (131/516). Tumor size >1 cm, location in the upper 1/3, central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM) and lymphovascular invasion were independent risk factors for DLNM. Patients with DLNM had a higher incidence of ipsilateral CLNM, contralateral CLNM (CCLNM) and LLNM, and larger numbers and size of metastatic CLNs than those without DLNM. The incidence of CLNM among cN0 patients with DLNM was higher than that among those without DLNM. The incidence of CCLNM among unilateral cN + patients with DLNM was similarly higher than that among patients without DLNM. CONCLUSIONS: DLNM indicates a high likelihood and large number of cervical lymph nodes metastases in PTC patients. Surgeons are strongly recommended to detect DLN status during operation by means of frozen pathology, so as to evaluate the possibility of cervical nodal metastasis and decide the appropriate extent of surgery.

Experimental and thermodynamic study of banana peel non-catalytic gasification characteristics.

The Gasification performance of banana peel was examined in a fixed bed reactor. Effect of temperature, steam to carbon ratio (S/C), drying treatment on syngas composition, gas yield, CO2 selectivity and carbon conversion efficiency (CCE) were investigated. The influence of temperature and S/C on hydrogen production was investigated by thermodynamic analysis. The transient characteristics of banana peel steam gasification were investigated by monitoring the evolutionary behavior of syngas production. An increase in S/C can lead to an increase in the selectivity of CO2, but excess steam (S/C > 21.7) causes a decrease in H2 yield and CCE. The increase of temperature is beneficial to the increase of CCE, but which leads to a decrease in CO2 selectivity. When S/C = 27.1, the effect of temperature on H2 yield can be divided into CCE control region and CO2 selectivity control region. At temperature < 1023 K, H2 yield is more sensitive to the changes of CCE. While at temperature > 1023 K, CO2 selectivity has a more significant effect on H2 yield. When S/C = 21.7 and temperature is 1023 K, the yield of H2 produced from the fresh banana peel gasification reaches the maximum value (76.1 ml/g).

A comparative study on droplet characteristics and specific charge of ethanol in two small-scale electrospray systems.

An investigation on the droplet characteristics of ethanol in small-scale combustors with two different systems was conducted experimentally and theoretically. The classical capillary-mesh electrode arrangement was applied in Type A electrospray system, and for Type B, an additional ring electrode is included. The droplet size and velocity were measured by a Phase Doppler Anemometer. The electric filed intensity was theoretically calculated in the two electrospray systems. Compared with Type A, Type B system has smaller droplet size and velocity in the same spraying mode. Meanwhile the electrospray process in Type B system is more stable than that in Type A with its smaller root mean square velocity. By measuring the spraying current, the average specific charge of the droplets for the two systems was obtained in different spraying modes. And it was found that the addition of the ring electrode can help to increase the droplet charge, which is the fundamental reason for Type B electrospray system to perform better. The corona charge of the droplets was theoretically calculated for the two electrospray systems. It was found that the calculated specific charge generated by corona charging was in good agreement with the experimental results.

Celastrol suppresses the proliferation of lung adenocarcinoma cells by regulating microRNA-24 and microRNA-181b.

Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b.

MiR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals.

MicroRNAs play important roles in tumorigenesis of various types of cancers. MiR-320a can inhibits cell proliferation of some cancers, but the biologic roles of miR-320a in lung cancer need to be further studied. Here, we investigated the roles of miR-320a in suppressing the proliferation of lung adenocarcinoma cells. MiR-320a treatment was found to effectively suppress LTEP-a-2 and A549 cell proliferation, and induce more apoptotic cells with irradiation treatment compared with control treatment. Our results also showed that miR-320a, as a novel miRNA, directly regulated signal transducer and activator of transcription 3 (STAT3) and its signals, such as Bcl-2, Bax, and Caspase 3. The siRNA-inhibited STAT3 levels further proved its roles in regulating STAT3 signals. Moreover, miR-320a treatment effectively suppressed cancer cell growth in mice xenografts compared with controls, and significantly inhibited cell migration in vitro and in vivo. Our findings collectively demonstrated that miR-320a, by directly regulating STAT3 signals, not only suppressed cell proliferation and metastasis, but also enhanced irradiation-induced apoptosis of adenocarcinomia cells.

The Paraoxonase Gene Cluster Protects Against Abdominal Aortic Aneurysm Formation.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening vascular pathology, the pathogenesis of which is closely related to oxidative stress. However, an effective pharmaceutical treatment is lacking because the exact cause of AAA remains unknown. Here, we aimed at delineating the role of the paraoxonases (PONs) gene cluster (PC), which prevents atherosclerosis through the detoxification of oxidized substrates, in AAA formation. APPROACH AND RESULTS: PC transgenic (Tg) mice were crossed to an Apoe-/- background, and an angiotensin II-induced AAA mouse model was used to analyze the effect of the PC on AAA formation. Four weeks after angiotensin II infusion, PC-Tg Apoe-/- mice had a lower AAA incidence, smaller maximal abdominal aortic external diameter, and less medial elastin degradation than Apoe-/- mice. Importantly, PC-Tg Apoe-/- mice exhibited lower aortic reactive oxidative species production and oxidative stress than did the Apoe-/- control mice. As a consequence, the PC transgene alleviated angiotensin II-induced arterial inflammation and suppressed arterial extracellular matrix degradation. Specifically, on angiotensin II stimulation, PC-Tg vascular smooth muscle cells exhibited lower levels of reactive oxidative species production and a decrease in the activities and expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. Moreover, PC-Tg serum also enhanced vascular smooth muscle cell oxidative stress resistance and further decreased the expression levels of matrix metalloproteinase-2 and matrix metalloproteinase-9, indicating that circulatory and vascular smooth muscle cell PC members suppress oxidative stress in a synergistic manner. CONCLUSIONS: Our findings reveal, for the first time, a protective role of the PC in AAA formation and suggest PONs as promising targets for AAA prevention.

Smad3-related miRNAs regulated oncogenic TRIB2 promoter activity to effectively suppress lung adenocarcinoma growth.

MicroRNAs (miRNAs) and Smad3, as key transcription factors in transforming growth factor-ß1 (TGF-ß1) signaling, help regulate various physiological and pathological processes. We investigated the roles of Smad3-regulated miRNAs with respect to lung adenocarcinoma cell apoptosis, proliferation, and metastasis. We observed that Smad3 and phospho-SMAD3 (p-Smad3) were decreased in miR-206- (or miR-140)-treated cells and there might be a feedback loop between miR-206 (or miR-140) and TGF-ß1 expression. Smad3-related miRNAs affected tribbles homolog 2 (TRIB2) expression by regulating trib2 promoter activity through the CAGACA box. MiR-206 and miR-140 inhibited lung adenocarcinoma cell proliferation in vitro and in vivo by suppressing p-Smad3/Smad3 and TRIB2. Moreover, lung adenocarcinoma data supported a suppressive role for miR-206/miR-140 and an oncogenic role for TRIB2-patients with higher TRIB2 levels had poorer survival. In summary, miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. MiR-206 and miR-140 also suppressed lung adenocarcinoma cell metastasis in vitro and in vivo by regulating EMT-related factors.

Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm.

RATIONALE: Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown. OBJECTIVE: In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation. METHODS AND RESULTS: The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell-specific knockout of SIRT1 accelerated angiotensin II-induced formation and rupture of AAAs and AAA-related pathological changes, whereas vascular smooth muscle cell-specific overexpression of SIRT1 suppressed angiotensin II-induced AAA formation and progression in Apoe-/- mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl2)-induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II-induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression. CONCLUSIONS: These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.