Characterization of small RNAs in the spleen of MASH in a non-human primate model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as a global health issue. This study examines the role of small RNAs in the spleen of MASH using a non-human primate model. We performed high-throughput small RNA sequencing on spleen tissues from MASH-primates, revealing significant alterations in the expression of small non-coding RNAs, especially miRNAs. Notably, miR-96, miR-182, miR-183, and miR-122 showed differential expression in MASH spleens. Predictive and validation studies have identified potential target genes, such as PTX3 and NFIX, that were significantly dysregulated in spleens of MASH. These findings characterized small RNAs in spleen of MASH and offer a novel insight for further research for MASH.

The myokine CCL5 recruits subcutaneous preadipocytes and promotes intramuscular fat deposition in obese mice.

Intramuscular fat (IMF) refers to the lipid stored in skeletal muscle tissue. The number and size of intramuscular adipocytes are the primary factors that regulate IMF content. Intramuscular adipocytes can be derived from either in situ or ectopic migration. In this study, it was discovered that the regulation of IMF levels is achieved through the chemokine (C-C motif) ligand 5 (CCL5)/chemokine (C-C motif) receptor 5 (CCR5) pathway by modulating adipocyte migration. In coculture experiments, C2C12 myotubes were more effective in promoting the migration of 3T3-L1 preadipocytes than C2C12 myoblasts, along with increasing CCL5. Correspondingly, overexpressing the CCR5, one of the receptors of CCL5, in 3T3-L1 preadipocytes facilitated their migration. Conversely, the application of the CCL5/CCR5 inhibitor, MARAVIROC (MVC), reduced this migration. In vivo, transplanted experiments of subcutaneous adipose tissue (SCAT) from transgenic mice expressing green fluorescent protein (GFP) provided evidence that injecting recombinant CCL5 (rCCL5) into skeletal muscle promotes the migration of subcutaneous adipocytes to the skeletal muscle. The level of CCL5 in skeletal muscle increased with obesity. Blocking the CCL5/CCR5 axis by MVC inhibited IMF deposition, whereas elevated skeletal muscle CCL5 promoted IMF deposition in obese mice. These results establish a link between the IMF and the CCL5/CCR5 pathway, which could have a potential application for modulating IMF through adipocyte migration.NEW & NOTEWORTHY C2C12 myotubes attract 3T3-L1 preadipocyte migration regulated by the chemokine (C-C motif) ligand 5 (CCL5)/ chemokine (C-C motif) receptor 5 (CCR5) axis. High levels of skeletal muscle-specific CCL5 promote the migration of subcutaneous adipocytes to skeletal muscle and induce the intramuscular fat (IMF) content.

Gene expression and expression quantitative trait loci analyses uncover natural variations underlying the improvement of important agronomic traits during modern maize breeding.

Maize (Zea mays L.) is a major staple crop worldwide, and during modern maize breeding, cultivars with increased tolerance to high-density planting and higher yield per plant have contributed significantly to the increased yield per unit land area. Systematically identifying key agronomic traits and their associated genomic changes during modern maize breeding remains a significant challenge because of the complexity of genetic regulation and the interactions of the various agronomic traits, with most of them being controlled by numerous small-effect quantitative trait loci (QTLs). Here, we performed phenotypic and gene expression analyses for a set of 137 elite inbred lines of maize from different breeding eras in China. We found four yield-related traits are significantly improved during modern maize breeding. Through gene-clustering analyses, we identified four groups of expressed genes with distinct trends of expression pattern change across the historical breeding eras. In combination with weighted gene co-expression network analysis, we identified several candidate genes regulating various plant architecture- and yield-related agronomic traits, such as ZmARF16, ZmARF34, ZmTCP40, ZmPIN7, ZmPYL10, ZmJMJ10, ZmARF1, ZmSWEET15b, ZmGLN6 and Zm00001d019150. Further, by combining expression quantitative trait loci (eQTLs) analyses, correlation coefficient analyses and population genetics, we identified a set of candidate genes that might have been under selection and contributed to the genetic improvement of various agronomic traits during modern maize breeding, including a number of known key regulators of plant architecture, flowering time and yield-related traits, such as ZmPIF3.3, ZAG1, ZFL2 and ZmBES1. Lastly, we validated the functional variations in GL15, ZmPHYB2 and ZmPYL10 that influence kernel row number, flowering time, plant height and ear height, respectively. Our results demonstrates the effectiveness of our combined approaches for uncovering key candidate regulatory genes and functional variation underlying the improvement of important agronomic traits during modern maize breeding, and provide a valuable genetic resource for the molecular breeding of maize cultivars with tolerance for high-density planting.

Differential expression and prognostic value of TLR4 in kidney renal clear cell carcinoma.

Human Toll-like receptor (TLR) family plays a crucial role in immunity and cancer progression. However, the specific role of human Toll-like receptor 4 (TLR4) in kidney renal clear cell carcinoma (KIRC) remains obscure. Thus, we used single-cell RNA sequencing (RNA-seq) and bulk RNA-seq data combined with in vitro studies to evaluate the expression and prognostic value of TLR4 in KIRC. In our study, we observed that TLR4 was over expressed in KIRC tissues compared to normal renal tissues. And the expression of TLR4 was higher in macrophages/monocytes than other cell types. Besides, there is a close association between TLR4 expression and immune cell infiltration (Neutrophils, Macrophages, T cells and B cells) in KIRC. Immunohistochemical staining also showed that TLR4 was overexpressed in inflammatory infiltration renal tissue compared with normal tissue. Meanwhile, high expression of TLR4 exhibited correlations with improved survival, lower tumor grade and stage. Interestingly, the protective significance of TLR4 only showed in female patients (HR = 0.37, P < 0.01), other than male patients (HR = 0.71, P = 0.08) with KIRC. Consistently, KIRC samples with lymph node metastasis showed lower expression of TLR4. Knockdown of TLR4 in 786-O cell line increased cell proliferation and clonogenic capacity. In summary, this study found TLR4 could inhibit the progression of kidney cancer and was associated with improved survival in KIRC. The overexpression of TLR4 in macrophages and the close association between TLR4 and immune cell infiltration also underline the critical role of TLR4 in building the immune microenvironment for kidney cancer. These results may offer insights into the mechanism and immune microenvironment of kidney cancer.

Differential expression of ADRB1 causes different responses to norepinephrine in adipocytes of Duroc-Landrace-Yorkshire pigs and min pigs.

Research has shown that pigs from different regions exhibit varying responses to cold stimuli. Typically, cold stimuli induce browning of white adipose tissue mediated by adrenaline, promoting non-shivering thermogenesis. However, the molecular mechanisms underlying differential response of pig breeds to norepinephrine are unclear. The aim of this study was to investigate the differences and molecular mechanisms of the effects of norepinephrine (NE) treatment on adipocytes of Min pigs (a cold-resistant pig breed) and Duroc-Landrace-Yorkshire (DLY) pigs. Real time-qPCR, western blot, and immunofluorescence were performed following NE treatment on cell cultures of adipocytes originating from Min pigs (n = 3) and DLY pigs (n = 3) to assess the expressions of adipogenesis markers, beige fat markers, and mitochondrial biogenesis markers. The results showed that NE did not affect browning of adipocytes in DLY pigs, whereas promoted browning of adipocytes in Min pigs. Further, the expression of ADRB1 (Adrenoceptor Beta 1, ADRB1) was higher in subcutaneous adipose tissue and adipocytes of Min pigs than those of DLY pigs. Overexpression of ADRB1 in DLY pig adipocytes enhanced sensitivity to NE, exhibiting decreased adipogenesis markers, upregulated beige fat markers, and increased mitochondrial biogenesis. Conversely, adipocytes treated with ADRB1 antagonist in Min pigs resulted in decreased cellular sensitivity to NE. Further studies revealed differential CpG island methylation in ADRB1 promoter region, with lower methylation levels in Min pigs compared to DLY pigs. In conclusion, differential methylation of the ADRB1 promoter region leads to different ADRB1 expression, resulting in varying responsiveness to NE in adipocytes of two pig breeds. Our results provide new insights for further analysis of the differential cold responsiveness in pig breeds from different regions.

Vitamin K3 promotes CCL5 expression to recruit preadipocytes deposition to skeletal muscle.

Intramuscular fat (IMF), also known as ectopic fat deposits in skeletal muscle. Researches of IMF mainly focus on increasing the number and size of intramuscular adipocytes in situ. However, recent studies have shown that chemokines secreted by skeletal muscle recruit adipocytes to increase intramuscular fat content. Chemokine ligand 5 (CCL5), a member of chemokine family, is involved in the regulation of cell migration, inflammatory responses, and energy metabolism. In this study, we determined Vitamin K3 (VK3) enhanced Ccl5 transcription and expression, thus resulting in increased preadipocyte migration. VK3-injected vastus lateralis (VL) was observed an increased CCL5 concentration and IMF deposition, whereas blockade of the CCL5/CCR5 axis decreased IMF deposition.VK3 treatment also increased the body weight and VL ratio in mice. In summary, VK3, which targets CCL5, is expected to be a novel pharmacological regulator for promoting IMF content.

Screening protective miRNAs and constructing novel lncRNAs/miRNAs/mRNAs networks and prognostic models for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents 10-20 % of all breast cancer (BC) cases and is characterized by poor prognosis. Given the urgent need to improve prognostication and develop specific therapies for TNBC, the identification of new molecular targets is of great importance. MicroRNA (miRNA) has been reported as a valuable and novel molecular target in the progression of TNBC. However, the expression and function of miRNAs in different tumors are heterogeneous. Herein, we first analyzed miRNA data from The Cancer Genome Atlas (TCGA) and surprisedly found that overexpressed miRNAs were associated with poor survival in all breast cancer patients, but the overexpressed miRNAs were associated with better survival in TNBC patients. Based on the heterogeneity of miRNA expression in TNBC, we conducted further analysis using univariate Cox proportional hazard regression models and identified 17 miRNAs with prognostic potential. Subsequently, a multivariate Cox model was employed to create a 3-miRNA prognostic model for predicting overall survival in TNBC patients. The diagnostic model exhibited an area under the curve (AUC) of 0.727, and multivariable Cox regression indicated that each covariate was associated with survival. These data indicate that this model is relatively accurate and robust for risk assessment, which have a certain value for clinical application. In order to explore the network behind the overexpressed miRNAs in TNBC, we established a novel network consisting of lncRNAs, miRNAs, and mRNAs through complete transcriptome data from matched samples in the TCGA database. In this network, IRS-1 appeared to be the top hub gene. Experimental results demonstrated that miR-15b-5p and miR-148a-3p effectively target IRS-1 in vitro, shedding light on the intricate regulatory mechanisms in TNBC mediated by the heterogeneous miRNAs. Besides, miR-148a-3p significantly inhibited cell migration and viability. Overall, this study may add valuable insights into the molecular landscape of TNBC based on miRNAs and have the potential to contribute to the development of targeted therapies and improved prognostic strategies of TNBC.

Disulfiram/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK/ERK and PI3K/AKT Pathways.

BRAFV600E, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Vemurafenib (PLX4032), a specific inhibitor of BRAFV600E kinase, exhibits antitumor activity in patients with BRAFV600E-mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to BRAF kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on BRAFV600E-mutated thyroid cancer cells and its effect on the response of these cells to BRAF kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRAFV600E-mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/AKT signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of BRAFV600E-mutated thyroid cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for BRAFV600E-mutated thyroid cancers.

Nonivamide induces brown fat-like characteristics in porcine subcutaneous adipocytes.

Obesity, which is associated with type 2 diabetes, is a threat to human health. There are studies, which suggest that some compounds can induce browning of white adipocytes to combat obesity. In this study, we selected nonivamide, an analog of capsaicin, to detect whether it influenced the browning of porcine white adipocytes. First, we found 25 µM nonivamide promoted apoptosis of porcine subcutaneous pre-adipocytes. After pre-adipocytes differentiation, nonivamide inhibited adipogenesis by reducing the expressions of Pparγ, Cebpα, while it promoted lipolysis by up-regulating Hsl, Atgl. Nonivamide also induced browning of porcine subcutaneous adipocytes by up-regulating the expression of brown and beige adipocyte gene markers, such as Prdm16, Cidea, and Slc27a1. Additionally, thermogenesis gene markers Cpt1a and Cpt1b were significantly up-regulated by nonivamide. Furthermore, nonivamide promoted mitochondrial biogenesis by up-regulating the expression of Tfam, Nrf1, Nrf2, and Tomm20. In conclusion, nonivamide is a potent compound to induce porcine adipocyte browning for treating obesity.

Extracellular vesicles derived from donor oviduct fluid improved birth rates after embryo transfer in mice.

Embryo transfer (ET) is an important procedure for assisted reproduction. However, the relatively lower success rate of ET hampers its application potential. In this study we aimed to elucidate the effects of extracellular vesicles derived from donor oviduct fluid (EDOF) on embryo development after ET. Extracellular vesicles from the oviduct were isolated and purified using ultracentrifugation and identified using transmission electron microscopy, NanoSight, bicinchoninic acid (BCA) protein assay and western blotting. The results revealed that extracellular vesicles were present in donor oviduct fluid in higher concentrations (P<0.05) and contained more proteins (P<0.05) than extracellular vesicles derived from recipient oviduct fluid (EROF). EDOF or EROF were supplemented in an ET medium (ETM) and the results showed that EDOF significantly improved birth rate via resisting apoptosis and promoting differentiation. In conclusion, our study indicated that there are differences in EDOF and EROF and that supplementing EDOF to ETM can improve the efficiency of ET; improved ET efficiency promotes the use of gene editing and benefits assisted reproductive technology and animal welfare.

Reconfigurable spintronic logic gate utilizing precessional magnetization switching.

In traditional von Neumann computing architecture, the efficiency of the system is often hindered by the data transmission bottleneck between the processor and memory. A prevalent approach to mitigate this limitation is the use of non-volatile memory for in-memory computing, with spin-orbit torque (SOT) magnetic random-access memory (MRAM) being a leading area of research. In this study, we numerically demonstrate that a precise combination of damping-like and field-like spin-orbit torques can facilitate precessional magnetization switching. This mechanism enables the binary memristivity of magnetic tunnel junctions (MTJs) through the modulation of the amplitude and width of input current pulses. Building on this foundation, we have developed a scheme for a reconfigurable spintronic logic gate capable of directly implementing Boolean functions such as AND, OR, and XOR. This work is anticipated to leverage the sub-nanosecond dynamics of SOT-MRAM cells, potentially catalyzing further experimental developments in spintronic devices for in-memory computing.

Generation of skyrmions by combining thermal and spin-orbit torque: breaking half skyrmions into skyrmions.

Skyrmions, swirling spin textures with topologically protected stability and low critical driven-current density, can be generated from the stripe domain with current pulses, bringing them closer to practical applications in racetrack memory. However, the mechanism of this topological transition from the stripe domain to the skyrmion remains unclear because the transition process occurs at a nanosecond timescale, giving rise to difficulties in observing this process using imaging tools. In this study, we controlled the domain wall - skyrmion transition by combining Joule heating with spin-orbit torque (SOT) and experimentally observed the details of this process, by which we confirmed the mechanism: the spatial variation of the topological charge density induces half skyrmions branching from the stripe domains, and these half skyrmions overcome the surface tension and break away from the stripe domain, resulting in the generation of skyrmions. The details were observed by employing Joule heating to overcome the pinning effect and manipulating the strength of the SOT to induce the branching and breaking of half skyrmions. These findings offer new insights into skyrmion generation and serve as an important step towards the development of highly efficient devices for processing and computing based on skyrmionics.

Whole Genome Resequencing Revealed the Genetic Relationship and Selected Regions among Baicheng-You, Beijing-You, and European-Origin Broilers.

As the only two You-chicken breeds in China, Baicheng-You (BCY) and Beijing-You (BJY) chickens are famous for their good meat quality. However, so far, the molecular basis of germplasm of the two You-chicken breeds is not yet clear. The genetic relationship among BCY, BJY, and European-origin broilers (BRs) was analyzed using whole genome resequencing data to contribute to this issue. A total of 18,852,372 single nucleotide polymorphisms (SNPs) were obtained in this study. After quality control, 8,207,242 SNPs were applied to subsequent analysis. The data indicated that BJY chickens possessed distant distance with BRs (genetic differentiation coefficient (FST) = 0.1681) and BCY (FST = 0.1231), respectively, while BCY and BRs had a closer relationship (FST = 0.0946). In addition, by using FST, cross-population extended haplotype homozygosity (XP-EHH), and cross-population composite likelihood ratio (XP-CLR) methods, we found 374 selected genes between BJY and BRs chickens and 279 selected genes between BCY and BJY chickens, respectively, which contained a number of important candidates or genetic variations associated with feather growth and fat deposition of BJY chickens and potential disease resistance of BCY chickens. Our study demonstrates a genome-wide view of genetic diversity and differentiation among BCY, BJY, and BRs. These results may provide useful information on a molecular basis related to the special characteristics of these broiler breeds, thus enabling us to better understand the formation mechanism of Chinese-You chickens.

Reversible conversion between skyrmions and skyrmioniums.

Skyrmions and skyrmioniums are topologically non-trivial spin textures found in chiral magnetic systems. Understanding the dynamics of these particle-like excitations is crucial for leveraging their diverse functionalities in spintronic devices. This study investigates the dynamics and evolution of chiral spin textures in [Pt/Co]3/Ru/[Co/Pt]3 multilayers with ferromagnetic interlayer exchange coupling. By precisely controlling the excitation and relaxation processes through combined magnetic field and electric current manipulation, reversible conversion between skyrmions and skyrmioniums is achieved. Additionally, we observe the topological conversion from a skyrmionium to a skyrmion, characterized by the sudden emergence of the skyrmion Hall effect. The experimental realization of reversible conversion between distinct magnetic topological spin textures represents a significant development that promises to expedite the advancement of the next generation of spintronic devices.

High PGAP3 expression is associated with lymph node metastasis and low CD8+T cell in patients with HER2+ breast cancer.

BACKGROUND: Breast cancer (BC) stands as the most prevalent malignancy among women and ranks as the second most frequently diagnosed cancer globally among newly identified cases. Post-GPI attachment to proteins factor 3（PGAP3）was reported to involve in lipid remodeling. However, its specific role in breast cancer remains inadequately elucidated. Consequently, the principal objective of this study was to investigate the clinical significance of PGAP3 in breast cancer. METHODS: We conducted an extensive analysis using both public databases and our own sample cohort to assess the role of PGAP3 in breast cancer. Immunohistochemistry was employed to assess PGAP3 expression, immune markers, and the co-expression of PGAP3 with key susceptibility genes. Data analysis was performed using the R programming language. RESULTS: Our findings revealed that PGAP3 is significantly overexpressed in breast cancer, particularly in human epidermal growth factor 2 positive (HER2 +) breast cancer cases (p < 0.001). Co-expression analyses demonstrated a significant correlation between PGAP3 and susceptibility genes associated with breast cancer, including BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C, and RAD51D (p < 0.05). Logistic regression analysis identified PGAP3 as a significant predictor of estrogen receptor (ER), progesterone receptor (PR), HER2, and lymph node metastasis status (p < 0.01). Furthermore, higher PGAP3 expression was associated with decreased infiltration of CD8 + T cells in breast cancer samples. CONCLUSION: Our study sheds light on the clinical significance of PGAP3 in breast cancer. PGAP3 is not only overexpressed in breast cancer but also correlates with key susceptibility genes, lymph node metastasis, and CD8 + T cell infiltration. These findings provide valuable insights into the potential role of PGAP3 as a biomarker in breast cancer and may contribute to our understanding of the disease's pathogenesis.

EGFL7 drives the evolution of resistance to EGFR inhibitors in lung cancer by activating NOTCH signaling.

Accumulating evidence supports evolutionary trait of drug resistance. Like resilience in other systems, most tumor cells experience drug-tolerant state before full resistance acquired. However, the underlying mechanism is still poorly understood. Here, we identify that EGF like domain multiple 7 (EGFL7) is a responsive gene to epidermal growth factor receptor (EGFR) kinase inhibition during a period when tumors are decimated. Moreover, our data reveal that the adaptive increase of EGFL7 during this process is controlled by the depression of nonsense-mediated mRNA decay (NMD) pathway. Upregulation of EGFL7 activates NOTCH signaling in lung cancer cells, which slows down the decrease of c-Myc caused by EGFR inhibition, thereby helping the survival of cancer cells. Our data, taken together, demonstrate that EGFL7 is a driver gene for resistance to EGFR kinase inhibition, and suggest that targeting EGFL7/NOTCH signaling may improve the clinical benefits of EGFR inhibitors in patients with EGFR mutant tumors.

Cyanocobalamin promotes muscle development through the TGF-ß signaling pathway.

Cyanocobalamin (CNCbl, the compound name of Vitamin B12) is the only mineral vitamin that is essential for growth and development and cannot be produced by animals. Some studies have found that CNCbl can promote the proliferation and migration of C2C12 cells, but the mechanism by which it affects muscle development is still unknown. In this study, we elucidated the effect of CNCbl on muscle development and studied its underlying mechanism. CNCbl could promote the differentiation of C2C12 cells and upregulate Acvr1, p-Smad2 and p-Smad3 in the TGF-ß signaling pathway in vitro. CD320 (the receptor in cell surface for binding with CNCbl transporter transcobalamin II) inhibition could reduce the uptake of CNCbl and significantly downregulate the expression of differentiation marker proteins MyoG and MYH2. Furthermore, the levels of p-Smad2 and p-Smad3 were also reduced with the inhibition of CD320, even though CNCbl was added to the C2C12 culture medium. In addition, the injection of CNCbl could accelerate the process of mouse muscle injury repair, enlarge the diameter of newly formed myofibers and upregulate the expression of MYH2, PAX7, CD320, Acvr1, p-Smad2 and p-Smad3 in vivo. These results suggest that CNCbl can promote muscle development and may play its role by regulating the expression of Acvr1, p-Smad2 and p-Smad3 related to the TGF-ß signaling pathway.

ACAT2 Is a Novel Negative Regulator of Pig Intramuscular Preadipocytes Differentiation.

Intramuscular fat (IMF) is considered as the fat deposited between muscle fibers. The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Therefore, in this study we extracted the muscle tissue centrifugal fluid (MTF) of the longissimus dorsi of Erhualian pigs to mimic the microenvironment of intramuscular pre-adipocytes. MTF of pigs with low intramuscular fat level can inhibit pig intramuscular pre-adipocytes differentiation. Then, proteomics technology (iTRAQ) was used to analyze the MTF with different IMF content, and it was found that individuals with high IMF had low ACAT2 (Acyl-CoA: cholesterol acyltransferases 2) levels, while individuals with low IMF had high ACAT2 levels. Significant changes took place in the pathways involved in coenzyme A, which are closely related to fat and cholesterol metabolism. Therefore, we speculate that ACAT2, as an important element involved in cholesterol metabolism, may become a potential molecular marker for the mechanism of pig intramuscular preadipocytes differentiation. Overexpression of ACAT2 in pig intramuscular pre-adipocytes can inhibit their differentiation, while adding ACAT2 inhibitor avasimibe can rescue the process. Knockdown of srebp2 or ldlr, which are two key genes closely related to ACAT2 and cholesterol metabolism, can inhibit pig intramuscular pre-adipocytes differentiation. Overall, our results suggest that ACAT2 is a novel negative regulator of intramuscular adipocyte differentiation through regulation of pparγ, cebpα signaling and srebp2/ldlr signaling involved in cholesterol metabolism.

Dipeptidyl Peptidase-4 Stabilizes Integrin α4ß1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway.

Background: Metastatic disease is a major cause of thyroid cancer-related death. However, the mechanisms responsible for thyroid cancer metastasis are unclear. Dipeptidyl peptidase-4 (DPP4) is a multifunctional cell surface glycoprotein that has been reported to be a negative prognostic factor in thyroid cancer. We explored the molecular mechanism of the role of DPP4 in thyroid cancer cell metastasis. Methods: The effects of DPP4 on thyroid cancer cell migration/invasion in vitro were assessed by transwell assays. A lung metastatic mouse model was also established to determine the effect of DPP4 on tumor metastasis in vivo. DPP4 inhibitor sitagliptin was used to test its effect on thyroid cancer cell metastasis. The mechanism of which DPP4 promotes thyroid cancer cell metastasis was explored by a series of molecular and biochemical experiments. Results: We observed that DPP4 was significantly upregulated in papillary thyroid cancers compared with control subjects, and its expression was positively associated with lymph node metastasis and BRAFV600E mutation. Functional studies showed that DPP4 knockdown significantly inhibited metastatic potential of thyroid cancer cells, and vice versa. However, DPP4 inhibitor sitagliptin did not affect the metastatic ability of thyroid cancer cells, indicating that the promoting effect of DPP4 on tumor metastasis was independent of its enzymatic activity. Mechanistically, DPP4 interacted with the α4 and ß1 integrin subunits, and stabilized the formation of integrin α4ß1 complex. DPP4-mediated integrin signal activation promoted the nuclear localization of c-Jun through the FAK/AKT pathway, thereby inducing the transcription of transforming growth factor-beta 1 (TGFB1 coding for protein TGF-ß1). TGF-ß1 then facilitated tumor metastasis by inducing the epithelial-mesenchymal transition. Conclusions: DPP4 promotes thyroid cancer cell metastasis through the integrins/FAK/AKT/c-Jun/TGF-ß1 signaling axis. These findings may have implications for an alternative therapeutic strategy for thyroid cancer.

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53.

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.