Publications by authors named "Yiyi Liu"

52 Publications

Associations of plasma metal concentrations with the risks of all-cause and cardiovascular disease mortality in Chinese adults.

Environ Int 2021 Aug 6;157:106808. Epub 2021 Aug 6.

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Exposure to metals/metalloids from both the natural environment and anthropogenic sources have a complex influence on human health. However, relatively few studies have explored the relations of exposure to multiple metals/metalloids with mortality. Therefore, this prospective study aims to examine the relations of multiple metal/metalloids exposures with all-cause and cardiovascular disease (CVD) mortality.

Methods: A total of 6155 participants within the Dongfeng-Tongji (DF-TJ) cohort were involved in this analysis, which were followed for mortality until December 31, 2018. We applied inductively coupled plasma mass spectrometry (ICP-MS) to measure baseline plasma concentrations of 23 metals. We utilized Cox regression models to calculate the hazard ratios (HRs) for all-cause and CVD mortality associated with metal concentrations. We proposed plasma metal score to assess the simultaneous exposure to multiple metals through summing each metal concentration weighted by the regression coefficients with all-cause mortality.

Results: During the follow-up (mean duration, 9.8 years), we ascertained 876 deaths, including 416 deaths of CVD (157 deaths of coronary heart disease and 259 deaths of stroke). In the multiple-metals model, after adjusting for potential confounders, plasma copper, molybdenum, and vanadium were positively associated with all-cause mortality, whereas manganese, selenium, and thallium were negatively associated with the risk of all-cause mortality, with adjusted HRs (95% Confidence Interval, CI) of the fourth quartiles were 1.73 (1.42-2.11, P-trend < 0.001) for copper, 1.33 (1.09-1.63, P-trend = 0.005) for molybdenum, 1.43 (1.16-1.77, P-trend < 0.001) for vanadium, 0.74 (0.58-0.94, P-trend = 0.005) for manganese, 0.68 (0.56-0.83, P-trend < 0.001) for selenium, and 0.74 (0.59-0.92, P-trend = 0.002) for thallium, respectively. Positive associations were observed between plasma copper, molybdenum, vanadium concentrations and CVD mortality, whereas negative associations were found for plasma selenium and thallium concentrations with CVD mortality in the multiple-metals model. Compared with the first quartiles, the HRs of fourth quartiles were 1.94 (1.45-2.58, P-trend < 0.001) for copper, 1.72 (1.26-2.35, P-trend < 0.001) for molybdenum, 1.81 (1.32-2.47, P-trend < 0.001) for vanadium, 0.67 (0.50-0.89, P-trend = 0.003) for selenium, and 0.58 (0.41-0.81, P-trend < 0.001) for thallium, respectively. The plasma metal score was significantly associated with higher risks of all-cause and CVD death in dose-response fashions. When compared with the first quartiles of plasma metal score, the HRs of fourth quartiles were 2.16 (1.76-2.64; P-trend < 0.001) for all-cause mortality and 3.00 (2.24-4.02; P-trend < 0.001) for CVD mortality.

Conclusions: The study indicated that several plasma metals/metalloids were key determinants and predictors of all-cause and CVD death in the Chinese population. Our findings highlighted the importance to comprehensively assess and monitor multiple metals/metalloids exposures.
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http://dx.doi.org/10.1016/j.envint.2021.106808DOI Listing
August 2021

Associations of plasma metal concentrations with incident dyslipidemia: Prospective findings from the Dongfeng-Tongji cohort.

Chemosphere 2021 Jul 9;285:131497. Epub 2021 Jul 9.

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Metal exposures are ubiquitous around the world, while it is lack of prospective studies to evaluate the associations of exposure to multiple metal/metalloids with incident dyslipidemia. A total of 2947 participants without dyslipidemia at baseline were included in the analyses. We utilized inductively coupled plasma mass spectrometry to measure the baseline plasma metal concentrations. Unconditional logistic regression models were applied to estimate the relations between plasma metals and risk of incident dyslipidemia, and principal component analysis was performed to extract principal components of metals. During 5.01 ± 0.31 years of follow-up, 521 subjects were diagnosed with incident dyslipidemia. After multivariable adjustment, the odds ratios (ORs) of dyslipidemia comparing the highest quartiles to the lowest were 1.58 (95% CI: 1.20, 2.08; P = 0.001) for aluminum, 1.34 (95% CI: 1.03, 1.75; P = 0.03) for arsenic, 1.44 (1.09, 1.91; P = 0.03) for strontium, and 1.47 (95% CI: 1.09, 2.00; P = 0.005) for vanadium. The four metals also showed significant associations with the subtypes of dyslipidemia, including low HDL-C and high LDL-C. The first principal component, which mainly represented aluminum, arsenic, barium, lead, vanadium, and zinc, was associated with increased risk of incident dyslipidemia, and the adjusted OR was 1.40 (95% CI: 1.07, 1.84; P = 0.02) comparing extreme quartiles. The study indicated that elevated plasma aluminum, arsenic, strontium, and vanadium concentrations were associated with a higher incidence of dyslipidemia. These findings highlight the importance of controlling metal exposures for dyslipidemia prevention.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131497DOI Listing
July 2021

Integrating Systems and Synthetic Biology to Understand and Engineer Microbiomes.

Annu Rev Biomed Eng 2021 07 29;23:169-201. Epub 2021 Mar 29.

Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA; email:

Microbiomes are complex and ubiquitous networks of microorganisms whose seemingly limitless chemical transformations could be harnessed to benefit agriculture, medicine, and biotechnology. The spatial and temporal changes in microbiome composition and function are influenced by a multitude of molecular and ecological factors. This complexity yields both versatility and challenges in designing synthetic microbiomes and perturbing natural microbiomes in controlled, predictable ways. In this review, we describe factors that give rise to emergent spatial and temporal microbiome properties and the meta-omics and computational modeling tools that can be used to understand microbiomes at the cellular and system levels. We also describe strategies for designing and engineering microbiomes to enhance or build novel functions. Throughout the review, we discuss key knowledge and technology gaps for elucidating the networks and deciphering key control points for microbiome engineering, and highlight examples where multiple omics and modeling approaches can be integrated to address these gaps.
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http://dx.doi.org/10.1146/annurev-bioeng-082120-022836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277735PMC
July 2021

miR-4721, Induced by EBV-miR-BART22, Targets to Enhance the Tumorigenic Capacity of NPC through the Pathway.

Mol Ther Nucleic Acids 2020 Dec 23;22:557-571. Epub 2020 Sep 23.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315 Guangzhou, China.

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation and . Mechanism analysis indicated that miR-4721 directly targetes GSK3β and reduces its expression, which therefore elevates β-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3β are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3β, which thus activates the WNT/β-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.
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http://dx.doi.org/10.1016/j.omtn.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566007PMC
December 2020

Plasmene nanosheets as optical skin strain sensors.

Nanoscale Horiz 2020 11 7;5(11):1515-1523. Epub 2020 Sep 7.

Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton 3800, Victoria, Australia.

Skin-like optoelectronic sensors can have a wide range of technical applications ranging from wearable/implantable biodiagnostics, human-machine interfaces, and soft robotics to artificial intelligence. The previous focus has been on electrical signal transduction, whether resistive, capacitive, or piezoelectric. Here, we report on "optical skin" strain sensors based on elastomer-supported, highly ordered, and closely packed plasmonic nanocrystal arrays (plasmene). Using gold nanocubes (AuNCs) as a model system, we find that the types of polymeric ligands, interparticle spacing, and AuNC sizes play vital roles in strain-induced plasmonic responses. In particular, brush-forming polystyrene (PS) is a "good" ligand for forming elastic plasmenes which display strain-induced blue shift of high-energy plasmonic peaks with high reversibility upon strain release. Further experimental and simulation studies reveal the transition from isotropic uniform plasmon coupling at a non-strained state to anisotropic plasmon coupling at strained states, due to the AuNC alignment perpendicular to the straining direction. The two-term plasmonic ruler model may predict the primary high-energy peak location. Using the relative shift of the averaged high-energy peak to the coupling peak before straining, a plasmene nanosheet may be used as a strain sensor with the sensitivity depending on its internal structures, such as the constituent AuNC size or inter-particle spacing.
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http://dx.doi.org/10.1039/d0nh00393jDOI Listing
November 2020

Vertically Aligned Gold Nanowires as Stretchable and Wearable Epidermal Ion-Selective Electrode for Noninvasive Multiplexed Sweat Analysis.

Anal Chem 2020 03 27;92(6):4647-4655. Epub 2020 Feb 27.

Department of Chemical Engineering, Monash University, Clayton, Victoria 3800, Australia.

The noninvasive continuous analysis of human sweat is of great significance for improved healthcare diagnostics and treatment in the future, for which a wearable potentiometry-based ion-selective electrode (ISE) has attracted increasing attention, particularly involving ion detection. Note that traditional solid-state ISE electrodes are rigid ion-to-electron transducers that are not conformal to soft human skin and cannot function under stretched states. Here, we demonstrated that vertically aligned mushroom-like gold nanowires (v-AuNW) could serve as stretchable and wearable ion-to-electron transducers for multiplexed, in situ potentiometric analysis of pH, Na, and K in sweat. By modifying v-AuNW electrodes with polyaniline, Na ionophore X, and a valinomycin-based selective membrane, we could specifically detect pH, Na, and K, respectively, with high selectivity, reproducibility, and stability. Importantly, the electrochemical performance could be maintained even under 30% strain and during stretch-release cycles without the need of extrinsic structural design. Furthermore, our stretchable v-AuNW ISEs could be seamlessly integrated with a flexible printed circuit board, enabling wireless on-body detection of pH, Na, and K with fast response and negligible cross-talk, indicating considerable promise for noninvasive wearable sweat analysis.
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http://dx.doi.org/10.1021/acs.analchem.0c00274DOI Listing
March 2020

Multiple plasma metals, genetic risk and serum C-reactive protein: A metal-metal and gene-metal interaction study.

Redox Biol 2020 01 10;29:101404. Epub 2019 Dec 10.

Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: C-reactive protein (CRP) is a well-recognized biomarker of inflammation, which can be used as a predictor of cardiovascular disease. Evidence have suggested exposure to multiple metals/metalloids may affect immune system and give rise to cardiovascular disease. However, it is lack of study to comprehensively evaluate the association of multiple metals and CRP, the interactions between metals, and the gene-metal interaction in relation to CRP levels.

Aims: To explore the associations of multiple plasma metals with serum CRP, and to test the interactions between metals, and gene-metal interactions on the levels of serum CRP.

Methods: We included 2882 participants from the Dongfeng-Tongji cohort, China, and measured 23 plasma metals and serum CRP concentrations. The genetic risk score (GRS) was calculated based on 7 established CRP-associated variants. For metals which were associated with the levels of CRP, we further tested the interactions between metals on CRP, and analyzed the gene-metal interactions on CRP.

Results: The median level for CRP in the total population was 1.17 mg/L. After multivariable adjustment, plasma copper was positively associated with serum CRP (FDR < 0.001), whereas selenium was negatively associated with serum CRP (FDR = 0.01). Moreover, selenium and zinc attenuated the positive association between high plasma copper and CRP (P for interaction < 0.001). Participants with a higher GRS had a higher CRP level, with the increase in ln-transformed CRP per increment of 5 risk alleles were 0.64 for weighted GRS, and 0.54 for unweighted GRS (both P < 0.001). Furthermore, the genetic association with CRP was modified by copper concentration (P for interaction < 0.001).

Conclusions: Our results suggest that serum CRP is positively associated with plasma concentration of copper, and inversely associated with selenium. Plasma zinc, selenium and CRP genetic predisposition would modify the associations between plasma copper and serum CRP.
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http://dx.doi.org/10.1016/j.redox.2019.101404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921203PMC
January 2020

Associations of plasma metal concentrations with the decline in kidney function: A longitudinal study of Chinese adults.

Ecotoxicol Environ Saf 2020 Feb 4;189:110006. Epub 2019 Dec 4.

Department of Occupational and Environmental Health Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.

Metals are widespread pollutants in the environment which have been reported to be associated with kidney dysfunction in many existing epidemiological studies. However, most of the studies are cross-sectional design and mainly focus on several toxic metals including arsenic, lead and cadmium. Therefore, we conducted this prospective study within the Dongfeng-Tongji cohort to evaluate the associations of plasma multiple metals with the decline in kidney function among Chinese middle-aged and elderly. In total, 1434 participants free of chronic diseases at baseline were included in analysis. We measured baseline plasma concentrations of 23 metals and calculated estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum creatinine, age, sex and ethnicity. Bonferroni correction was used for multiple testing to reduce the probability of a type I error. Principal component analysis was conducted to evaluate the combined effect of multiple metal co-exposure. Most of the plasma metal concentrations were within the literature reported reference values, whereas the concentration of lead and nickel exceeded the guideline value. We found that plasma concentrations of aluminum, arsenic, barium, lead, molybdenum, rubidium, strontium, vanadium and zinc were significantly associated with the decline in kidney function measured by annual eGFR decline, rapid renal function decline (defined as an annual decline in eGFR ≥ 5 mL/min/1.73 m) or incident eGFR < 60 mL/min/1.73 m, with the adjusted beta coefficients (95% CI) for annual eGFR decline 0.50 (0.30, 0.69), 0.98 (0.74, 1.23), 0.56 (0.32, 0.79), 0.21 (0.03, 0.39), 0.35 (0.16, 0.54), 0.94 (0.71, 1.17), 0.37 (0.15, 0.60), 0.78 (0.54, 1.02), and 0.74 (0.57, 0.91), respectively. The metals exposures were linked with increased risks of impaired kidney function. Associations of principal components representing these metals with the decline in kidney function were significant and suggest a possible additional health risk by co-exposure. Participants engaged in manufacturing had higher plasma levels of several metals compared with those who had been involved in management- or administration-related work. Our findings suggest that exposure to multiple metals contribute to the decline in kidney function among the middle-aged and elderly. Co-exposure to multiple metals may have synergetic effect on the kidney function. Further studies are warranted to confirm our findings and clarify the potential mechanisms.
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http://dx.doi.org/10.1016/j.ecoenv.2019.110006DOI Listing
February 2020

MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis.

Aging (Albany NY) 2019 11 25;11(22):10697-10710. Epub 2019 Nov 25.

Southern Medical University, Nanfang Hospital, Department of Oncology, Guangzhou 510515, Guangdong, P. R. China.

Mitogen-activated protein kinase kinase 4 (MAP2K4) is a member of the mitogen-activated protein kinase (MAPK) activator family. MAPK signaling plays a significant role in cell proliferation, differentiation, transcriptional regulation, and development. However, specific function and mechanism of MAP2K4 in breast cancer have not been clarified. According to our study, overexpressed MAP2K4 in breast cancer cells increased proliferation, migration, and invasion in vivo and in vitro, while MAP2K4 knockdown restored the effects. Subsequent mechanistic analyses demonstrated that MAP2K4 promoted cell proliferation, migration, and invasion by activating phosphoinositide-3-kinase (PI3K)/AKT signaling, the downstream proteins, c-JUN, the G1/S cell cycle, and the epithelial-to-mesenchymal transition (EMT). Meanwhile, MAP2K4 interacted with Vimentin and further propagated the malignant phenotype. Furthermore, patients with high MAP2K4 and Vimentin expression levels had poorer overall survival rates than those with low expression levels of both proteins. Our studies demonstrated that MAP2K4 has the potential to serve as an oncogene in breast cancer and it activates the phosphorylated PI3K/AKT signaling pathway to activate downstream cycle-associated proteins and EMT signals while interacting with Vimentin to promote breast cancer cells proliferation, migration, and invasion. In our study, MAP2K4 and Vimentin co-expression is confirmed to be an unfavorable factor in breast cancer.
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http://dx.doi.org/10.18632/aging.102485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914392PMC
November 2019

HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma.

Theranostics 2019 12;9(25):7583-7598. Epub 2019 Oct 12.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University; Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.

Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. MiRNA expression in HCC was analyzed by bioinformatics analysis and hybridization. The biological effect of miR-5188 was demonstrated in both and studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity . Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with β-catenin in the cytoplasm to reduce the nuclear translocation of β-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/β-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.
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http://dx.doi.org/10.7150/thno.37717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831466PMC
September 2020

Machine learning based temperature prediction of poly(N-isopropylacrylamide)-capped plasmonic nanoparticle solutions.

Phys Chem Chem Phys 2019 Nov 5;21(44):24808-24819. Epub 2019 Nov 5.

Advanced Computing and Simulation Laboratory (AχL), Department of Electrical and Computer Systems Engineering, Monash University, Clayton, Victoria 3800, Australia.

The temperature-dependent optical properties of gold nanoparticles that are capped with the thermo-sensitive polymer: 'poly(N-isopropylacrylamide)' (PNIPAM), have been studied extensively for several years. Also, their suitability to function as nanoscopic thermometers for bio-sensing applications has been suggested numerous times. In an attempt to establish this, many have studied the temperature-dependent optical resonance characteristics of these particles; however, developing a simple mathematical relationship between the optical measurements and the solution temperature remains an open challenge. In this paper, we attempt to systematically address this problem using machine learning techniques to quickly and accurately predict the solution-temperature, based on spectroscopic data. Our emphasis is on establishing a simple and practically useful solution to this problem. Our dataset comprises spectroscopic absorption data from both nanorods and nanobipyramids capped with PNIPAM, measured at discretely varied and pre-set temperature states. Specific regions of the spectroscopic data are selected as features for prediction using random forest (RF), gradient boosting (GB) and adaptive boosting (AB) regression techniques. Our prediction results indicate that RF and GB techniques can be used successfully to predict solution temperatures instantly to within 1 °C of accuracy.
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http://dx.doi.org/10.1039/c9cp04544aDOI Listing
November 2019

Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway.

EBioMedicine 2019 Oct 5;48:386-404. Epub 2019 Oct 5.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China. Electronic address:

Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related tumor. The role of EBV-encoding miR-BART22 is still unclear in NPC. This study aimed to identify the detailed mechanisms by which EBV-miR-BART22 functions as a tumor-promoting factor and evaluate the action of cinobufotalin in treating EBV-miR-BART22-overexpressing NPC cells.

Methods: Using real-time PCR, western blotting, immunohistochemistry, and In situ hybridization, we detected the expression of miR-BART22 and MAP2K4 in tissues and cells, as well as evaluated their clinical relevance in NPC patients. The effects of miR-BART22 on cell metastasis, stemness and DDP chemoresistance were examined by sphere formation assay, side population analysis, transwell, boyden, in vivo xenograft tumor mouse model et al. Western blotting, immunofluorescence staining, luciferase reporter assay, ChIP, EMSA and Co-IP assay et al. were performed to explore the detailed molecular mechanism of EBV-miR-BART22 in NPC. Finally, we estimated the effects and molecular basis of Cinobufotalin on EBV-miR-BART22-overexpressing NPC cells in vitro and in vivo assays.

Findings: We observed that EBV-miR-BART22 not only promoted tumor stemness and metastasis, but also enhanced the resistance to Cisplatin (DDP) in vitro and in vivo. Mechanistic analysis indicated that EBV-miR-BART22 directly targeted the MAP2K4 and upregulated non-muscle myosin heavy chain IIA (MYH9) expression by PI3K/AKT/c-Jun-induced transcription. Further, MYH9 interacted with glycogen synthase 3β(GSK3β) protein and induced its ubiquitin degradation by activating PI3K/AKT/c-Jun-induced ubiquitin transcription and the latter combined with increased TRAF6 E3 ligase, which further bound to GSK3β protein. Reductions in the GSK3β protein thus promoted β-catenin expression and nuclear translocation, which induced tumor stemness and the epithelial-to-mesenchymal transition (EMT) signals. Furthermore, we observed that cinobufotalin, a new chemically synthesized compound, significantly suppressed EBV-miR-BART22-induced DDP chemoresistance by upregulating MAP2K4 to suppress MYH9/GSK3β/β-catenin and its downstream tumor stemness and EMT signals in NPC. Finally, clinical data revealed that increased miR-BART22 and reduced MAP2K4 expression caused the poor prognoses of NPC patients.

Interpretation: Our study provides a novel mechanism that cinobufotalin reversed the DDP chemoresistance and EMT induced by EBV-miR-BART22 in NPC.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838365PMC
October 2019

Local Crack-Programmed Gold Nanowire Electronic Skin Tattoos for In-Plane Multisensor Integration.

Adv Mater 2019 Oct 25;31(41):e1903789. Epub 2019 Aug 25.

Department of Chemical Engineering, Monash University, Clayton, Victoria, 3800, Australia.

Sensitive, specific, yet multifunctional tattoo-like electronics are ideal wearable systems for "any time, any where" health monitoring because they can virtually become parts of the human skin, offering a burdenless "unfeelable" wearing experience. A skin-like, multifunctional electronic tattoo made entirely from gold using a standing enokitake-mushroom-like vertically aligned nanowire membrane in conjunction with a programmable local cracking technology is reported. Unlike previous multifunctional systems, only a single material type is needed for the integrated gold circuits involved in interconnects and multiplexed specific sensors, thereby avoiding the use of complex multimaterials interfaces. This is possiblebecause the programmable local cracking technology allows for the arbitrary fine-tuning of the properties of elastic gold conductors from strain-insensitive to highly strain-sensitive simply by adjusting localized crack size, shape, and orientations-a capability impossible to achieve with previous bulk cracking technology. Furthermore, in-plane integration of strain/pressure sensors, anisotropic orientation-specific sensors, strain-insensitive stretchable interconnects, temperature sensors, glucose sensors, and lactate sensors without the need of soldering or gluing are demonstrated. This strategy opens a new general route for the design of next-generation wearable electronic tattoos.
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http://dx.doi.org/10.1002/adma.201903789DOI Listing
October 2019

Circulating Multiple Metals and Incident Stroke in Chinese Adults.

Stroke 2019 07 6;50(7):1661-1668. Epub 2019 Jun 6.

From the Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating) (Y.X., Y. Yuan, Y.L., Y. Yu, N.J., L.Z., H.W., X.Z., M.H., T.W.), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background and Purpose- Circulating metals synchronously reflect multiple metal exposures from both natural and anthropogenic sources, which may be linked with the risk of stroke. However, there is a lack of prospective studies investigating the associations of multiple metal exposures with incident stroke. Methods- We performed a nested case-control study within the ongoing Dongfeng-Tongji cohort launched in 2008. A total of 1304 incident stroke cases (1035 ischemic strokes and 269 hemorrhagic strokes) were prospectively identified by December 31, 2016, and matched to incident identity sampled controls according to age (within 1 year), sex, and blood sampling date (within 1 month). We determined the concentrations of 24 plasma metals and assessed the associations of plasma multiple metal concentrations with incident stroke using conditional logistic regression and elastic net model. Results- The average follow-up was 6.1 years. After adjusting for established risk confounders, copper, molybdenum, and titanium were significantly associated with higher risk of ischemic stroke (odds ratios according to per interquartile range increase, 1.29 [95% CI, 1.13-1.46], 1.19 [95% CI, 1.05-1.35], and 1.30 [95% CI, 1.07-1.59]), whereas rubidium and selenium were associated with lower risk of hemorrhagic stroke (odds ratios according to per interquartile range increase, 0.66 [95% CI, 0.50-0.87] and 0.68 [95% CI, 0.51-0.91]). The predictive plasma metal scores based on multiple metal exposures were significantly associated with higher risk of ischemic and hemorrhagic stroke (adjusted odds ratios according to per interquartile range increase, 1.37 [95% CI, 1.20-1.56] and 1.53 [95% CI, 1.16-2.01]). Conclusions- Plasma copper, molybdenum, and titanium were associated with higher risk of ischemic stroke, whereas plasma rubidium and selenium were associated with lower risk of hemorrhagic stroke. These findings may have important public health implications given the ever-increasing burden of stroke worldwide.
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http://dx.doi.org/10.1161/STROKEAHA.119.025060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594729PMC
July 2019

Covalent-Cross-Linked Plasmene Nanosheets.

ACS Nano 2019 Jun 7;13(6):6760-6769. Epub 2019 Jun 7.

Department of Chemical Engineering , Monash University , Clayton , Victoria 3800 , Australia.

Thiol-polystyrene (SH-PS)-capped plasmonic nanoparticles can be fabricated into free-standing, one-nanoparticle-thick superlattice sheets (termed plasmene) based on physical entanglement between ligands, which, however, suffer from irreversible dissociation in organic solvents. To address this issue, we introduce coumarin-based photo-cross-linkable moieties to the SH-PS ligands to stabilize gold nanoparticles. Once cross-linked, the obtained plasmene nanosheets consisting of chemically locked nanoparticles can well maintain structural integrity in organic solvents. Particularly, arising from ligand-swelling-induced enlargement of the interparticle spacing, these plasmene nanosheets show significant optical responses to various solvents in a specific as well as reversible manner, which may offer an excellent material for solvent sensing and dynamic plasmonic display.
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http://dx.doi.org/10.1021/acsnano.9b01343DOI Listing
June 2019

VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer.

Int J Cancer 2020 01 19;146(2):496-509. Epub 2019 Jun 19.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.

The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) -induced CRC mice models and nicotine-treated CRC cells via the PI3K/AKT/c-Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and the downstream cell cycle or EMT-related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c-Jun-mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B-modulating signal in VPS33B-overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.
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http://dx.doi.org/10.1002/ijc.32429DOI Listing
January 2020

2D Freestanding Janus Gold Nanocrystal Superlattices.

Adv Mater 2019 Jul 9;31(28):e1900989. Epub 2019 May 9.

Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton, 3800, Victoria, Australia.

2D freestanding nanocrystal superlattices represent a new class of advanced metamaterials in that they can integrate mechanical flexibility with novel optical, electrical, plasmonic, and magnetic properties into one multifunctional system. The freestanding 2D superlattices reported to date are typically constructed from symmetrical constituent building blocks, which have identical structural and functional properties on both sides. Here, a general ligand symmetry-breaking strategy is reported to grow 2D Janus gold nanocrystal superlattice sheets with nanocube morphology on one side yet with nanostar on the opposite side. Such asymmetric metallic structures lead to distinct wetting and optical properties as well as surface-enhanced Raman scattering (SERS) effects. In particular, the SERS enhancement of the nanocube side is about 20-fold of that of the nanostar side, likely due to the combined "hot spot + lightening-rod" effects. This is nearly 700-fold of SERS enhancement as compared with the symmetric nanocube superlattices without Janus structures.
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http://dx.doi.org/10.1002/adma.201900989DOI Listing
July 2019

The effects of HSP27 against UVB-induced photoaging in rat skin.

Biochem Biophys Res Commun 2019 05 20;512(3):435-440. Epub 2019 Mar 20.

Department of Dermatology, The First Affliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, China. Electronic address:

Skin photoaging refers to the phenomenon of skin aging or accelerated aging as a result of long-term UV exposure. Ultraviolet radiation can lead to DNA damage, cell apoptosis, cell growth inhibition and carcinogenic effects. Evidence suggests that hsp27 can protect cells from apoptosis induced by various stimuli in vivo and in vitro. However, modulation in hsp27 expression toward skin protection against UVB treatment has not been investigated clearly. In this study, we aimed to investigate the effects of hsp27 against UVB-induced photoaging in rat skin and to explore the underlying mechanisms. In the present study, we identified that the level of hsp27 increased after UVB irradiation induced chronic photoaging rat model. In order to investigate the function of hsp27 in UVB-induced skin photoaging, we used adeno-associated virus (AAV) to specificity reduce the expression of hsp27 in rat skin. In contrast to UVB group, we found that collagen fibers were disorganized and elastic fibers were thickened and twisted in UVB-AAV group. In the UVB-AAV group, reduced hsp27 enhanced the oxidative stress. Aging markers (SA-β-Gal staining and the protein levels of p16, p53, p21) were significantly changed in the hsp27 decreased group. However, in hsp27 deletion group, the expression of antiapoptotic factor bcl-2 was decreased, while the apoptosis factor bax was increased after UVB irradiation. These findings suggested that hsp27 was involved in oxidative stress, aging and apoptosis of skin after UV exposure. Management the expression of hsp27 can be used as a potential intervention method to alleviate UVB-induced skin damage.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.076DOI Listing
May 2019

Enokitake Mushroom-like Standing Gold Nanowires toward Wearable Noninvasive Bimodal Glucose and Strain Sensing.

ACS Appl Mater Interfaces 2019 Mar 28;11(10):9724-9729. Epub 2019 Feb 28.

The Melbourne Centre for Nanofabrication , Clayton , Victoria 3800 , Australia.

We have recently demonstrated that Enokitake mushroom-like gold with nanoparticles as the "head" and nanowires as the "tail" could grow directly on elastomeric substrates, which are extremely stretchable electrodes that can be used as wearable sensors for detecting strain and pressure. In this work, we show that such electrodes can also be used as intrinsically stretchable glucose biosensors. By modifying the vertical gold nanowire electrodes with glucose oxidase and Prussian blue nanoparticles, a limit of detection of 10 μM, sensitivity of 23.72 μA·mM·cm, and high selectivity can be achieved. The as-obtained glucose biosensors were able to maintain a high sensing performance under various mechanical deformations. Even for 30% strain, a sensitivity of 4.55 μA·mM·cm toward glucose detection in the artificial sweat was possible. Furthermore, it was found that strains could be simultaneously detected with a gauge factor of 2.30 (strain 0-10%) and 22.64 (strain 10-20%), demonstrating the potential of such bimodal sensors to allow simultaneous monitoring of physical and biological signals.
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http://dx.doi.org/10.1021/acsami.8b19383DOI Listing
March 2019

Whole-genome sequencing of 175 Mongolians uncovers population-specific genetic architecture and gene flow throughout North and East Asia.

Nat Genet 2018 12 5;50(12):1696-1704. Epub 2018 Nov 5.

School of Life Science, Inner Mongolia University for the Nationalities, Tongliao, China.

The genetic variation in Northern Asian populations is currently undersampled. To address this, we generated a new genetic variation reference panel by whole-genome sequencing of 175 ethnic Mongolians, representing six tribes. The cataloged variation in the panel shows strong population stratification among these tribes, which correlates with the diverse demographic histories in the region. Incorporating our results with the 1000 Genomes Project panel identifies derived alleles shared between Finns and Mongolians/Siberians, suggesting that substantial gene flow between northern Eurasian populations has occurred in the past. Furthermore, we highlight that North, East, and Southeast Asian populations are more aligned with each other than these groups are with South Asian and Oceanian populations.
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http://dx.doi.org/10.1038/s41588-018-0250-5DOI Listing
December 2018

A location- and sharpness-specific tactile electronic skin based on staircase-like nanowire patches.

Nanoscale Horiz 2018 Nov 1;3(6):640-647. Epub 2018 Aug 1.

Department of Chemical Engineering, Monash University, Clayton, Victoria 3800, Australia.

Human skin can sense an external object in a location-specific manner, simultaneously recognizing whether it is sharp or blunt. Such tactile capability can be achieved in both natural and stretched states. It is impractical to mimic this tactile function of human skin by designing pixelated sensor arrays across our whole curvilinear human body. Here, we report a new tactile electronic skin sensor based on staircase-like vertically aligned gold nanowires (V-AuNWs). With a back-to-back linear or spiral assembly of two staircase structures into a single sensor, we are able to recognize pressure in a highly location-specific manner for both non-stretched and stretched states (up to 50% strain); with a concentric design on the fingertip, we can identify the sharpness of an external object. We believe that our strategy opens up a new route to highly specific second-skin-like tactile sensors for electronic skin (E-skin) applications.
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http://dx.doi.org/10.1039/c8nh00125aDOI Listing
November 2018

Vertical Gold Nanowires Stretchable Electrochemical Electrodes.

Anal Chem 2018 11 5;90(22):13498-13505. Epub 2018 Nov 5.

Department of Chemical Engineering , Monash University , Clayton , Victoria 3800 , Australia.

Conventional electrodes produced from gold or glassy carbon are outstanding electrochemical platforms for biosensing applications due to their chemical inertness and wide electrochemical window, but are intrinsically rigid and planar in nature. Hence, it is challenging to seamlessly integrate them with soft and curvilinear biological tissues for real-time wearable or implantable electronics. In this work, we demonstrate that vertically gold nanowires (v-AuNWs) possess an enokitake-like structure, with the nanoparticle (head) on one side and nanowires (tail) on the opposite side of the structure, and can serve as intrinsically stretchable, electrochemical electrodes due to the stronger nanowire-elastomer bonding forces preventing from interfacial delamination under strains. The exposed head side of the electrode comprising v-AuNWs can achieve a detection limit for HO of 80 μM, with a linear range of 0.2-10.4 mM at 20% strain, with a reasonably high sensitivity using chronoamperometry. This excellent electrochemical performance in the elongated state, in conjunction with low-cost wet-chemistry fabrication, demonstrates that v-AuNWs electrodes may become a next-generation sensing platform for conformally integrated, in vivo biodiagnostics.
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http://dx.doi.org/10.1021/acs.analchem.8b03423DOI Listing
November 2018

Variable importance-weighted Random Forests.

Quant Biol 2017 Dec 6;5(4):338-351. Epub 2017 Nov 6.

Department of Biostatistics, School of Public Health, Yale University, New Haven, CT 06511, USA.

Background: Random Forests is a popular classification and regression method that has proven powerful for various prediction problems in biological studies. However, its performance often deteriorates when the number of features increases. To address this limitation, feature elimination Random Forests was proposed that only uses features with the largest variable importance scores. Yet the performance of this method is not satisfying, possibly due to its rigid feature selection, and increased correlations between trees of forest.

Methods: We propose variable importance-weighted Random Forests, which instead of sampling features with equal probability at each node to build up trees, samples features according to their variable importance scores, and then select the best split from the randomly selected features.

Results: We evaluate the performance of our method through comprehensive simulation and real data analyses, for both regression and classification. Compared to the standard Random Forests and the feature elimination Random Forests methods, our proposed method has improved performance in most cases.

Conclusions: By incorporating the variable importance scores into the random feature selection step, our method can better utilize more informative features without completely ignoring less informative ones, hence has improved prediction accuracy in the presence of weak signals and large noises. We have implemented an R package "viRandomForests" based on the original R package "randomForest" and it can be freely downloaded from http://zhaocenter.org/software.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051549PMC
December 2017

Fractal Gold Nanoframework for Highly Stretchable Transparent Strain-Insensitive Conductors.

Nano Lett 2018 06 16;18(6):3593-3599. Epub 2018 May 16.

Department of Chemical Engineering , Monash University , Clayton , Victoria 3800 , Australia.

Percolation networks of one-dimensional (1D) building blocks (e.g., metallic nanowires or carbon nanotubes) represent the mainstream strategy to fabricate stretchable conductors. One of the inherent limitations is the control over junction resistance between 1D building blocks in natural and strained states of conductors. Herein, we report highly stretchable transparent strain-insensitive conductors using fractal gold (F-Au) nanoframework based on a one-pot templateless wet chemistry synthesis method. The monolayered F-Au nanoframework (∼20 nm in thickness) can be obtained from the one-pot synthesis without any purification steps involved and can be transferred directly to arbitrary substrates like polyethylene terephthalate, food-wrap, polydimethylsiloxane (PDMS), and ecoflex. The F-Au thin film with no capping agents leads to a highly conductive thin film without any post-treatment and can be stretched up to 110% strain without significantly losing conductivity yet with the optical transparency of 70% at 550 nm. Remarkably, the F-Au thin film shows the strain-insensitive behavior up to 20% stretching strain. This originates from the unique fractal nanomesh-like structure which can absorb external mechanical forces, thus maintaining electron pathways throughout the nanoframework. In addition, a semitransparent bilayered F-Au film on 100% prestrained PDMS could achieve to a high stretchability of 420% strain with negligible resistance changes under low-level strains.
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http://dx.doi.org/10.1021/acs.nanolett.8b00694DOI Listing
June 2018

2D Binary Plasmonic Nanoassemblies with Semiconductor n/p-Doping-Like Properties.

Adv Mater 2018 Jun 14;30(26):e1801118. Epub 2018 May 14.

Department of Chemical Engineering, Faculty of Engineering, Monash University, Clayton, 3800, Victoria, Australia.

The electronic, optical, thermal, and magnetic properties of an extrinsic bulk semiconductor can be finely tuned by adjusting its dopant concentration. Here, it is demonstrated that such a doping concept can be extended to plasmonic nanomaterials. Using two-dimensional (2D) assemblies of [email protected] and Au nanocubes (NCs) as a model system, detailed experimental and theoretical studies are carried out, which reveal collective semiconductor n/p-doping-like plasmonic properties. A threshold doping concentration of [email protected] NCs is observed, below which p-doping dominates and above which n-doping prevails. Furthermore, [email protected] NC dopants can be converted into corresponding Au seed "voids" dopants by selectively removing Ag without changing the overall structural integrity. The results show that the plasmonic doping concept may serve as a general design principle guiding synthesis and assembly of plasmonic metamaterials for programmable optoelectronic devices.
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http://dx.doi.org/10.1002/adma.201801118DOI Listing
June 2018

Resveratrol protects HaCaT cells from ultraviolet B-induced photoaging via upregulation of HSP27 and modulation of mitochondrial caspase-dependent apoptotic pathway.

Biochem Biophys Res Commun 2018 05 31;499(3):662-668. Epub 2018 Mar 31.

Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, China. Electronic address:

The skin is the outermost protective barrier between the internal and external environment in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of photoaging. Evidence suggests that resveratrol suppresses UVB-induced photoaging. In this study, we aimed to investigate the protective effects of resveratrol against UVB-induced photoaging in HaCaT cells and to determine the underlying mechanisms. Apoptosis of normal or HSP27-overexpressing HaCaT cells in the presence of UVB was analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Resveratrol inhibited UVB-induced apoptosis by upregulating the expression of HSP27, reducing the production of proapoptotic proteins such as p65, Bax, and cleaved caspase-3, and promoting the expression of anti-apoptotic protein Bcl-2. However, UVB irradiation on HaCaT cells pretreated with resveratrol led to the upregulation of Bax, downregulation of Bcl-2, and promotion of p65 and caspase-3 activation after silencing of HSP27 gene. These findings suggest that the inhibition of HSP27 expression can partially reverse the anti-apoptotic effect of resveratrol and confirm that resveratrol can regulate HSP27 and thus control p65 and caspase-3 activation. In summary, resveratrol plays a role in photoprotection by upregulating HSP27 expression, increasing Bcl-2/Bax ratio, and inhibiting caspase-3 activity and p65 expression.
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http://dx.doi.org/10.1016/j.bbrc.2018.03.207DOI Listing
May 2018

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance.

Mol Ther 2018 04 3;26(4):1066-1081. Epub 2018 Feb 3.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China. Electronic address:

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.
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http://dx.doi.org/10.1016/j.ymthe.2018.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079479PMC
April 2018
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