MCM8 interacts with DDX5 to promote R-loop resolution.

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.

Transcription-replication conflicts in primordial germ cells necessitate the Fanconi anemia pathway to safeguard genome stability.

Preserving a high degree of genome integrity and stability in germ cells is of utmost importance for reproduction and species propagation. However, the regulatory mechanisms of maintaining genome stability in the developing primordial germ cells (PGCs), in which rapid proliferation is coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter a constitutively high frequency of transcription-replication conflicts (TRCs), which lead to R-loop accumulation and impose endogenous replication stress on PGCs. We further demonstrate that the Fanconi anemia (FA) pathway is activated by TRCs and has a central role in the coordination between replication and transcription in the rapidly proliferating PGCs, as disabling the FA pathway leads to TRC and R-loop accumulation, replication fork destabilization, increased DNA damage, dramatic loss of mitotically dividing mouse PGCs, and consequent sterility of both sexes. Overall, our findings uncover the unique source and resolving mechanism of endogenous replication stress during PGC proliferation, provide a biological explanation for reproductive defects in individuals with FA, and improve our understanding of the monitoring strategies for genome stability during germ cell development.

Capsaicin enhances cisplatin-induced anti-metastasis of nasopharyngeal carcinoma by inhibiting EMT and ERK signaling via SERPINB2.

Cisplatin (DDP)-based combined chemotherapy or concurrent chemoradiotherapy is the mainstay treatment for advanced-stage nasopharyngeal carcinoma (NPC), but needs improvement due to its severe side effects. Capsaicin (CAP) can enhance the anti-tumor activity of cytotoxic drugs. The aim of this study was to investigate the anti-metastasis activity of CAP in combination with DDP in NPC. Herein, CAP and DDP showed synergistic cytotoxic effects on NPC cells. CAP alone and DDP alone inhibited NPC migration and invasion in vitro and in vivo, and the combination of CAP and DDP had the greatest effect. Moreover, CAP upregulated the mRNA and protein expressions of SERPINB2. Further results showed that both SERPINB2 mRNA and protein expressions were downregulated in NPC cell lines and tissues and SERPINB2 overexpression inhibited NPC migration and invasion in vitro and in vivo, while silencing SERPINB2 acted oppositely. In addition, SERPINB2 was abnormally expressed in head and neck squamous cell carcinoma (HNSC) and other multiple cancers and downregulation of SERPINB2 predicted poor prognosis in HNSC according to the Cancer Genome Atlas (TCGA) database. We further found that SERPINB2 overexpression inhibited epithelial-mesenchymal transition (EMT) and the phosphorylated ERK (p-ERK), and the inhibitory effect was enhanced by CAP and DDP. Altogether, our results suggest that the combined inhibition of CAP and DDP on NPC metastasis may be related to the inhibition of EMT and ERK signals mediated by SERPINB2, and CAP may help to improve the efficacy of DDP in the treatment of NPC and develop new therapeutic approaches.

DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development.

When DNA interstrand crosslink lesions occur, a core complex of Fanconi anemia proteins promotes the ubiquitination of FANCD2 and FANCI, which recruit downstream factors to repair the lesion. However, FANCD2 maintains genome stability not only through its ubiquitination-dependent but also its ubiquitination-independent functions in various DNA damage response pathways. Increasing evidence suggests that FANCD2 is essential for fertility, but its ubiquitination-dependent and ubiquitination-independent roles during germ cell development are not well characterized. In this study, we analyzed germ cell development in Fancd2 KO and ubiquitination-deficient mutant (Fancd2K559R/K559R) mice. We showed that in the embryonic stage, both the ubiquitination-dependent and ubiquitination-independent functions of FANCD2 were required for the expansion of primordial germ cells and establishment of the reproductive reserve by reducing transcription-replication conflicts and thus maintaining genome stability in primordial germ cells. Furthermore, we found that during meiosis in spermatogenesis, FANCD2 promoted chromosome synapsis and regulated crossover formation independently of its ubiquitination, but that both ubiquitinated and nonubiquitinated FANCD2 functioned in programmed double strand break repair. Finally, we revealed that on meiotic XY chromosomes, H3K4me2 accumulation required ubiquitination-independent functionality of FANCD2, while the regulation of H3K9me2 and H3K9me3 depended on FANCD2 ubiquitination. Taken together, our findings suggest that FANCD2 has distinct functions that are both dependent on and independent of its ubiquitination during germ cell development.

UBE2T resolves transcription-replication conflicts and protects common fragile sites in primordial germ cells.

The proper development of primordial germ cells (PGCs) is an essential prerequisite for gametogenesis and mammalian fertility. The Fanconi anemia (FA) pathway functions in maintaining the development of PGCs. FANCT/UBE2T serves as an E2 ubiquitin-conjugating enzyme that ubiquitylates the FANCD2-FANCI complex to activate the FA pathway, but its role in the development of PGCs is not clear. In this study, we found that Ube2t knockout mice showed defects in PGC proliferation, leading to severe loss of germ cells after birth. Deletion of UBE2T exacerbated DNA damage and triggered the activation of the p53 pathway. We further demonstrated that UBE2T counteracted transcription-replication conflicts by resolving R-loops and stabilizing replication forks, and also protected common fragile sites by resolving R-loops in large genes and promoting mitotic DNA synthesis to maintain the genome stability of PGCs. Overall, these results provide new insights into the function and regulatory mechanisms of the FA pathway ensuring normal development of PGCs.

NUMA1 modulates apoptosis of esophageal squamous cell carcinoma cells through regulating ASK1-JNK signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide with a low survival rate due to a lack of therapeutic targets. Here, our results showed that nuclear mitotic apparatus protein 1 (NUMA1) transcript and protein levels are significantly upregulated in ESCC patient samples and its high expression predicated poor prognosis. Knock-down of NUMA1 promoted cell apoptosis and suppressed cell proliferation and colony formation. By using cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models, we found silencing the NUMA1 expression suppressed tumor progression. In addition, conditional knocking-out of NUMA1 reduced 4NQO-induced carcinogenesis in mice esophagus, which further confirmed the oncogenic role of NUMA1 in ESCC. Mechanistically, from the immunoprecipitation assay we revealed that NUMA1 interacted with GSTP1 and TRAF2, promoted the association of TRAF2 with GSTP1 while inhibited the interaction of TRAF2 and ASK1, thus to regulate sustained activation of JNK. In summary, our findings suggest that NUMA1 plays an important role during ESCC progression and it functions through regulating ASK1-MKK4-SAPK/JNK signaling pathway.

FAAP100 is required for the resolution of transcription-replication conflicts in primordial germ cells.

BACKGROUND: The maintenance of genome stability in primordial germ cells (PGCs) is crucial for the faithful transmission of genetic information and the establishment of reproductive reserve. Numerous studies in recent decades have linked the Fanconi anemia (FA) pathway with fertility, particularly PGC development. However, the role of FAAP100, an essential component of the FA core complex, in germ cell development is unexplored. RESULTS: We find that FAAP100 plays an essential role in R-loop resolution and replication fork protection to counteract transcription-replication conflicts (TRCs) during mouse PGC proliferation. FAAP100 deletion leads to FA pathway inactivation, increases TRCs as well as cotranscriptional R-loops, and contributes to the collapse of replication forks and the generation of DNA damage. Then, the activated p53 signaling pathway triggers PGC proliferation defects, ultimately resulting in insufficient establishment of reproductive reserve in both sexes of mice. CONCLUSIONS: Our findings suggest that FAAP100 is required for the resolution of TRCs in PGCs to safeguard their genome stability.

Functions of lysine 2-hydroxyisobutyrylation and future perspectives on plants.

Lysine 2-hydroxyisobutyrylation (Khib) is a novel protein post-translational modifications (PTMs) observed in both eukaryotes and prokaryotes. Recent studies suggested that this novel PTM has the potential to regulate different proteins in various pathways. Khib is regulated by lysine acyltransferases and deacylases. This novel PTM reveals interesting connections between modifications and protein physiological functions, including gene transcription, glycolysis and cell growth, enzymic activity, sperm motility, and aging. Here, we review the discovery and the current understanding of this PTM. Then, we outline the networks of complexity of interactions among PTMs in plants, and raise possible directions of this novel PTM for future investigations in plants.

Green Approach for Rare Earth Element (REE) Recovery from Coal Fly Ash.

Due to the growing demands of rare earth elements (REEs) and the vulnerability of REEs to potential supply disruption, there have been increasing interests in recovering REEs from waste streams such as coal fly ash (CFA). Meanwhile, CFA as a large industrial waste stream in the United States (U.S.) poses significant environmental and economic burdens. Recovery of REEs from CFA is a promising solution to the REE scarcity issue and also brings opportunities for CFA management. This study demonstrates a green system for REE recovery from Class F and C CFA that consists of three modules: REE leaching using citrate, REE separation and concentration using oxalate, and zeolite synthesis using secondary wastes from Modules I and II. In Module I, ∼10 and 60% REEs were leached from the Class F and C CFA samples, respectively, using citrate at pH 4. In Module II, the addition of oxalate selectively precipitated and concentrated REEs from the leachate via the formation of weddellite (CaC2O4·2H2O), while other trace metals remained in solution. In Module III, zeolite was synthesized using wastes from Modules I and II. This study is characterized by the successful recovery of REEs and upcycling of secondary wastes, which addresses both REE recovery and CFA management challenges.

Interplay Between TGF-ß Signaling and MicroRNA in Diabetic Cardiomyopathy.

In diabetic patients, concomitant cardiovascular disease is the main factor contributing to their morbidity and mortality. Diabetic cardiomyopathy (DCM) is a form of cardiovascular disease associated with diabetes that can result in heart failure. Transforming growth factor-ß (TGF-ß) isoforms play a crucial role in heart remodeling and repair and are elevated and activated in myocardial disorders. Alterations in certain microRNAs (miRNA) are closely related to diabetic cardiomyopathy. One or more miRNA molecules target the majority of TGF-ß pathway components, and TGF-ß directly or via SMADs controls miRNA synthesis. Based on these interactions, this review discusses potential cross-talk between TGF-ß signaling and miRNA in DCM in order to investigate the creation of potential therapeutic targets.

Intracellular hydroxyproline imprinting following resolution of bleomycin-induced pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with few treatment options. The poor success in developing anti-IPF strategies has impelled researchers to reconsider the importance of the choice of animal model and assessment methodologies. Currently, it is still not settled whether the bleomycin-induced lung fibrosis mouse model finally returns to resolution. METHODS: This study aimed to follow the dynamic fibrotic features of bleomycin-treated mouse lungs over extended durations through a combination of the latest technologies (micro-computed tomography imaging and histological detection of degraded collagens) and traditional methods. In addition, we also applied immunohistochemistry to explore the distribution of all hydroxyproline-containing molecules. RESULTS: As determined by classical biochemical methods, total lung hydroxyproline contents reached a peak at 4 weeks after bleomycin injury and maintained a steady high level thereafter until the end of the experiments (16 weeks). This result seemed to partially contradict with the changes of other fibrosis evaluation parameters, which indicated a gradual degradation of collagens and a recovery of lung aeration after the fibrosis peak. This inconsistency was well reconciled by our data from immunostaining against hydroxyproline and fluorescent peptide staining against degraded collagen, together showing large amounts of hydroxyproline-rich degraded collagen fragments detained and enriched within the intracellular regions at 10 or 16 weeks rather than at 4 weeks after bleomycin treatment. CONCLUSIONS: Our present data not only offer respiratory researchers a new perspective towards the resolution nature of mouse lung fibrosis, but also remind them to be cautious when using the hydroxyproline content assay to evaluate the severity of fibrosis.

Borderline Metal Centers on Nonporous Metal-Organic Framework Nanowire Boost Fast Li-Ion Interfacial Transport of Composite Polymer Electrolyte.

Metal-organic frameworks (MOFs) fillers are emerging for composite polymer electrolytes (CPEs). Enhancing Lewis acid-base interaction (LABI) among MOFs, polymer and Li-salt is expected to promote Li+ -transport. However, it is unclear how to customize a strong LABI interface. The large surface-area of classical MOFs also interferes with clarifying the LABI influence on Li+ -transport. Herein, Bi3+ as metal centers to design colloidal-dispersed nonporous MOFs (Bi/HMT-MOFs) nanowire with a surface-area of only 17.13 m2 g-1 to prepare polyethylene oxide (PEO)-based CPEs (BMCPE) is chosen. The nonporous feature can exclude the surface-area effect on Li+ -transport. More interestingly, Bi3+ is a typical borderline acid, which can interact with both hard-basic PEO and soft-basic Li-salt anion. Accordingly, Bi/HMT-MOFs are uniformly dispersed in the BMCPE to form a strong LABI interface with PEO and Li-salt, promoting Li-salt dissociation and providing rapid Li+ -transport channels. Despite the ultralow surface-area of Bi/HMT-MOFs, BMCPE exhibits significantly enhanced ion-conductivity and Li+ transference number, which completely rival traditional MOFs-filled CPEs. BMCPE also enables symmetric and full cells with excellent high-rate performance and long-term cycling stability. In contrast, when Bi3+ sites are obscured, electrochemical performances are obviously decreased. Therefore, employing borderline metal centers will be an effective strategy to construct a LABI interface for high-performance MOFs-filled CPEs.

Deubiquitinating Enzyme USP21 Inhibits HIV-1 Replication by Downregulating Tat Expression.

Ubiquitination plays an important role in human immunodeficiency virus 1 (HIV-1) infection. HIV proteins such as Vif and Vpx mediate the degradation of the host proteins APOBEC3 and SAMHD1, respectively, through the proteasome pathway. However, whether deubiquitylating enzymes play an essential role in HIV-1 infection is largely unknown. Here, we demonstrate that the deubiquitinase USP21 potently inhibits HIV-1 production by indirectly downregulating the expression of HIV-1 transactivator of transcription (Tat), which is essential for transcriptional elongation in HIV-1. USP21 deubiquitylates Tat via its deubiquitinase activity, but a stronger ability to reduce Tat expression than a dominant-negative ubiquitin mutant (Ub-KO) showed that other mechanisms may contribute to USP21-mediated inhibition of Tat. Further investigation showed that USP21 downregulates cyclin T1 mRNA levels by increasing methylation of histone K9 in the promoter of cyclin T1, a subunit of the positive transcription elongation factor b (P-TEFb) that interacts with Tat and transactivation response element (TAR) and is required for transcription stimulation and Tat stability. Moreover, USP21 had no effect on the function of other HIV-1 accessory proteins, including Vif, Vpr, Vpx, and Vpu, indicating that USP21 was specific to Tat. These findings improve our understanding of USP21-mediated functional suppression of HIV-1 production. IMPORTANCE Ubiquitination plays an essential role in viral infection. Deubiquitinating enzymes (DUBs) reverse ubiquitination by cleaving ubiquitins from target proteins, thereby affecting viral infection. The role of the members of the USP family, which comprises the largest subfamily of DUBs, is largely unknown in HIV-1 infection. Here, we screened a series of USP members and found that USP21 inhibits HIV-1 production by specifically targeting Tat but not the other HIV-1 accessory proteins. Further investigations revealed that USP21 reduces Tat expression in two ways. First, USP21 deubiquitinates polyubiquitinated Tat, causing Tat instability, and second, USP21 reduces the mRNA levels of cyclin T1 (CycT1), an important component of P-TEFb, that leads to Tat downregulation. Thus, in this study, we report a novel role of the deubiquitinase, USP21, in HIV-1 infection. USP21 represents a potentially useful target for the development of novel anti-HIV drugs.

Tumor cell-derived autophagosomes (DRibbles)-activated B cells induce specific naïve CD8+ T cell response and exhibit antitumor effect.

Dendritic cell (DC) vaccine has been proved to be an effective way in cancer immunotherapy in both preclinical and clinical studies. However, limitations in DC isolation and culture have hampered its practice and promoted the development of other antigen-presenting cells (APCs) sources to fulfill that role. Our previous studies have shown that B cells loaded by tumor cell-derived autophagosomes, which we named as DRibbles (defective ribosomal products-containing blebs), could reactivate DC-induced effector T cell response. In this study, the roles of DRibble-loaded B cells in priming naïve CD8+ T cell responses and controlling tumors were investigated. We found that high-mobility group box 1 protein (HMGB1) on DRibbles was involved in DRibble-induced B cell activation, and the DRibble-triggered B cell phagocytosis via the caveolae-mediated endocytosis pathway. By using OT-I mouse-derived T cells, we demonstrated that DRibble-loaded B cells could activate specific naïve CD8+ T cells in vitro and ex vivo. In a tumor-bearing mouse model, DRibble-loaded B cells elicited systemic antitumor immunity and significantly suppressed the tumor growth. Moreover, the antitumor efficacy of DRibble-loaded B cells was enhanced when they were combined with CpG and anti-CD40 stimulation. These results suggest that DRibble-loaded B cells represent a viable and practical therapeutic vaccination strategy that might have important clinical implications for tumor immunotherapy.

Targeting the microRNAs in exosome: A potential therapeutic strategy for alleviation of diabetes-related cardiovascular complication.

Diabetes-related cardiovascular disease (CVD) is a global health issue that causes thousands of people's death around the world annually. Diabetes-related CVD is still prevailing despite the progression being made in its diagnosis and treatment. Therefore it is urgent to find therapeutic strategies.to prevent it. MicroRNA (miRNA) is a single-stranded non-coding RNA involved in the process of post-transcriptional control of gene expression in eukaryotes. A large number of literatures reveal that miRNAs are implicated in diabetes-related CVD. The increase of miRNAs in exosomes may promote the occurrence and development of diabetes-related cardiovascular complication. However, some other studies identify that miRNAs in exosomes are supposed to be involved in cardiac regeneration and confer cardiac protection effect. Therefore, targeting the miRNA in exosome is regarded as a potent therapeutic measure to alleviate diabetes-related CVD. In this article, we review current knowledge about the role of exosomal miRNAs in diabetes-related cardiovascular complication, such as coronary heart disease, Peripheral artery disease, stroke, diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy. Exosomal miRNAs are considered to be central regulators of diabetes-Related CVD and provide a therapeutic tool for diagnosis and treatment of diabetes-related cardiovascular complication.

COVID-19 and Strategies for Its Therapeutics.

Currently the epidemic of SARS-CoV-2-caused COVID-19 is a major threat to global public health. The latest clinical data, laboratory results, and autopsy information are summarized herein to provide a brief review of the significant issues surrounding SARS-CoV-2 and COVID-19. In this review, we also cover research on the ways in which the virus enters the human body, general clinical symptoms, immunopathological responses in severe cases of COVID-19, and the issues surrounding the potential therapeutic responses to the illness.

Ornithine decarboxylase inhibition downregulates multiple pathways involved in the formation of precancerous lesions of esophageal squamous cell cancer.

The high incidence and mortality of esophageal squamous cell cancer (ESCC) is a major health problem worldwide. Precancerous lesions of ESCC may either progress to cancer or revert to normal epithelium with appropriate interventions; the bidirectional instability of the precancerous lesions of ESCC provides opportunities for intervention. Reports suggest that the upregulation of ornithine decarboxylase (ODC) is closely related to carcinogenesis. In this study, we investigated whether ODC may act as a target for chemoprevention in ESCC. Immunohistochemistry (IHC) assays indicate that ODC expression is higher in esophageal precancerous lesions compared with normal tissue controls. Its overexpression promotes cell proliferation and transformation of normal esophageal epithelial cells, and its activity is increased after N-nitrosomethylbenzylamine (NMBA) induction in Shantou human embryonic esophageal cell line (SHEE) and human immortalized cells (Het1A) cells. In addition, p38 α, extracellular regulated kinase (ERK1/2) in the mitogen-activated protein kinase pathway and protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathways are activated in response to NMBA treatment. Difluoromethylornithine (DFMO) is an ODC inhibitor, which inhibits NMBA-induced activation of p38 α, ERK1/2 and AKT/mTOR/p70S6K pathways; this has been verified by Western blotting. DFMO was also found to suppress the development of esophageal precancerous lesions in an NMBA-induced rat model; IHC demonstrated p38 α, ERK1/2, and AKT/mTOR/p70S6K pathways to be downregulated in these rats. These findings indicate the mechanisms by which ODC inhibition suppresses the development of esophageal precancerous lesions by downregulating p38 α, ERK1/2, and AKT/mTOR/p70S6k signaling pathways, ODC may be a potential target for chemoprevention in ESCC.

Role of PIWI-interacting RNAs on cell survival: Proliferation, apoptosis, and cycle.

PIWI-interacting RNAs (piRNAs) are a kind of non-coding small RNAs, which play a biological role by specifically binding to PIWI proteins. Studies have demonstrated that piRNAs play a significant role in germline cell growth by repressing transposable elements, especially in the regulation of DNA methylation. Recently increasing evidence revealed that piRNAs involved in the regulation of cell proliferation, apoptosis, and cycle; however, the mechanism of piRNAs is unclear. This review summarizes the research progress regarding the roles of piRNAs in the cell proliferation, apoptosis, and cycle.

Promotion of Microbial Oxidation of Structural Fe(II) in Nontronite by Oxalate and NTA.

Iron redox cycling occurs extensively in soils and sediments. Previous research has focused on microbially mediated redox cycling of aqueous Fe. At circumneutral pH, most Fe occurs in solid phase, where Fe and organic ligands interact closely. However, the role of organic ligands in microbial oxidation of solid-phase Fe(II) is not well understood. Here, we incubated reduced nontronite NAu-2 (rNAu-2) with an iron-oxidizing bacterium and in the presence of oxalate and nitrilotriacetic acid. These ligands significantly enhanced the rate and extent of microbial oxidation of structural Fe(II) in rNAu-2. Aqueous and solid-phase analyses, coupled with biogeochemical modeling, revealed a pathway for ligand-enhanced bio-oxidation of solid-phase Fe(II): (1) dissolution of rNAu-2 to form aqueous Fe(II)-ligand complex; (2) bio-oxidation to Fe(III)-ligand complex; (3) rapid reduction of Fe(III)-ligand complex to Fe(II)-ligand complex by structural Fe(II) in rNAu-2. In this process, the Fe(II)-ligand and Fe(III)-ligand complexes effectively serve as electron shuttle to expand the bioavailable pool of solid-phase Fe(II). These results have important implications for a better understanding of the bioavailability and reactivity of solid-phase Fe pool in the environment.

Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro.

BACKGROUND: As a novel type of isothiocyanate derived from radish seeds from cruciferous vegetables, sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) has various important biological effects, such as anti-oxidative and anti-bacterial effects. Recently, sulforaphene has attracted increasing attention for its anti-tumor effects and its ability to suppress the development of multiple tumors through different regulatory mechanisms. However, it has not yet been widely investigated for the treatment of esophageal cancer. METHODS: We observed an increased apoptosis in esophageal cancer cells on sulforaphene treatment through flow cytometry (FCM) analysis and transmission electron microscopy (TEM). Through mass spectrometry (MS) analysis, we further detected global changes in the proteomes and phosphoproteomes of esophageal cancer cells on sulforaphene treatment. The molecular mechanism of sulforaphene was verified by western blot,the effect and mechanism of SFE on esophageal cancer was further verified by patient-derived xenograft mouse model. RESULTS: We identified multiple cellular processes that were changed after sulforaphene treatment by proteomics. We found that sulforaphene could repress the phosphorylation of CREB through MSK2, leading to suppression of Bcl-2 and further promoted cell apoptosis. Additionally, we confirmed that sulforaphene induces tumor cell apoptosis in mice. Interestingly, we also observed the obvious inhibition of cell migration and invasion caused by sulforaphene treatment by inhibiting the expression of cadherin, indicating the complex effects of sulforaphene on the development of esophageal cancer. CONCLUSIONS: Our data demonstrated that sulforaphene induced cell apoptosis and inhibits the invasion of esophageal cancer through a mechanism involving the inhibition of the MSK2-CREB-Bcl2 and cadherin pathway. Sulforaphene could therefore serve as a promising anti-tumor drug for the treatment of esophageal cancer.