Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.

Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.

METTL3 orchestrates glycolysis by stabilizing the c-Myc/WDR5 complex in triple-negative breast cancer.

BACKGROUND: The carcinogenic transcription factor c-Myc is the most aggressive oncogene, which drive malignant transformation and dissemination of triple-negative breast cancer (TNBC). Recruitment of many cofactors, especially WDR5, a protein that nucleates H3K4me chromatin modifying complexes, play a pivotal role in regulating c-Myc-dependent gene transcription, a critical process for c-Myc signaling to function in a variety of biological and pathological contexts. For this reason, interrupting the interaction between c-Myc and the transcription cofactor WDR5 may become the most promising new strategy for treating c-Myc driven TNBC. METHODS: Immunoprecipitation and mass spectrometry (IP-MS) is used to screen proteins that bind c-Myc/WDR5 interactions. The interaction of METTL3 with c-Myc/WDR5 in breast cancer tissues and TNBC cells was detected by Co-IP and immunofluorescence. Subsequently, we further analyzed the influence of METTL3 expression on c-Myc/WDR5 protein expression and its interaction stability by Western blot and Co-IP. The correlation between METTL3 and c-Myc pathway was analyzed by ChIP-seq sequencing and METTL3 knockdown transcriptome data. The effect of METTL3 expression on c-Myc transcriptional activity was detected by ChIP-qPCR and Dual Luciferase Reporter. At the same time, the overexpression vector METTL3-MUT (m6A) was constructed, which mutated the methyltransferase active site (Aa395-398, DPPW/APPA), and further explored whether the interaction between METTL3 and c-Myc/WDR5 was independent of methyltransferase activity. In addition, we also detected the changes of METTL3 expression on TNBC's sensitivity to small molecule inhibitors such as JQ1 and OICR9429 by CCK8, Transwell and clonal formation assays. Finally, we further verified our conclusions in spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. RESULTS: METTL3 was found to bind mainly to c-Myc/WDR5 protein in the nucleus. It enhances the stability of c-Myc/WDR5 interaction through its methyltransferase independent mechanism, thereby enhancing the transcriptional activity of c-Myc on downstream glucose metabolism genes. Notably, the study also confirmed that METTL3 can directly participate in the transcription of glucose metabolism genes as a transcription factor, and knockdown METTL3 enhances the drug sensitivity of breast cancer cells to small molecule inhibitors JQ1 and OICR9429. The study was further confirmed by spontaneous tumor formation mouse MMTV-PyMT and nude mouse orthotopic transplantation tumor models. CONCLUSION: METTL3 binds to the c-Myc/WDR5 protein complex and promotes glycolysis, which plays a powerful role in promoting TNBC progression. Our findings further broaden our understanding of the role and mechanism of action of METTL3, and may open up new therapeutic avenues for effective treatment of TNBC with high c-Myc expression.

Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation.

BRAF is frequently mutated in various cancer types and contributes to tumorigenesis and metastasis. As an important switch in RAS signaling pathway, BRAF typically enables the activation of MEK and ERK, and its mutation significantly promotes metastasis. However, whether BRAF could stimulate metastasis via a distinct manner is still unknown. Herein, we found that a portion of the BRAF protein localized at the plasma membrane and that the BRAFV600E mutation led to abundant formation of filopodia, which is a hallmark of invasive cancer cells. Mechanistically, BRAF physically interacts with the pseudopod formation-related protein Vasodilator-stimulated phosphoprotein (VASP), and BRAF specifically catalyzes VASP phosphorylation at Ser157. VASP depletion or disruption of Ser157 phosphorylation preferentially reduced the motility, invasion and metastasis of tumor cells harboring oncogenic BRAF or KRAS. Moreover, in clinical cancer tissues, BRAFV600E was positively correlated with the extent of invasion, and tissues with BRAFV600E expression exhibited elevated levels of VASP Ser157 phosphorylation. Our study therefor reveals a noncanonical mechanism by which oncogenic BRAF or KRAS promotes metastasis, suggests that VASP Ser157 phosphorylation might serve as a valuable therapeutic target in BRAF or KRAS mutant cancers.

Gender Differences in Migrant Workers Health in China.

Objectives: This study aimed to explore the distribution and differences in the health status of migrant workers in China by gender and age. In addition, it investigated the causes of health inequalities among them. Methods: This paper analyzes the differences in health status across age groups for migrant workers of different genders based on the data from the China Migrant Dynamic Survey in 2018. It also empirically assesses how education level and health insurance impact gender-related health inequalities. Results: The results suggest that female migrant workers in China have significantly lower health levels than males. Furthermore, these differences in health are exacerbated with age. This disparity may be attributed to lower participation in social insurance participation and less educational attainment among female migrant workers than their male counterparts. Conclusion: The government should take effective practical measures to increase the social insurance participation rate of female migrant workers. Moreover, investing in female education to reduce health inequality among migrant workers is essential.

IGF2BP2-modified UBE2D1 interacts with Smad2/3 to promote the progression of breast cancer.

Recent studies have suggested that ubiquitin-conjugating enzyme E2D1 (UBE2D1) is involved in tumor progression. In this study, we found that UBE2D1 expression was upregulated in breast cancer (BC) and was related to the prognosis of BC patients. Through in vitro and in vivo experiments, we demonstrated the aberrant expression of UBE2D1 promoted the proliferation and migration of BC cells, and the IGF2BP2-mediated N6-methyladenosine (m6A) modification increased the stability of UBE2D1 mRNA. Mechanistically, UBE2D1 expression regulated the activity of TGF-ß signaling through modulating the expression and the phosphorylation level of Smad2/3. Furthermore, UBE2D1 directly bound to Smad2/3 and affected the subsequent binding of Smad2 and Smad3, which is a necessary step for TGF-ß signaling activation. Thus, our study reveals a pro-oncogenic role of UBE2D1 in the progression of BC and may provide novel strategies for BC treatment.

Mettl3 synergistically regulates TGF-ß/SMAD2/3 to promote proliferation and metastasis of gastric cancer.

Transforming Growth factor-ß (TGF-ß)/Smad signaling is a complex regulatory network that both inhibits and promotes tumorigenesis. However, the mechanisms underlying the function of TGF-ß/Smad signaling pathway remain to be fully elucidated. As a methyltransferase, METTL3 is closely related to tumor development, but the role of METTL3 in the proliferation and metastasis of TGF-ß/Smad-activated gastric cancer (GC) is unclear. In this study, we identified TGF-ß/Smad2/3 axis as an important carcinogenic pathway in GC, which significantly promoted the proliferation and metastasis of GC. Furthermore, we found that Smad3 mRNA could be modified by m6A, which was subsequently recognized and stabilized by IGF2BP2, thereby enhancing Smad3 protein expression and promoting the activation of TGF-ß/Smad pathway. Importantly, we also found that METTL3 could combine with p-Smad3 to regulate the transcription of downstream target genes. Therefore, this study revealed a novel mechanism by which METTL3 synergistically regulates TGF-ß/Smad2/3 signaling and provide a new potential therapeutic target for the treatment of GC.

Role of coke media strategy in an adsorption-biological coupling technology for wastewater treatment performance, microbial community, and metabolic pathways features.

With the increase of wastewater discharge, the requirement of wastewater treatment technology is gradually increased. How to treat wastewater economically, while making the treatment process short, easy to manage and low running cost, is the focus of attention. Adsorption-biological coupling technology could make adsorption and biodegradation complement each other, which has coupled accumulation effect. In this study, with coke as the adsorbent, the efficiency of the adsorption-biological coupling reactor on the treatment of total phosphorus (TP), chemical oxygen demand (COD), and ammonia nitrogen (NH3-N) in domestic wastewater under different influent modes was investigated. Meanwhile, microbial community and metabolic pathways analysis of the reactor were carried out. Results showed that when the influent modes of the coupling reactor was once a day and the daily sewage treatment capacity was 2 L, the treatment efficiency of TP, COD, and NH3-N was the best. The removal rate of TP and NH3-N was 87.96% and 96.14%, respectively. The dominant phylum was Proteobacteria (39.84-44.49%), and the dominant genus was Sphingomonas (4.27-7.16%), and Gemmatimonas (1.27-3.58%). According to the metagenomic analysis, carbon metabolism process was evenly distributed in U (upper), M (middle), and L (lower) layers of the coupling reactor. Phosphate metabolism was mainly in the U layer at first, then in the M and L layers gradually. Carbon metabolism and phosphate metabolism provided sufficient energy for microbial degradation of pollutants. Nitrogen removal in the reactor mainly happened in the S and Z layers by nitrification (M00528) and denitrification (M00529), respectively.

The role of circadian rhythm in osteoporosis; a review.

Osteoporosis is characterized by a high incidence rate, with significant effects on people's lives. The underlying mechanisms are complex, with no treatments for the condition. Recent studies have indicated that melatonin can be used to treat osteoporosis by promoting osteoblast proliferation and differentiation, and inhibiting osteoclast differentiation. Specifically, in vivo mechanisms are initiated by stabilizing biological rhythms in bone tissue. In healthy organisms, these biological rhythms are present in bone tissue, and are characterized by bone formation during the day, and bone resorption at night. When this rhythm is disrupted, osteoporosis occurs. Thus, taking appropriate medication at different times of the day could produce different effects on osteoporosis rhythms. In this review, we characterized these processes, and provided treatments and management strategies for individuals with osteoporosis.

Melatonin inhibits osteoclastogenesis via RANKL/OPG suppression mediated by Rev-Erbα in osteoblasts.

Diabetic osteoporosis is secondary osteoporosis and a serious complication of diabetes with a high incidence rate and poor prognosis. The specific mechanism of diabetic osteoporosis is unclear, and prevention and treatment options are limited. Recently, melatonin has been found to prevent and treat diabetic osteoporosis. Herein, we investigated the mechanism whereby melatonin inhibits osteoclastogenesis and identified a new target for osteoporosis treatment. We established an in vitro osteoblast-osteoclast co-culture system as a diabetic osteoporosis model. Osteoclastogenesis was determined using tartrate-resistant acid phosphatase staining and cathepsin K expression. Real-time PCR was used to ascertain expression of microRNA mir-882, targeting Rev-Erbα. Western blotting was performed to detect the expression of Rev-Erbα, receptor activator of NF-kB ligand (RANKL), and osteoprotegerin (OPG), and ELISA was utilized to analyse the secreted form of RANKL. High glucose promoted osteoclastogenesis and elevated the RANKL/OPG ratio in osteoblasts, while melatonin reversed these effects. High glucose inhibited Rev-Erbα expression, while melatonin promoted its expression. Conversely, high glucose promoted mir-882 expression, while melatonin inhibited it. We infer that melatonin inhibits RANKL expression in osteoblasts via the mir-882/Rev-Erbα axis, thus inhibiting osteoclastogenesis. Our findings provide insights into diabetic osteoporosis and identify a new therapeutic target for osteoporosis.

Employment Management Policies for College Graduates under COVID-19 in China: Diffusion Characteristics and Core Issues.

The outbreak of COVID-19 epidemic has been having a great impact on the job market, so that graduates from all over the world are facing a more complex employment environment. Unemployment of the educated labor force often results in a waste of human capital and leads to serious economic and social problems. In the face of the impact of COVID-19, the Chinese government quickly introduced a series of employment policies for college graduates to relieve their employment pressure and create opportunities of career development. How did these employment policies for college graduates spread rapidly under the unconventional state of the COVID-19 epidemic? What are the diffusion characteristics? What are the core issues and measures? What are the differences between governments at all levels? These problems with rich connotation and research value needed to be further clarified. Based on the 72 employment support policies collected from the Chinese government network, this paper conducted a text analysis of the policies and found that in the process dimension, the employment policies of college graduates accumulated and exploded from bottom to top in the short term, and the policies diffusion followed the gradual model of "east-middle-west". In the content dimension, there were five core issues: financial subsidies, innovation and entrepreneurship to drive employment, public institutions to absorb, optimizing public services, and lowering the support threshold. Meanwhile, there were obvious differences in the choice of policy tools, policy intensity, and implementation ideas in each region. The findings are of important significance for developed and developing countries to better respond to the impact of various emergency situations.

A Quantitative Study of Early Childhood Care and Education Services Under the Age of Three: Evidence From Sichuan Province, China.

In China, early childhood care and education services for children under the age of three are neglected to some extent. Based on survey data from the Health Commission in Sichuan Province of China, this study analyzes the situation of early childhood care and education services in Sichuan through a qualitative method, using an analytical framework of matching the demand and supply. The findings reveal a mismatch between demand and supply of early childhood care and education services. This gap is likely to have a negative impact on children's self-development, family stability, and even the construction of national early childhood care and education service system. Drawing on the findings, suggestions for improving the mismatch between demand and supply are provided at the state, community and institution levels.

Institutional Design and Incentives for Migrant Workers to Participate in Social Insurance in China: Evidence From a Policy Experiment in Chengdu City.

Rural-to-urban migration has increased rapidly in China since the early 1980s, with the number of migrants has reached 376 million by 2020. Despite this sharp trend and the significant contributions that migrants have made to urban development, the migrant workers have had very limited access to the social insurance that the majority of urban workers enjoy. Against the background of the social insurance system adjustment in Chengdu in 2011, this study uses a difference-in-differences (DID) model to empirically test the impacts of changes in the social insurance policy contribution rates on the social insurance participation rates of migrant workers, using the China Migrants Dynamic Survey (CMDS) data for 2009-2016. We find that the social insurance participation rate of migrant workers was significantly reduced after they were incorporated into the urban worker insurance system. There was no significant change in the wages of migrant workers, but the working hours were increased and their consumption level decreased. In other words, simply changing the social insurance model of migrant workers from "comprehensive social insurance" to "urban employee insurance" reduces the incentives for migrant workers to participate in insurance and harms the overall welfare of migrant workers. Our study indicates that the design of the social security policy is an important reason for the lower participation rate of migrants. It is necessary to solve the problem of insufficient incentives through the targeted social security policies; primarily, the formulation of a social security policy contribution rate suitable for the migrants, and the establishment of a comprehensive social security policy and the gradual integration of the social security system.

Melatonin inhibits RANKL­induced osteoclastogenesis through the miR­882/Rev­erbα axis in Raw264.7 cells.

Melatonin, secreted in a typical diurnal rhythm pattern, has been reported to prevent osteoporosis; however, its role in osteoclastogenesis remains unclear. In the present study, the ability of melatonin to inhibit receptor activator of nuclear factor­κB ligand (RANKL)­induced osteoclastogenesis and the associated mechanism were investigated. Raw264.7 cells were cultured with RANKL (100 ng/ml) and macrophage colony­stimulating factor (M­CSF; 30 ng/ml) for 7 days, and tartrate­resistant acid phosphatase (TRAP) staining was used to detect osteoclastogenesis following treatment with melatonin. In addition, the effect of melatonin on cathepsin K and microRNA (miR)­882 expression was investigated via western blotting and reverse transcription­quantitative PCR. Melatonin significantly inhibited RANKL­induced osteoclastogenesis in Raw264.7 cells. From bioinformatics analysis, it was inferred that nuclear receptor subfamily 1 group D member 1 (NR1D1/Rev­erbα) may be a target of miR­882. In vitro, melatonin upregulated Rev­erbα expression and downregulated miR­882 expression in the osteoclastogenesis model. Rev­erbα overexpression boosted the anti­osteoclastogenesis effects of melatonin, whereas miR­882 partially diminished these effects. The present results indicated that the miR­882/Rev­erbα axis may serve a vital role in inhibiting osteoclastogenesis following RANKL and M­CSF treatment, indicating that Rev­erbα agonism or miR­882 inhibition may represent mechanisms through which melatonin prevents osteoporosis.

The Promotional Effect of Health Education on the Medical Service Utilization of Migrants: Evidence From China.

There were 376 million migrants in China by 2020, who made significant contributions to urban development. However, they used limited medical services and had lower self-reported health status than inflow city residents. Based on this, this study uses the cross-sectional data of the 2017 China Migrants Dynamic Survey (CMDS) to construct a multiple linear regression model to empirically study the role of health education in improving medical services utilization for migrants. It finds that compared to migrants without health education, the probability of the medical service utilization for migrants with health education has increased significantly, and counseling is more effective than other methods for health education. This promotion effect of health education has been established after a series of robustness tests. Furthermore, this study finds that the closer the migrants are to medical service resources, the greater the effect of health education on medical services utilization for migrants. The heterogeneity test shows that the effect of health education on medical services utilization for migrants is greater among the non-elderly and those with lower education levels. From the perspective of health education, the findings in this study provide empirical evidence to support the government in formulating policies to improve the utilization of medical services for migrants and reduce health inequality.

The Effects of Open Innovation Based on Mergers and Acquisitions on Innovative Behavior of Enterprises: Evidence From Chinese Listed Enterprises.

Finding the factors driving enterprise innovation behavior from multiple dimensions is of great significance for promoting enterprise innovation. Open innovation based on overseas mergers and acquisitions (M&A) has become one of the main ways for enterprises to obtain knowledge and technology. However, there is still no agreement on whether open innovation based on overseas M&A can promote innovation behavior of enterprises. Based on data from M&A transaction and enterprise patent of China's Shanghai and Shenzhen A-share listed companies from 2011 to 2018, this study constructs a propensity score matching and difference-in-difference model from the perspective of innovation performance and innovation investment empirically studies the influence of open innovation mode based on overseas M&A on the innovation behavior of enterprises and finds that open innovation based on overseas M&A can significantly promote the innovation performance and innovation investment. Meanwhile dynamic effects test shows this promotion effect is sustainable; it reaches the maximum in the year of overseas M&A and decreases in the next two years. In addition, the impacts are heterogeneous due to enterprise ownership and enterprise technology intensity. The findings extends the scope of understanding innovation behavior of enterprises from overseas M&A and provide solid evidence of significant business implications for the promotion of entrepreneurial innovation.

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation.

Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

Betulinic acid inhibits cell proliferation and migration in gastric cancer by targeting the NF-κB/VASP pathway.

Gastric cancer (GC) is one of the most common malignant neoplasms of the digestive system, with China leading in terms of morbidity and mortality rates. Betulinic acid (BA) is a widely-occurring pentacyclic triterpenoid that has been reported to exhibit potent anti-inflammatory, antioxidant, and antitumor activities. BA can combat tumors by inducing apoptosis, regulating cell cycle, and inhibiting autophagy, but its mechanism of action in the context of GC is unclear. A preliminary study found that higher expression of vasodilator-stimulated phosphoprotein (VASP) was correlated with migration in the GC cell line. In this study, BGC-823 cells and MNK45 cells were treated with BA for investigating its effect on the proliferation and migration of cells. Moreover, the expression of VASP and upstream signal molecules were also investigated in this background. The results showed BA could inhibit the proliferation and migration the GC cells. Furthermore, NF-κB acted as a transcription factor to upregulate VASP expression. Moreover, BA could downregulate the expression of VASP at the protein and mRNA level by inhibiting NF-κB activity. In conclusion, these results suggest that BA could inhibit the expression of VASP by negatively regulating NF-κB, thereby inhibiting the proliferation and migration of the GC cells. Our study provides a theoretical basis for exploring the molecular mechanism underlying BA-induced inhibition of proliferation and migration in GC cells.

CircRNA inhibits DNA damage repair by interacting with host gene.

BACKGROUND: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. METHOD: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. RESULTS: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. CONCLUSION: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

Melatonin rescues glucocorticoid-induced inhibition of osteoblast differentiation in MC3T3-E1 cells via the PI3K/AKT and BMP/Smad signalling pathways.

AIMS: High-dose glucocorticoid (GC) administration causes osteoporosis. Many previous studies from our group and other groups have shown that melatonin participates in the regulation of osteoblast proliferation and differentiation, especially low concentrations of melatonin, which enhance osteoblast osteogenesis. However, the role of melatonin in glucocorticoid-induced osteoblast differentiation remains unknown. MATERIALS AND METHODS: An examination of the expression of osteoblast differentiation markers (ALP, OCN, COLL-1), as well as alkaline phosphatase staining and alkaline phosphatase enzymatic activity assay to measure osteoblast differentiation and quantifying Alizarin red S staining to measure mineralization, were performed to determine the effects of dexamethasone (Dex) and melatonin on the differentiation of MC3T3-E1 cells. We used immunofluorescence staining to detect the expression of Runx2 in melatonin-treated MC3T3-E1 cells. The expression of mRNA was determined by qRT-PCR, and protein levels were measured by western blotting. KEY FINDINGS: In the present study, we found that 100 µM Dex significantly reduced osteoblast differentiation and mineralization in MC3T3-E1 cells and that 1 µM melatonin attenuated these inhibitory effects. We found that only inhibition of PI3K/AKT (MK2206) and BMP/Smad (LDN193189) signalling abolished melatonin-induced differentiation and mineralization. Meanwhile, MK2206 decreased the expression of P-AKT and P-Smad1/5/9 and LDN193189 decreased the expression of P-Smad1/5/9 but had no obvious effect on P-AKT expression in melatonin-treated and Dex-induced MC3T3-E1 cells. SIGNIFICANCE: These findings suggest that melatonin rescues Dex-induced inhibition of osteoblast differentiation in MC3T3-E1 cells via the PI3K/AKT and BMP/Smad signalling pathways and that PI3K/AKT signalling may be the upstream signal of BMP/Smad signalling.

The Wnt/ß-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer.

Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/ß-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/ß-catenin signaling pathway, and activation of Wnt/ß-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of ß-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, ß-catenin, and TCF4 can form VASP/DVL3/ß-catenin/TCF4 protein complex, activating Wnt/ß-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc, and cyclin D1. Thus, our study reveals that there is a Wnt/ß-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.