Hepatic serum amyloid A1 upregulates interleukin-17 (IL-17) in γδ T cells through Toll-like receptor 2 and is associated with psoriatic symptoms in transgenic mice.

Serum amyloid A (SAA) is an acute phase protein with pro-inflammatory cytokine-like properties. Recent studies have revealed that SAA promoted interleukin-17 (IL-17) production by various cells, including γδ T cells. γδ T cells are innate immune cells and express Toll-like receptor 2 (TLR2) on their surface, which is one of the SAA receptors. In this study, we investigated the relationship between γδ T cells and SAA1 through TLR2, by using hepatic SAA1-overexpressing transgenic (TG) mice. By injecting CU-CPT22, which is a TLR2 inhibitor, into the mice, we confirmed that SAA1 induced IL-17 in γδ T cells through TLR2. In vitro studies have confirmed that SAA1 increased IL-17 secretion in γδ T cells in combination with IL-23. We also observed a thickened epidermis layer and granulocyte penetration into the skin similar to the pathology of psoriasis in TG mice. In addition, strongly expressed SAA1 and penetration of γδ T cells in the skin of TG mice were detected. The exacerbation of psoriasis is associated with an increase in IL-17 levels. Therefore, these symptoms were induced by IL-17-producing γδ T cells increased by SAA1. Our study confirmed that SAA1 was a prominent protein that increased IL-17 levels through TLR2 in γδ T cells, confirming the possibility that SAA1 may exacerbate inflammatory diseases through γδ T cells.

Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment, progressive neurodegeneration, and amyloid-ß (Aß) lesion. In the neuronal death and disease progression, inflammation is known to play an important role. Our previous study on acute-phase protein serum amyloid A1 (SAA1) overexpressed mice showed that the liver-derived SAA1 accumulated in the brain by crossing the brain blood barrier (BBB) and trigger the depressive-like behavior on mouse. Since SAA1 involved in immune responses in other diseases, we focused on the possibility that SAA1 may exacerbate the neuronal inflammation related to Alzheimer's disease. A APP/SAA overexpressed double transgenic mouse was generated using amyloid precursor protein overexpressed (APP)-c105 mice and SAA1 overexpressed mice to examine the function of SAA1 in Aß abundant condition. Comparisons between APP and APP/SAA1 transgenic mice showed that SAA1 exacerbated amyloid aggregation and glial activation; which lead to the memory decline. Behavior tests also supported this result. Overall, overexpression of SAA1 intensified the neuronal inflammation in amyloid abundant condition and causes the greater memory decline compared to APP mice, which only expresses Aß 1-42.

Lin28a expression protects against streptozotocin-induced ß-cell destruction and prevents diabetes in mice.

Lin28, which is highly expressed during embryogenesis, has been shown to play an important role in cell growth and embryonic development. Meanwhile, Lin28 represses let-7 miRNA biogenesis and block pre-let-7 processing in the cytoplasm. The let-7 family of miRNAs is known to repress oncogenesis and cell cycle progression by targeting oncogenic genes and signalling pathways. Consequently, Lin28 acts as an oncogene by upregulating let-7 targets through the repression of let-7 biogenesis. A recent genome-wide association study (GWAS) showed that many genes related to Type 2 diabetes (T2D) are also oncogenes or cell cycle regulators. The role of Lin28 in mouse growth and glucose metabolism in metabolic-related tissues has also been studied. In these studies, whole-body Lin28 overexpression was found to promote glucose utilization and prevent weight gain by inhibiting let-7 biogenesis. Furthermore, Lin28 has been found to directly stimulate skeletal myogenesis and cell growth. Therefore, we determined whether similar effects mediated by Lin28a, which is essential for cell growth and proliferation, may also apply to pancreatic ß-cells. We found that overexpression of Lin28a protects pancreatic ß-cells from streptozotocin (STZ)-induced ß-cell destruction in vitro and in vivo. Furthermore, Lin28a-overexpressing transgenic (Tg) mice had higher insulin secretion in the presence of glucose than in control mice. Our findings suggest that the Lin28/let-7 axis is an important regulator of pancreatic ß-cell functions and that precise modulation of this axis may be helpful in treating metabolic diseases such as diabetes. SIGNIFICANCE OF THE STUDY: We demonstrate that Lin28a prevents pancreatic ß-cell death against streptozotocin (STZ)-induced ß-cell destruction in vitro and in vivo. Furthermore, Lin28a promotes cell survival and proliferation by activating the PI3K-Akt signalling pathway, which may be dependent on let-7 regulation. Taken together, our results imply that the Lin28a/let-7 axis is an important regulator of pancreatic ß-cell functions and that precise modulation of this axis may be helpful in treating metabolic diseases such as diabetes.

Critical roles of hMAGEA2 in induced pluripotent stem cell pluripotency, proliferation, and differentiation.

Induced pluripotent stem (iPS) cells are important for clinical application and stem cell research. Although human melanoma-associated antigen A2 (hMAGEA2) expression is known to affect differentiation in embryonic stem cells, its specific role in iPS cells remains unclear. To evaluate the function of hMAGEA2 and its characteristics in iPS cells, we produced hMAGEA2-overexpressing iPS cells from hMAGEA2-overexpressing transgenic mice. Although the iPS cells with overexpressed hMAGEA2 did not differ in morphology, their pluripotency, and self-renewal related genes (Nanog, Oct3/4, Sox2, and Stat3), expression level was significantly upregulated. Moreover, hMAGEA2 contributed to the promotion of cell cycle progression, thereby accelerating cell proliferation. Through embryoid body formation in vitro and teratoma formation in vivo, we demonstrated that hMAGEA2 critically decreases the differentiation ability of iPS cells. These data indicate that hMAGEA2 intensifies the self-renewal, pluripotency, and degree of proliferation of iPS cells, while significantly repressing their differentiation efficiency. Therefore, our findings prove that hMAGEA2 plays key roles in iPS cells.

Critical role of Rgs19 in mouse embryonic stem cell proliferation and differentiation.

Mouse embryonic stem cells (ESCs) are self-renewing, pluripotent, and have the ability to differentiate into the three germ layers required to form all embryonic tissues. These properties are maintained by both intrinsic and extrinsic factors. Many studies have contributed to the understanding of the molecular signal transduction required for pluripotency and controlled differentiation. Such an understanding is important in the potential application of stem cells to cell therapy for disease, and thus there is an interest in understanding the cell cycle regulation, pluripotency, and differentiation of ESCs. The regulator of G protein signaling (RGS) family consists of over 20 members. Rgs19, one such protein, specifically interacts with Gαi to enhance its GTPase activity. Growth factor receptors use Gi proteins for signal transduction, and Rgs19 may thus be involved in the regulation of cell proliferation. In a previous gain-of-function study, Rgs19 overexpression was found to enhance proliferation in various cell types. Our data demonstrate a role for Rgs19 in the regulation of ESC differentiation. Based on the presence of Rgs19 in ESCs, the morphological and molecular properties of wild-type and Rgs19 +/- ESCs during LIF withdrawal, in vitro differentiation, and teratoma formation were compared. Our findings provide insight for the first time into the mechanisms involved in Rgs19 regulation of mouse ESC proliferation and differentiation.

Gestational loss and growth restriction by angiogenic defects in placental growth factor transgenic mice.

OBJECTIVE: Angiogenesis is an important biological process during development, reproduction, and in immune responses. Placental growth factor (PlGF) is a member of vascular endothelial growth factor that is critical for angiogenesis and vasculogenesis. We generated transgenic mice overexpressing PlGF in specifically T cells using the human CD2-promoter to investigate the effects of PlGF overexpression. APPROACH AND RESULTS: Transgenic mice were difficult to obtain owing to high lethality; for this reason, we investigated why gestational loss occurred in these transgenic mice. Here, we report that placenta detachment and inhibition of angiogenesis occurred in PlGF transgenic mice during the gestational period. Moreover, even when transgenic mice were born, their growth was restricted. CONCLUSIONS: Conclusively, PlGF overexpression prevents angiogenesis by inhibiting Braf, extracellular signal-regulated kinase activation, and downregulation of HIF-1α in the mouse placenta. Furthermore, it affected regulatory T cells, which are important for maintenance of pregnancy.

[6]-shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascades is considered to be a rational therapeutic and preventive strategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components, including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclin D1/3, which are target proteins in the Akt signaling pathway. The induction of apoptosis in NCI-H1650 cells by [6]-shogaol corresponded with the cleavage of caspase-3 and caspase-7. Moreover, intraperitoneal administration of [6]-shogaol inhibited the growth of NCI-H1650 cells as tumor xenografts in nude mice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.

Over-expression of Roquin aggravates T cell mediated hepatitis in transgenic mice using T cell specific promoter.

Chronic hepatitis is a major cause of liver cancer, so earlier treatment of hepatitis might be reducing liver cancer incidence. Hepatitis can be induced in mice by treatment with Concanavalin A (Con A); the resulting liver injury causes significant CD4(+) T cell activation and infiltration. In these T cells, Roquin, a ring-type E3 ubiquitin ligase, is activated. To investigate the role of Roquin, we examined Con A-induced liver injury and T cell infiltration in transgenic (Tg) mice overexpressing Roquin specifically in T cells. In Roquin Tg mice, Con A treatment caused greater increases in both the levels of liver injury enzymes and liver tissue apoptosis, as revealed by TUNEL and H&E staining, than wild type (WT) mice. Further, Roquin Tg mice respond to Con A treatment with greater increases in the T cell population, particularly Th17 cells, though Treg cell counts are lower. Roquin overexpression also enhances increases in pro-inflammatory cytokines, including IFN-γ, TNF-α and IL-6, upon liver injury. Furthermore, Roquin regulates the immune response and apoptosis in Con A induced hepatitis via STATs, Bax and Bcl2. These findings suggest that over-expression of Roquin exacerbates T-cell mediated hepatitis.

Overexpression of Jazf1 reduces body weight gain and regulates lipid metabolism in high fat diet.

Jazf1 is a 27 kDa nuclear protein containing three putative zinc finger motifs that is associated with diabetes mellitus and prostate cancer; however, little is known about the role that this gene plays in regulation of metabolism. Recent evidence indicates that Jazf1 transcription factors bind to the nuclear orphan receptor TR4. This receptor regulates PEPCK, the key enzyme involved in gluconeogenesis. To elucidate Jazf1's role in metabolism, we fed a 60% fat diet for up to 15 weeks. In Jazf1 overexpression mice, weight gain was found to be significantly decreased. The expression of Jazf1 in the liver also suppressed lipid accumulation and decreased droplet size. These results suggest that Jazf1 plays a critical role in the regulation of lipid homeostasis. Finally, Jazf1 may provide a new therapeutic target in the management of obesity and diabetes.

Effect of novel cyclohexane diester and benzene diester derivatives on melanogenesis.

In order to investigate potent whitening agents, we synthesized 15 cyclohexane diester derivatives and 15 benzene diester derivatives. To evaluate their structure-cytotoxicity relationships, we performed cell cytotoxicity tests on B16F10 mouse melanoma cells. To understand their whitening effects, melanin synthesis inhibitory activities in B16F10 cells and mushroom tyrosinase inhibitory activities were performed. In most cases, cell cytotoxicity was observed to be lower in 1,3-diester than in 1,2- and 1,4-diesters; when it came to the structural isomer of the side chain, all derivatives except the 1,2-cyclohexane diester derivatives showed lower cell cytotoxicity in the branch type of the side chain than in the linear type. Among the compounds evaluated, the compounds cyclohexane-1,3-diyl bis(decanoate), cyclohexane-1,4-diyl dioctanoate, and 1,3-phenylene bis (2-ethylhexanoate) emerged as potent melanin synthesis inhibitors. Our goal was to determine the expression levels of proteins involved in melanogenesis, Western blotting and RT-PCR showing that these compounds decreased tyrosinase, TRP-1, and TRP-2 while demonstrating significantly low cytotoxicity.

Enforced expression of roquin protein in T cells exacerbates the incidence and severity of experimental arthritis.

To investigate the role of Roquin, a RING-type ubiquitin ligase family member, we used transgenic mice with enforced Roquin expression in T cells, with collagen-induced arthritis (CIA). Wild-type (WT) and Roquin transgenic (Tg) mice were immunized with bovine type II collagen (CII). Arthritis severity was evaluated by clinical score; histopathologic CIA severity; proinflammatory and anti-inflammatory cytokine levels; anti-CII antibody levels; and populations of Th1, Th2, germinal center B cells, and follicular helper T cells in CIA. T cell proliferation in vitro and cytokine levels were determined to assess the response to CII. Roquin Tg mice developed more severe CIA and joint destruction compared with WT mice. Production of TNF-α, IFN-γ, IL-6, and pathogenic anti-collagen CII-specific IgG and IgG2a antibodies was increased in Roquin Tg mice. In addition, in vitro T cell assays showed increased proliferation and proinflammatory cytokine production in response to CII as a result of enforced Roquin expression in T cells. Furthermore, the Th1/Th2 balance was altered by an increased Th1 and decreased Th2 population. These findings suggest that overexpression of Roquin exacerbates the development of CIA and that enforced expression of Roquin in T cells may promote autoimmune diseases such as CIA.

Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis.

OBJECTIVE: Calcineurin-binding protein 1 (CABIN-1) regulates calcineurin phosphatase activity as well as the activation, apoptosis, and inflammatory responses of fibroblast-like synoviocytes (FLS), which actively participate in the chronic inflammatory responses in rheumatoid arthritis (RA). However, the mechanism of action of CABIN-1 in FLS apoptosis is not clear. This study was undertaken to define the regulatory role of CABIN-1 in FLS from mice with collagen-induced arthritis (CIA). METHODS: Transgenic mice overexpressing human CABIN-1 in joint tissue under the control of a type II collagen promoter were generated. Expression of human CABIN-1 (hCABIN-1) in joints and FLS was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of cytokines, matrix metalloproteinases (MMPs), and apoptosis-related genes in FLS was determined by enzyme-linked immunosorbent assay, gelatin zymography, and RT-PCR, respectively. Joints were stained with hematoxylin and eosin and with tartrate-resistant acid phosphatase for histologic analysis. RESULTS: Human CABIN-1-transgenic mice with CIA had less severe arthritis than wild-type mice with CIA, as assessed according to hind paw thickness and histologic features. The milder arthritis was accompanied by significantly enhanced apoptosis in transgenic mice, evidenced by a significantly greater number of TUNEL-positive cells in synovial tissue. Expression of inflammatory cytokines and MMPs in the transgenic mice with CIA was reduced, and they exhibited decreased Akt activation and increased expression of p53, caspase 3, caspase 9, and Bax. CONCLUSION: Our findings demonstrate that hCABIN-1 plays a critical role in promoting apoptosis of FLS and in attenuating inflammation and cartilage and bone destruction in RA. These results help elucidate the pathogenic mechanisms of RA and suggest that CABIN-1 is a potential target for treatment of this disease.

The role of Roquin overexpression in the modulation of signaling during in vitro and ex vivo T-cell activation.

The T-cell receptor (TCR) engages with an antigen and initiates a signaling cascade that leads to the activation of transcription factors. Roquin, a protein encoded by the RC3H1 gene and characterized as an immune regulator, was recently identified as a novel RING-type ubiquitin ligase family member, but the mechanisms by which Roquin regulates T-cell responses are unclear. We used the EL-4 murine lymphoma cell line to elucidate the role of Roquin in vitro. Roquin-overexpressing EL-4 cells became hyper-responsive after anti-CD3/CD28 stimulation in vitro and were a major source of the cytokines IL-2 and TNF-α. Upon activation, these cells showed particularly enhanced production of IL-2 and TNF-α. To clarify the important role played by Roquin in T-cell responses ex vivo, we generated T-cell-specific Roquin transgenic (Tg) mice. Roquin-Tg CD4(+) T-cells showed enhanced production of IL-2 and TNF-α in response to TCR stimulation with anti-CD28 co-stimulation. Further studies are necessary to investigate the role of Roquin in the regulation of primary T-cell activation, survival, and differentiation.

Jazf1 acts as a regulator of insulin-producing ß-cell differentiation in induced pluripotent stem cells and glucose homeostasis in mice.

Genetic susceptibility of type 2 diabetes and Juxtaposed with another zinc finger protein 1 (Jazf1) has been reported; however, the precise role of Jazf1 in metabolic processes remains elusive. In this study, using Jazf1-knockout (KO)-induced pluripotent stem cells (iPSC), pancreatic beta cell line MIN6 cells, and Jazf-1 heterozygous KO (Jazf1+/- ) mice, the effect of Jazf1 on gradual differentiation was investigated. We checked the alterations of the genes related with ß-cell specification, maturation, and insulin release against glucose treatment by the gain and loss of the Jazf1 gene in the MIN6 cells. Because undifferentiated Jazf1-KO iPSC were not significantly different from wild-type (WT) iPSC, the size and endoderm marker expression after embryoid body (EB) and teratoma formation were investigated. Compared to EB and teratomas formed with WT iPSC, the EB and teratomas from with Jazf1-KO iPSC were smaller, and in teratomas, the expression of proliferation markers was reduced. Moreover, the expression of the gene sets for ß-cell differentiation and the levels of insulin and C-peptide secreted by insulin precursor cells were notably reduced in ß-cells differentiated from Jazf1-KO iPSC compared with those differentiated from WT iPSC. A comparison of Jazf1+/- and WT mice showed that Jazf1+/- mice had lower levels of serum insulin, pancreatic insulin expression, and decreased pancreatic ß-cell size, which resulted in defects in the glucose homeostasis. These findings suggest that Jazf1 plays a pivotal role in the differentiation of ß-cells and glucose homeostasis.

JAZF1 heterozygous knockout mice show altered adipose development and metabolism.

BACKGROUND: Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models. RESULTS: The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ-a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency. CONCLUSION: Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders.

Effects of Dimethyl Sulfoxide on the Pluripotency and Differentiation Capacity of Mouse Embryonic Stem Cells.

Mouse embryonic stem cells (mESCs) go through self-renewal in the existence of the cytokine leukemia inhibitory factor (LIF). LIF is added to the mouse stem cells culture medium, and its removal results in fast differentiation. Dimethyl sulfoxide (DMSO) is one of the most used solvents in drug test. We exposed 4-day mESC cultures to different concentrations of DMSO (0.1%, 0.5%, 1.0%, and 2.0%) to identify the safest dose exhibiting efficacy as a solvent. mESCs grown under general pluripotency conditions in the absence of LIF were treated with DMSO. In addition, as a control for differentiation, mESCs were grown in the absence of LIF. DMSO upregulated the mRNA expression level of pluripotency markers. Moreover, DMSO reduced the mRNA expression levels of ectodermal marker (ß-tubulin3), mesodermal marker (Hand1), and endodermal markers (Foxa2 and Sox17) in mESCs. These results indicate that DMSO treatment enhances the pluripotency and disrupts the differentiation of mESCs. We also show that members of the Tet oncogene family are critical to inhibiting the differentiation and methylation of mESCs. DMSO is appropriate to sustain the pluripotency of mESCs in the absence of LIF, and that mESCs can be sustained in an undifferentiated state using DMSO. Therefore, DMSO may, in part, function as a substitute for LIF.

Effects of Cr, W, and Mo on the High Temperature Oxidation of Ni-Based Superalloys.

The oxidation behavior of Ni-9.5Co-(8~12)Cr-(2.5~5.5)Mo-(4~8)W-3Al-5Ti-3Ta-0.1C-0.01B alloys was investigated at 850 °C and 1000 °C The mass change, the phase of oxides, and the cross-sectional structure of specimens were analyzed after cyclic oxidation tests. The oxide scale was composed mainly of Cr2O3 and NiCr2O4, but NiO, TiO2, and CrTaO4 were also found. Al2O3 was formed beneath the Cr oxide layer. The Cr oxide layer and internal Al oxide acted as barriers to oxidation at 850 °C, while Al oxide was predominantly protective at 1000 °C. Cr increased the mass gain after oxidation test at both temperatures. Mo increased the oxidation rate at 850 °C but decreased the oxidation rate at 1000 °C. W slightly increased the mass gain at 850 °C but did not produce a significant effect at 1000 °C. The effects of Cr, Mo, W, and the temperature were discussed as well as the volatilization of oxides, the valence number of elements, and diffusion retardation.

Jazf1 promotes prostate cancer progression by activating JNK/Slug.

Juxtaposed with another zinc finger protein 1 (Jazf1) is a zinc finger protein and is known to affect both prostate cancer and type 2 diabetes. Jazf1 inhibits testicular nuclear receptor 4 (TR4) activation through protein-protein interaction, which results in weight loss and alleviates diabetes. However, the role of Jazf1 in prostate cancer is still poorly understood. Hence, we investigated whether the expression of Jazf1 is associated with prostate cancer progression. We confirmed the upregulation of Jazf1 expression in human prostate tissue samples. In addition, using Jazf1 overexpressing prostate cancer cell lines, DU145 and LNCaP, we found Jazf1 promoted cell proliferation and colony formation ability. We also observed that Jazf1 dramatically enhanced cell migration and invasion in transwell assays. Additionally, we checked the upregulation of vimentin and downregulation of E-cadherin expression in Jazf1-overexpressing DU145 and LNCaP cells. Moreover, we found that Slug, which is known to be regulated by JNK/c-Jun phosphorylation, was upregulated in the microarray analysis of two prostate cancer cell lines. Jazf1 promotes the phosphorylation of JNK/c-Jun, likely promoting cell proliferation and invasion through Slug. In a xenograft model, tumors overexpressing Jazf1 were larger than control tumors, and tumors with decreased Jazf1 were smaller. These data indicated that Jazf1 enhances prostate cancer progression and metastasis via regulating JNK/Slug signaling. Taken together, these results suggest that Jazf1 plays an important role in both androgen dependent and independent prostate cancer.

hMAGEA2 promotes progression of breast cancer by regulating Akt and Erk1/2 pathways.

Breast cancer is the most abundant cancer worldwide and a severe problem for women. Notably, breast cancer has a high mortality rate, mainly because of tumor progression and metastasis. Triple-negative breast cancer (TNBC) is highly progressive and lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Therefore, there are no established therapeutic targets against TNBC. In this study, we investigated whether the expression of human melanoma-associated antigen A2 (MAGEA2) is associated with TNBC. We found that hMAGEA2 is significantly overexpressed in human TNBC tissues; we also observed oncogenic properties using TNBC cell lines (MDA-MB-231 and MDA-MB-468). The overexpression of hMAGEA2 in MDA-MB-231 cell line showed dramatically increased cellular proliferation, colony formation, invasion, and xenograft tumor formation and growth. Conversely, knockdown of hMAEGA2 in MDA-MB-468 cell line suppressed cellular proliferation, colony formation, and xenograft tumor formation. Additionally, we showed that hMAGEA2 regulated the activation of Akt and Erk1/2 signaling pathways. These data indicate that hMAGEA2 is important for progression of TNBC and may serve as a novel molecular therapeutic target.

Serum amyloid A1 levels and amyloid deposition following a high-fat diet challenge in transgenic mice overexpressing hepatic serum amyloid A1.

Serum amyloid A (SAA) is an acute-phase response protein in the liver, and SAA1 is the major precursor protein involved in amyloid A amyloidosis. This amyloidosis has been reported as a complication in chronic inflammatory conditions such as arthritis, lupus, and Crohn's disease. Obesity is also associated with chronic, low-grade inflammation and sustained, elevated levels of SAA1. However, the contribution of elevated circulating SAA1 to metabolic disturbances and their complications is unclear. Furthermore, in several recent studies of transgenic (TG) mice overexpressing SAA1 that were fed a high-fat diet (HFD) for a relatively short period, no relationship was found between SAA1 up-regulation and metabolic disturbances. Therefore, we generated TG mice overexpressing SAA1 in the liver, challenged these mice with an HFD, and investigated the influence of elevated SAA1 levels. Sustained, elevated levels of SAA1 were correlated with metabolic parameters and local cytokine expression in the liver following 16 weeks on the HFD. Moreover, prolonged consumption (52 weeks) of the HFD was associated with impaired glucose tolerance and elevated SAA1 levels and resulted in systemic SAA1-derived amyloid deposition in the kidney, liver, and spleen of TG mice. Thus, we concluded that elevated SAA1 levels under long-term HFD exposure result in extensive SAA1-derived amyloid deposits, which may contribute to the complications associated with HFD-induced obesity and metabolic disorders.