Roles of gut microbiota in androgenetic alopecia: insights from Mendelian randomization analysis.

Background: Androgenetic alopecia (AGA) is the most common type of androgen-associated hair loss. Previous studies have indicated an association between the gut microbiota and AGA. To delve deeper, we executed a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between the gut microbiota and AGA. Methods: A two-sample MR investigation was utilized to delve into the intricate interplay between gut microbiota and AGA. Information regarding 211 gut microbial taxa was sourced from the MiBioGen consortium. The summary statistics of the genome-wide association studies (GWAS) for AGA were obtained from the FinnGen biobank, which included 195 cases and 201,019 controls. Various analytical approaches, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were employed to evaluate the causal impact of gut microbiota on AGA. Sensitivity analyses were subsequently conducted to affirm the robustness of the findings. Results: A two-sample MR investigation unveiled the genus Olsenella, genus Ruminococcaceae UCG-004, and genus Ruminococcaceae UCG-010 were identified as risk factors associated with AGA. In contrast, the family Acidaminococcaceae and genus Anaerofilum, along with the genus Ruminiclostridium 9, demonstrated a protective effect. The sensitivity analyses provided additional assurance that the findings of the current study were less susceptible to the influence of confounding variables and biases. Conclusion: The MR study has established a link between specific gut microbiota and AGA, offering evidence for the identification of more precisely targeted probiotics. This discovery has the potential to aid in the prevention, control, and reversal of AGA progression.

WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis.

AMPK plays significant roles in the modulation of metabolic reprogramming and viral infection. However, the detailed mechanism by which AMPK affects viral infection is unclear. The present study aims to determine how AMPK influences white spot syndrome virus (WSSV) infection in shrimp (Marsupenaeus japonicus). Here, we find that AMPK expression and phosphorylation are significantly upregulated in WSSV-infected shrimp. WSSV replication decreases remarkably after knockdown of Ampkα and the shrimp survival rate of AMPK-inhibitor injection shrimp increases significantly, suggesting that AMPK is beneficial for WSSV proliferation. Mechanistically, WSSV infection increases intracellular Ca2+ level, and activates CaMKK, which result in AMPK phosphorylation and partial nuclear translocation. AMPK directly activates mTORC2-AKT signaling pathway to phosphorylate key enzymes of glycolysis in the cytosol and promotes expression of Hif1α to mediate transcription of key glycolytic enzyme genes, both of which lead to increased glycolysis to provide energy for WSSV proliferation. Our findings reveal a novel mechanism by which WSSV exploits the host CaMKK-AMPK-mTORC2 pathway for its proliferation, and suggest that AMPK might be a target for WSSV control in shrimp aquaculture.

Global, regional, and national HIV/AIDS disease burden levels and trends in 1990-2019: A systematic analysis for the global burden of disease 2019 study.

Background: Since the first HIV/AIDS case appeared in 1980s, HIV/AIDS has been the focus of international attention. As a major public health problem, there are epidemiological uncertainties about the future of HIV/AIDS. It is important to monitor the global statistics of HIV/AIDS prevalence, deaths, disability adjusted life years (DALYs), and risk factors for adequate prevention and control. Methods: The Global Burden of Disease Study 2019 database was used to analyze the burden of HIV/AIDS in 1990-2019. By extracting global, regional, and national data on HIV/AIDS prevalence, deaths, and DALYs, we described the distribution by age and sex, explored the risk factors, and analyzed the trends in HIV/AIDS. Results: In 2019, there were 36.85 million HIV/AIDS cases (95% UI: 35.15-38.86 million), 863.84 thousand deaths (95% UI: 78.61-99.60 thousand), and 47.63 million (95% UI: 42.63-55.65 million) DALYs. The global age-standardized HIV/AIDS prevalence, death, and DALY rates were 454.32 (95% UI: 433.76-478.59), 10.72 (95% UI: 9.70-12.39), and 601.49 (95% UI: 536.16-703.92) per 100,000 cases, respectively. In 2019, the global age-standardized HIV/AIDS prevalence, death, and DALY rates increased by 307.26 (95% UI: 304.45-312.63), 4.34 (95% UI: 3.78-4.90), and 221.91 (95% UI: 204.36-239.47) per 100,000 cases, respectively, compared to 1990. Age-standardized prevalence, death, and DALY rates decreased in high sociodemographic index (SDI) areas. High age-standardized rates were observed in low sociodemographic index areas, while low age-standardized rates were observed in high sociodemographic index areas. In 2019, the high age-standardized prevalence, death, and DALY rates were predominant in Southern Sub-Saharan Africa, and global DALYs peaked in 2004 and subsequently decreased. The highest global HIV/AIDS DALYs were in the 40-44 age group. The main risk factors affecting HIV/AIDS DALY rates included behavioral risks, drug use, partner violence, and unsafe sex. Conclusions: HIV/AIDS disease burden and risk factors vary by region, sex, and age. As access to health care increases across countries and treatment for HIV/AIDS infection improves, the HIV/AIDS disease burden is concentrated in areas with low SDIs, particularly in South Africa. Regional differences should be fully considered to target optimal prevention strategies and treatment options based on risk factors.

Activation of NRF2 blocks HIV replication and apoptosis in macrophages.

Abnormal oxidative stress caused by human immunodeficiency virus (HIV) infection affects viral replication and causes non-acquired immune deficiency syndrome-related complications in infected individuals. The transcription factor NFE2-related factor 2 (NRF2), a key regulator of oxidative stress, responds to abnormal oxidative stress by regulating the expression of NRF2-dependent cytoprotective genes. The present study aimed to determine whether inhibition of oxidative stress could control HIV replication and improve cell survival. In this study, the NRF2 activator, methyl bardoxolone, was used to treat cells for HIV infection. The effects on HIV replication and apoptosis pathways were confirmed by NRF2 activation or knockdown. The results showed that NRF2 activation could block HIV replication in macrophages before the integration phase and inhibited the expression of apoptotic pathways in virus-exposed macrophages. The study presents an unconventional anti-viral strategy of activation antioxidant response for HIV infection blocking.

Reticulocalbin 1 is required for proliferation and migration of non-small cell lung cancer cells regulated by osteoblast-conditioned medium.

Reticulocalbin1 (RCN1) is implicated in tumorigenesis and tumour progression. However, whether RCN1-mediated bone metastasis of non-small cell lung cancer (NSCLC) cells was elusive. Here, we assessed the effect of osteoblast-conditioned medium (CM) on proliferation and migration of NSCLC cell line, NCI-H1299 and NCI-H460 cells, and identified the soluble mediators in CMs from osteoblasts and NSCLC cells using MTT, Clonogenicity, Transwell, wound healing, RT-PCR, and Western blotting assays, and LC-MS/MS analysis, respectively. Furthermore, the role of RCN1 was investigated in NSCLC cells cultured with or without osteoblast-CM. Tumour growth and bone resorption were measured in a nude mouse model bearing NCI-H1299 cells transduced with shRNA/RCN1 vector using in vivo imaging technique and micro-CT. The results showed that RCN1 with a higher abundance in osteoblast-CM, which was present in extracellular vesicles (EVs), enhanced RCN1 expression in NSCLC cells. Osteoblast-CM partially offset the inhibitory effect of RCN1 depletion on proliferation and migration of NSCLC cells. RCN1 depletion-induced endoplasmic reticulum (ER) stress caused by increasing GRP78, CHOP, IRE1α, p-IRE1α, p-PERK and p-JNK, which was positively regulated by self-induced autophagy, contributed to suppression of proliferation and migration in NCI-H1299 cells. Therefore, osteoblasts produced RCN1 to transfer into NSCLC cells partially through EVs, facilitating proliferation and migration of NSCLC cells via blocking ER stress. RCN1 could be required for proliferation and migration of NSCLC cells regulated by osteoblast-CM.

Inactivation of Latent HIV-1 Proviral DNA Using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Treatment and the Assessment of Off-Target Effects.

Viral DNA integrated in host cells is a major barrier to completely curing HIV-1. However, genome editing using the recently developed technique of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 has the potential to eradicate HIV-1. The present study aimed to use a lentiviral vector-based CRISPR/Cas9 system combined with dual-small/single guide RNAs (sgRNAs) to attack HIV-1 DNA in the latency reactivation model J-Lat 10.6 cell line and to assess off-target effects using whole-genome sequencing (WGS). We designed 12 sgRNAs targeting HIV-1 DNA, and selected high-efficiency sgRNAs for further pairwise combinations after a preliminary evaluation of the editing efficiency. Three combinations of dual-sgRNAs/Cas9 with high editing efficiency were screened successfully from multiple combinations. Among these combinations, the incidences of insertions and deletions in the sgRNA-targeted regions reached 76% and above, and no credible off-target sites were detected using WGS. The results provided comprehensive basic experimental evidence and methodological recommendations for future personalized HIV-1 treatment using CRISPR/Cas9 genome editing technology.

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro.

Our previous studies indicated that phosphoinositide specific phospholipase Cγ1 (PLCγ1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLCγ1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLCγ1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLCγ1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLCγ1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLCγ1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLCγ1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLCγ1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLCγ1. PLCγ1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPKα, mTOR, and ERK levels. However, PLCγ1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP1. Additionally, the abrogation of PLCγ1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLCγ1 inhibition could be partially attributed to PLCγ1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLCγ1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.

Ethical considerations of cellular immunotherapy for cancer.

With the rapid development of immunology, molecular biology, and associated technologies such as next-generation sequencing, cellular immunotherapy has recently become the fourth major cancer treatment. Immunotherapies based on T cells, natural killer cells, and dendritic cells play key roles in cancer immunotherapy. However, their application in clinical practice raises several ethical issues. Thus, studies should focus on proper adherence to basic ethical principles that can effectively guide and solve related clinical problems in the course of treatment, improve treatment effects, and protect the rights and interests of patients. In this review, we discuss cellular immunotherapy-related ethical issues and highlight the ethical practices and current status of cellular immunotherapy in China. These considerations may supplement existing ethical standards in cancer immunotherapy.

Hepatitis B Virus Core Antigen Stimulates IL-6 Expression via p38, ERK and NF-κB Pathways in Hepatocytes.

BACKGROUND: Hepatitis B virus (HBV) causes both acute and chronic liver injury. Viral proteins are involved in the pathological progress. Hepatitis B core antigen (HBcAg), a component of viral nucleocapsid, is not only essential for HBV lifecycle, but also exhibits strong immunogenicity. The cytoplasmic location of HBcAg in liver biopsy is associated with liver injury and inflammation, but the exact mechanisms remain to be elaborated. METHODS: Huh7, SMMC-7721 and L-02 cells were transfected with pEGFP-N1-HBcAg to establish an intracellular HBcAg expression model. The mRNA and protein levels of Interleukin (IL)-6 were detected by qPCR and ELISA respectively. The signaling pathway-related proteins were investigated by western blot and immunofluorescence assay. RESULTS: HBcAg increased the expression and secretion of IL-6 through activating extracellular signal-related kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB). These activations can be blocked by specific inhibitors of the three pathways. CONCLUSIONS: HBcAg actives p38, ERK1/2 and NF-κB to enhance the production of IL-6 in hepatocytes. This provides a molecular mechanism to explain the association of cytoplasmic HBcAg with severe liver injury and inflammation.

Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner.

During hepatitis B virus (HBV) infection, three viral envelope proteins of HBV are overexpressed in the endoplasmic reticulum (ER). The large S protein (LHBs) and truncated middle S protein (MHBst) have been documented to play roles in regulating host gene expression and contribute to hepatic disease development. As a predominant protein at the ultrastructural level in biopsy samples taken from viremic patients, the role of the middle S protein (MHBs) remains to be understood despite its high immunogenicity. When we transfected hepatocytes with an enhanced green fluorescent protein (EGFP)-tagged MHBs expressing plasmid, the results showed that expression of MHBs cause an upregulation of IL-6 at the message RNA and protein levels through activating the p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB) pathways. The use of specific inhibitors of the signaling pathways can diminish this upregulation. The use of BAPTA-AM attenuated the stimulation caused by MHBs. We further found that MHBs accumulated in the endoplasmic reticulum and increased the amount of glucose regulated protein 78 (GRP78/BiP). Our results provide a possibility that MHBs could be involved in liver disease progression.

The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis.

BACKGROUND: The anti-tumor effects of quercetin have been reported, but the underlying molecular mechanisms remain to be elucidated. The aim of present study was to explore the role of miRNA in the anticancer effects of quercetin. METHODS: The differential miRNAs expression between the HepG2 and Huh7 cells treated by quercetin were detected by microarray. The xCELLigence, Flow cytometry, RT-PCR and Western blot were used to analyze the cell proliferation, cell apoptosis, cell cycle arrest, anti-tumor genes, and protein expression. RESULTS: miR-34a was up-regulated in HepG2 cells treated by quercetin exhibiting wild-type p53. When inhibiting the miR-34a, the sensitivity of the cells to quercetin decreased and the expression of the SIRT1 was up-regulated, but the acetylation of p53 and the expression of some genes related to p53 down-regulated. CONCLUSION: miR-34a plays an important role in the anti-tumor effects of querctin in HCC, miR-34a may be a tiemolecule between the p53 and SIRT1 and is composed of a p53/miR-34a/SIRT1 signal feedback loop, which could enhance apoptosis signal and significantly promote cell apoptosis.

Interleukin-22 mediates early host defense against Rhizomucor pusilluscan pathogens.

BACKGROUND: In recent years, the fungal infectious disease zygomycosis has increased in incidence worldwide, especially among the immunodeficient population. Despite the rates of zygomycosis-related death and deformation being very high, the mechanism(s) by which the fungal pathogens cause these severe manifestations remain unknown. METHODS: Using the associated Rhizomucor variabilis species, which can selectively induce cutaneous zygomycosis in otherwise healthy individuals, we investigated the host mechanisms of infection-related responses, including cytokine and chemokine expression as well as contributions of particular T cell subsets. siRNA specifically targeting IL-22,IL-17 and IFN-γ were used to down-regulate expression of those molecules. RESULTS: In mouse models of infection, IL-22 was implicated in development of Rhizomucor spp.-induced skin lesions. In cultured human peripheral blood monocytes, R. pusilluscan, which is often found in immunodeficient patients, induced the production of IL-22, while R. variabilis did not. Moreover, Rhizomucor spp.-induced secretion of Il-22 from CCR6(+)CCR4(+)CCR10(+) cells was down-regulated by knockdown of IL-22 related signaling receptors, RORC and ARH. CONCLUSION: Our data strongly suggest that avoidance of IL-22 may be one mechanism by which mucor species produce morbidity and mortality in infected individuals.

HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells.

BACKGROUND & AIMS: Human epidermal growth factor receptor 2 (HER2) (neu/ERBB2) is overexpressed on many types of cancer cells, including gastric cancer cells; HER2 overexpression has been associated with metastasis and poor prognosis. We investigated the mechanisms by which HER2 regulates cell migration and invasion. METHODS: HER2 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody, trastuzumab. We identified proteins that interact with HER2 or microRNAs (miRNAs) involved in HER2 signaling. We used various software programs to identify miRNAs that regulate factors in the HER2 signaling pathway. We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients. RESULTS: We found that CD44 binds directly to HER2, which up-regulates the expression of metastasis-associated protein-1, induces deacetylation of histone H3 lysine 9, and suppresses transcription of microRNA139 (miR-139) to inhibit expression of its target gene, C-X-C chemokine receptor type 4 (CXCR4). Knockdown of HER2 and CD44 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice. Lymph node metastasis was associated with high levels of HER2, CD44, and CXCR4, and reduced levels of miR-139 in human metastatic gastric tumors. Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and/or DNA methyltransferase resulted in up-regulation of miR-139. CONCLUSIONS: HER2 interaction with CD44 up-regulates CXCR4 by inhibiting expression of miR-139, at the epigenetic level, in gastric cancer cells. These findings indicate how HER2 signaling might promote gastric tumor progression and metastasis.

HER2-mediated upregulation of MMP-1 is involved in gastric cancer cell invasion.

HER2 overexpression is associated with metastasis-the main cause of death in individuals with gastric cancer. In this study, we demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-1, while HER2 overexpression improved the transcription of MMP-1 through the activation of an MMP-1 promoter. The promoter region of MMP-1 between -2500 and -2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (-70 to+63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-1 was knocked down. Conversely, the overexpression of MMP-1 partly rescued the invasion ability of cell strains with knocked-down HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-1 may be required to effectively block HER2 signaling in gastric cancer therapy.

The proapoptotic activity of C-terminal domain of apoptosis-inducing factor (AIF) is separated from its N-terminal.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that mediates both NADH-oxidizing and caspase-independent apoptosis. Further, the proapoptotic activity of AIF is located in the C-terminus of AIF, although the precise minimum sequence responsible for apoptosis induction remains to be investigated. In the present study, we generated two truncated AIFs, AIFDelta1-480-FLAG, which is a FLAG-tagged C-terminal peptide comprising amino acids from 481 to 613, and AIF360-480 containing amino acids from 360 to 480 of AIF. We used confocal microscopy to demonstrate that both the truncated proteins are expressed and located in the cytoplasm of transfected cells. AIFDelta1-480 but not AIF360-480 induces apoptosis in transfected cells. We also found that the expression of AIFDelta1-480 could initiate the release of cytochrome c from the mitochondria. The suppression of caspase-9 via siRNA blocked the proapoptotic activity of AIFDelta1-480. Therefore, AIFDelta1-480 is sufficient for inducing caspase-9-dependent apoptotic signaling, probably by promoting the release of cytochrome c. At last, we generated a chimeric immuno-AIFDelta1-480 protein, which comprised an HER2 antibody, a Pseudomonas exotoxin A translocation domain and AIFDelta1-480. Human Jurkat cells transfected with the immuno-AIFDeltal-480 gene could express and secrete the chimeric protein, which selectively recognize and kill HER2-overexpressing tumor cells. Our study demonstrates the feasibility of the immuno-AIFDeltal-480 gene as a novel approach to treating HER2-overexpressing cancers.

Inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering RNAs targeting HER2/neu.

Amplification and over-expression of HER2/neu oncogene is found in diverse types of human cancers, and is closely related to tumor occurrence, metastasis, angiogenesis and chemotherapy resistance. Therapeutic agents targeting HER2/neu have been intensively addressed over the past decades. In non-small cell lung cancers (NSCLCs), the prevalence of HER2/neu activation, its role in prognosis, and its possible implications as a therapeutic target, are still to be elucidated. Here we show that the abundant or moderate over-expression of HER2/neu could be detected in both pulmonary adenocarcinoma and pulmonary large cell carcinoma cell lines. Stable knockdown of HER2/neu expression in the NSCLC cell line SPC-A-1 was achieved by vector-based small interfering RNAs (siRNAs), which consequently caused significant decrease in cell proliferation and clone forming efficiency, as well as cell cycle arrest at G(1) phase. Compared with the parental NSCLC cells, HER2/neu knockdown cells exhibited attenuated capacities in developing tumors in nude mice, and the growth tumors xenografts derived from these cells were dramatically regressed. These data provided direct evidence that HER2/neu signaling is essential for tumorigenicity of NSCLC cells, and suggested that siRNAs targeted to HER2/neu may provide a novel therapeutic strategy in the treatment of NSCLC, especially when combined with traditional therapeutics or via development of vector-based siRNAs of multiple targets that synergistically contribute to carcinogenesis, e.g. EGFR and HER2/neu.

The proapoptotic activity of C-terminal domain of apoptosis-inducing factor (AIF) is separated from its N-terminal

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that mediates both NADH-oxidizing and caspase-independent apoptosis. Further, the proapoptotic activity of AIF is located in the C-terminus of AIF, although the precise minimum sequence responsible for apoptosis induction remains to be investigated. In the present study, we generated two truncated AIFs, AIFΔ1-480-FLAG, which is a FLAG-tagged C-terminal peptide comprising amino acids from 481 to 613, and AIF360-480 containing amino acids from 360 to 480 of AIF. We used confocal microscopy to demonstrate that both the truncated proteins are expressed and located in the cytoplasm of transfected cells. AIFΔ1-480 but not AIF360-480 induces apoptosis in transfected cells. We also found that the expression of AIFΔ1-480 could initiate the release of cytochrome c from the mitochondria. The suppression of caspase-9 via siRNA blocked the proapoptotic activity of AIFΔ1-480. Therefore, AIFΔ 1-480 is sufficient for inducing caspase-9-dependent apoptotic signaling, probably by promoting the release of cytochrome c. At last, we generated a chimeric immuno-AIFΔ 1-480 protein, which comprised an HER2 antibody, a Pseudomonas exotoxin A translocation domain and AIFΔ 1-480. Human Jurkat cells transfected with the immuno-AIFΔl-480 gene could express and secrete the chimeric protein, which selectively recognize and kill HER2-overexpressing tumor cells. Our study demonstrates the feasibility of the immuno-AIFΔl-480 gene as a novel approach to treating HER2-overexpressing cancers.

Involvement of metastasis tumor antigen 1 in hepatic regeneration and proliferation.

BACKGROUND/AIMS: Metastasis tumor antigen 1 (MTA1), an integral part of nucleosome remodeling and histone deacetylation (NuRD) complexes, is well correlated with the potential of metastasis, with the ability to regulate divergent cellular pathways by modifying the acetylation status of crucial target genes. However, additional biological functions of this molecule remain largely unexplored. This study was undertaken to explore the potential role of this molecule in mouse liver. METHODS: MTA1 expression was firstly explored in mouse partial hepatectomy model (PHx). The effect of overexpression of MTA1 on hepatic proliferation and differentiation was then examined in vivo by hydrodynamic-based gene transfer method and in vitro using transformed cell line AML12 overexpressing MTA1, respectively. RESULTS: Consistent with the hepatic regeneration, MTA1 expression was significantly increased 24h post-PHx, with a maximum level at 48h after PHx. MTA1 immunoreactivity was generally elevated right after PHx and the staining appeared to experience a cytoplasm-to-nuclear transition. Overexpression of exogenous MTA1 could notably stimulate hepatic proliferation in vivo and could also accelerate hepatocyte differentiation in vitro. CONCLUSION: These data underscore a hepatocelluar facet of this recently defined molecule, which may represent as a novel regulator and a new therapeutic target for the treatment of impaired liver.

Stable knockdown of estrogen receptor alpha by vector-based RNA interference suppresses proliferation and enhances apoptosis in breast cancer cells.

Breast cancer, the most common malignancy in women, has a known association with the steroid hormone estrogen. Estrogen receptor alpha (ERalpha) plays an important role in the clinical care of breast cancer patients, both as a prognostic factor and as a therapeutic target. Here, we show that a small interfering RNA (siRNA) against ERalpha downregulates ERalpha expression in human MCF-7 and Bcap-37 breast cancer cells, causing a significant decrease in breast cancer cell proliferation. Tumor cells lacking ERalpha expression grew at a much slower rate than did control cells in vitro. Moreover, ERalpha knockdown in breast cancer cells resulted in decreased, even completely abrogated tumor growth in BALB/c nude mice, providing direct evidence for an essential role of ERalpha in breast cancer growth. Our results suggest siRNA-mediated gene silencing of ERalpha may impair tumorigenicity, and even suppress the tumor growth.