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Activation and proliferation - Top 30 Publications

The TCP4 transcription factor regulates trichome cell differentiation by directly activating GLABROUS INFLORESCENCE STEMS in Arabidopsis thaliana.

Trichomes are the first cell type to be differentiated during the morphogenesis of leaf epidermis and serve as an ideal model to study cellular differentiation. A large number of genes involved in the patterning and differentiation of trichome cells have been studied over past decades, and the majority of these genes encode transcription factors that specifically regulate epidermal cell development. However, the upstream regulators of these genes that link early leaf morphogenesis with cell type differentiation are less studied. The TCP proteins are the plant specific transcription factors involved in regulating diverse aspects of plant development including lateral organ morphogenesis by modulating cell proliferation and differentiation. Here, we show that the miR319-regulated class II TCP proteins, notably TCP4, suppress trichome branching in Arabidopsis leaves and inflorescence stem by direct transcriptional activation of GLABROUS INFLORESCENCE STEMS (GIS), a known negative regulator of trichome branching. The trichome branch number is increased in plants with reduced TCP activity and decreased in the gain-of-function lines of TCP4. Biochemical analyses show that TCP4 binds to the upstream regulatory region of GIS and activates its expression. Detailed genetic analyses show that GIS and TCP4 work in same pathway and GIS function is required for TCP4-mediated regulation of trichome differentiation. Taken together, these results identify a role for the class II TCP genes in trichome differentiation, thus providing a connection between organ morphogenesis and cellular differentiation. This article is protected by copyright. All rights reserved.

Down-regulation of miR-378a-3p induces decidual cell apoptosis: a possible mechanism for early pregnancy loss.

Do microRNAs (miRNAs) contribute to human early pregnancy loss (EPL)?

Bortezomib in Kidney Transplant: Current use and Perspectives.

Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders.

Ibrutinib and idelalisib block immunophenotypic changes associated with the adhesion and activation of CLL cells in the tumor microenvironment.

The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow.

Capillarisin blocks prostate-specific antigen expression on activation of androgen receptor in prostate carcinoma cells.

Capillarisin (Cap), an active ingredient of Artemisia capillaris extracts, has known for its anti-inflammatory, antioxidant, and anticancer properties. Functions of Cap in prostate cancer are not clear. We investigate effects of Cap on downregulation of prostate specific antigen (PSA) via modulation of androgen receptor (AR) in prostate carcinoma cells.

ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer.

Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt-PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of this study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non-small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression-free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen-activated protein kinase (MAPK) pathway in a RhoA-independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR-29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR-29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients. This article is protected by copyright. All rights reserved.

miR-15a-5p suppresses endometrial cancer cell growth via Wnt/β-catenin signaling pathway by inhibiting WNT3A.

Endometrial cancer is one of the three most common types of gynecologic cancer. The global incidence has increased in recent years. microRNAs (miRNAs) regulate numerous biological processes by binding to the 3'UTR of target mRNA to down-regulate protein synthesis.

Inhibition of epidermal growth factor receptor by ferulic acid and 4-vinylguaiacol in human breast cancer cells.

To examine the potential of ferulic acid and 4-vinylguaiacol for inhibiting epidermal growth factor receptor (EGFR) in human breast cancer cells in vitro.

Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis.

Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.

Maternal histone acetyltransferase KAT8 is required for porcine preimplantation embryo development.

K (lysine) acetyltransferase 8 (KAT8), an acetyltransferase that specifically catalyzes histone H4 lysine 16 acetylation, is critical for key biological processes including cell proliferation and maintenance of genome stability. However, the role of KAT8 during preimplantation development in pigs remains unclear. Results herein showed that KAT8 mRNA is maternally derived and it is required for successful development of early embryos. An abundance of KAT8 transcripts are expressed in oocytes and its abundance continuously decreases throughout meiotic maturation and preimplantation development. In addition, KAT8 expression is insensitive to RNA polymerase II inhibitor after embryonic genome activation, suggesting its maternal origin. The levels of KAT8 mRNA and H4K16 acetylation were effectively knocked down by siRNA microinjection. Knockdown of KAT8 significantly reduced the blastocyst formation rate and total cell number per blastocyst. Analysis of trophectoderm lineage and marker of DNA double-strand breaks revealed that the impaired developmental competence and quality of embryos might be attributed to defects in both the first two lineages development and genome integrity. Taken together, these results demonstrate that maternal KAT8 is indispensible for porcine early embryo development potentially through maintaining the proliferation of the first two lineages and genome integrity.

Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models.

Immune checkpoint blockers (ICB) have emerged as a promising new class of antitumor agents which significantly change the treatment landscape in a range of tumors; however, cancer patients benefited from ICB-based immunotherapy remains limited, scoring the need to explore the combination treatments with synergistic mechanisms of action. Axl receptor tyrosine kinase critically involves in the carcinogenesis of multiple cancers due to its dual roles in both promoting cancer invasion and metastasis and suppressing myeloid cell activation and function. Here, we found that Axl inhibition by tyrosine kinase inhibitors induces antitumor efficacy critically depending on immune effector mechanisms in two highly clinical relevant murine tumor models. Mechanistic investigation defined that Axl inhibition reprograms the immunological microenvironment leading to the increased proliferation, activation and effector function of tumor-infiltrating CD4(+) and CD8(+) T cells possibly through preferential accumulation and activation of CD103(+) cross-presenting dendritic cells. More importantly, we show that Axl inhibition induces an adaptive immune resistance evidenced by unregulated PD-L1 expression on tumor cells and combined Axl inhibition with PD-1 blockade mounts a potent synergistic antitumor efficacy leading to tumor eradication. Thus, Axl-directed therapy in Axl expressing tumors could hold a great potential to subvert the innate and/or adaptive resistance to and broaden the coverage of population benefited from ICB-based immunotherapy.

Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines.

Human papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1α expression in HNSCC.

DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway.

The role of DHX15, a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in DHX15 (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, DHX15 was commonly overexpressed in AML patients and associated with poor overall survival (OS) (P=0.019) and relapse-free survival (RFS) (P=0.032). In addition, we found a distinct expression pattern of DHX15. DHX15 was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. DHX15 was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. DHX15 silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of DHX15 expression rescued cell viability and reduced cell apoptosis. In addition, we found that DHX15 was down-regulated when cell apoptosis was induced by ATO (arsenic trioxide); overexpression of DHX15 caused dramatic resistance to ATO-induced cell apoptosis, suggesting an important role for DHX15 in cell apoptosis. We further explored the mechanism of DHX15 in apoptosis and found that overexpression of DHX15 activated NF-kB transcription. Knockdown of DHX15 inhibited the nuclear translocation and activation of the NF-kB subunit P65 in leukemia cells. Several downstream targets of the NF-kB pathway were also down-regulated, and apoptosis-associated genes CASP3 and PARP were activated. In conclusion, this study represents the first demonstration that DHX15 plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML.

Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin.

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.

N-Myc downstream-regulated gene 2 restrains glycolysis and glutaminolysis in clear cell renal cell carcinoma.

Glycolysis and glutaminolysis are heavily involved in the metabolic reprogramming of cancer cells. The activation of oncogenes and inactivation of tumor suppressor genes has a marked effect on the cellular metabolic processes glycolysis and glutaminolysis. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that previous studies have demonstrated can inhibit the growth, proliferation and metastasis of clear cell renal cell carcinoma (ccRCC) cells. However, the function of NDRG2 in ccRCC metabolism remains unknown. In the present study, NDRG2 significantly inhibited the consumption of glucose and glutamine, as well as the production of lactate and glutamate in ccRCC. NDRG2 significantly suppressed the expression of glucose transporter 1, hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A, glutamine transporter ASC amino acid transporter 2 and glutaminase 1 at the mRNA (by quantitative polymerase chain reaction) and protein level (by western blot analysis), all of which are key regulators and enzymes in glycolysis and glutaminolysis. Data from the present study also revealed that overexpression of NDRG2 suppressed cell proliferation in ccRCC in vitro and in vivo, demonstrated by colony formation assays, wound healing assay and nude mouse transplantation tumor experiment. The present findings demonstrate for the first time that NDRG2 acts as a key inhibitor of glycolysis and glutaminolysis in ccRCC and could be a promising target for the metabolic treatment of ccRCC.

TRIM37 promotes tumor cell proliferation and drug resistance in pediatric osteosarcoma.

Osteosarcoma (OS) is among the most frequently occurring bone tumors, particularly in children. Clinical treatment of OS is limited due to several factors including resistance to chemotherapy drugs and metastasis, and the underlying molecular mechanisms remain unclear. In the present study, tripartite motif containing 37 (TRIM37) expression levels were upregulated in tumor samples and associated with the development of drug resistance in OS. Furthermore, chemotherapy drug treatment (doxorubicin, cisplatin and methotrexate) induced TRIM37 expression in OS cells in vitro. TRIM37 mRNA and protein were upregulated in 41 pediatric osteosarcoma clinical specimens. To further elucidate the effect of TRIM37, gain and loss-of-function analysis was performed. Overexpression of TRIM37 induced cell proliferation and drug resistance ability of OS cells, whilst TRIM37 knockdown suppressed cell growth rate and restored chemosensitivity. TRIM37-regulated genes were subsequently analyzed by expression microarray and gene set enrichment analysis. Using the Wnt/β-catenin inhibitor XAV-939, the present study demonstrated that TRIM37-induced chemoresistance is partially dependent on the activation of the Wnt/β-catenin signaling pathway. Collectively, the results of the present study suggest that TRIM37 may have a key role in the development of OS and in the ability for the cells to acquire drug resistance, thus it may be a novel target for the treatment of OS.

CD40L Expression Allows CD8(+) T Cells to Promote Their Own Expansion and Differentiation through Dendritic Cells.

CD8(+) T cells play an important role in providing protective immunity against a wide range of pathogens, and a number of different factors control their activation. Although CD40L-mediated CD40 licensing of dendritic cells (DCs) by CD4(+) T cells is known to be necessary for the generation of a robust CD8(+) T cell response, the contribution of CD8(+) T cell-expressed CD40L on DC licensing is less clear. We have previously shown that CD8(+) T cells are able to induce the production of IL-12 p70 by DCs in a CD40L-dependent manner, providing some evidence that CD8(+) T cell-mediated activation of DCs is possible. To better understand the role of CD40L on CD8(+) T cell responses, we generated and characterized CD40L-expressing CD8(+) T cells both in vitro and in vivo. We found that CD40L was expressed on 30-50% of effector CD8(+) T cells when stimulated and that this expression was transient. The expression of CD40L on CD8(+) T cells promoted the proliferation and differentiation of both the CD40L-expressing CD8(+) T cells and the bystander effector CD8(+) T cells. This process occurred via a cell-extrinsic manner and was mediated by DCs. These data demonstrate the existence of a mechanism where CD8(+) T cells and DCs cooperate to maximize CD8(+) T cell responses.

Chronic Inflammation Increases the Sensitivity of Mouse Treg for TNFR2 Costimulation.

TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. In vitro, TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported in vitro expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. In vivo application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression in vivo. These findings support the important role of TNFR2 for Treg cells in immune regulation.

MicroRNA-4443 Causes CD4+ T Cells Dysfunction by Targeting TNFR-Associated Factor 4 in Graves' Disease.

Aberrant CD4+ T cell function plays a critical role in the process of Graves' disease (GD). MicroRNAs (miRNAs) are important regulators of T cell activation, proliferation, and cytokine production. However, the contribution of miRNAs to CD4+ T cell dysfunction in GD remains unclear.

T-Cell Composition of the Lymph Node Is Associated with the Risk for Early Rejection after Renal Transplantation.

The T-cell composition within the lymph node (LN) of end-stage renal disease (ESRD) patients differs from the composition within the circulation. Activation of the alloreactive T-cell response within secondary lymphoid organs is important after organ transplantation. However, to date no data are present on LN T-cell subsets and the risk for acute rejection after kidney transplantation.

Different Non-Saccharomyces Yeast Species Stimulate Nutrient Consumption in S. cerevisiae Mixed Cultures.

The growing interest of the winemaking industry on the use of non-Saccharomyces starters has prompted several studies about the physiological features of this diverse group of microorganisms. The fact that the proposed use of these new starters will almost invariably involve either simultaneous or sequential inoculation with Saccharomyces cerevisiae has also driven the attention to the potential biological interactions between different starters during wine fermentation. Our current understanding is that alternative yeast starters will affect wine features by both direct and indirect mechanisms (through metabolic or other types of interactions with S. cerevisiae). There are still few studies addressing the question of yeast-yeast interactions in winemaking by a transcriptomic approach. In a previous report, we revealed early responses of S. cerevisiae and Torulaspora delbrueckii to the presence of each other under anaerobic conditions, mainly the overexpression of genes related with sugar consumption and cell proliferation. We have now studied the response, under aerobic conditions, of S. cerevisiae to other two non-Saccharomyces species, Hanseniaspora uvarum and Candida sake, keeping T. delbrueckii as a reference; and always focusing on the early stages of the interaction. Results point to some common features of the way S. cerevisiae modifies its transcriptome in front of other yeast species, namely activation of glucose and nitrogen metabolism, being the later specific for aerobic conditions.

Intravesicular administration of sodium hyaluronate ameliorates the inflammation and cell proliferation of cystitis cystica et glandularis involving interleukin-6/JAK2/Stat3 signaling pathway.

Cystitis cystica et glandularis (CCEG) is a chronic cystitis that causes extreme agony in affected patients. However, there are lack of effective conservative treatments. In this study, it is evident that intravesicular sodium hyaluronate (SH) therapy significantly improved the clinical symptoms of CCEG patients and ameliorated the bladder mucosal inflammation and cell proliferation characteristics of the disease. Immunohistochemical staining showed that the staining intensities of hyaluronidase (HYAL 1/2), CD44, IL-6 and phosphorylated signal transducer and activator of transcription 3 (p-Stat3) in bladder mucosal tissue were significantly increased in CCEG patients compared with control patients and that intravesicular SH treatment suppressed these protein expression. We established a CCEG rat model by treating rats with E. coli intravesicularly, and we found that HYAL 1/2 and CD44 expression levels were significantly increased in the E. coli group compared with the NC group. Activation of the IL-6/JAK2/Stat3 pathway and the expression levels of the downstream pro-apoptotic proteins Mcl-1 and Bcl-xL were also significantly increased in the E. coli group compared with the NC group. The above changes were significantly mitigated by intravesicular SH treatment. Therefore, SH may serve as an effective therapy for CCEG by inhibiting bladder mucosal inflammation and proliferation.

MiR-30e inhibits tumor growth and chemoresistance via targeting IRS1 in Breast Cancer.

MicroRNA-30e (miR-30e) is downregulated in various tumor types. However, its mechanism in inhibiting tumor growth of breast cancer remains to be elucidated. In this study, we found that miR-30e was significantly downregulated in tumor tissues of breast cancer (BC) patients and cell lines, and overexpression of miR-30e inhibited cell proliferation, migration and invasion. To understand the potential mechanism of miR-30e in inhibiting tumor growth, we showed that miR-30e blocked the activation of AKT and ERK1/2 pathways, and the expression of HIF-1α and VEGF via directly targeting IRS1. Moreover, miR-30e regulates cell proliferation, migration, invasion and increases chemosensitivity of MDA-MB-231 cells to paclitaxel by inhibiting its target IRS1. MiR-30e also inhibited tumor growth and suppressed expression of IRS1, AKT, ERK1/2 and HIF-1α in mouse xenograft tumors. To test the clinical relevance of these results, we used 40 pairs of BC tissues and adjacent normal tissues, analyzed the levels of miR-30e and IRS1 expression in these tissues, and found that miR-30e levels were significantly inversely correlated with IRS1 levels in these BC tissues, suggesting the important implication of our findings in translational application for BC diagnostics and treatment in the future.

ΔNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ∆Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.

PU.1-deficient mice are resistant to thioacetamide-induced hepatic fibrosis: PU.1 finely regulates Sirt1 expression via transcriptional promotion of miR-34a/-29c in HSCs.

PU.1 is a critical transcription factor involving in many pathological processes. However, its exact role in activation of hepatic stellate cells (HSCs) and liver fibrosis was rarely reported. Here, we found that, in HSCs of PU.1(+/-) mice, Sirt1 mRNA expression was not changed but Sirt1 protein was significantly increased, suggesting its promoting role in Sirt1 translation. We then isolated HSCs from WT and PU.1(+/-) mice, and the pcDNA-PU.1 expression vector was transfected into PU.1(+/-) HSCs. We checked the levels of miR-34a and miR-29c, two Sirt1-targeting miRNAs, and protein levels of PU.1 and Sirt1. The results showed that miR-34a/-29c were significantly reduced and Sirt1 protein was increased in PU.1(+/-) HSCs, compared with WT HSCs. Besides, PU.1 overexpression inversed the reduction of miR-34a/-29c levels and the increase of Sirt1 protein in both PU.1(+/-) HSCs and WT HSCs. Additionally, ChIP-qPCR assay comfirmed that PU.1 directly bound to both the promoter regions of miR-34a and miR-29c. Importantly, PU.1 overexpression promoted the proliferation, migration, activation, oxidative stress and inflammatory response in WT HSCs, while the promotion could be inversed by either overexpression of Sirt1 or inhibition of miR-34a/-29c. Moreover, animal model of liver fibrosis was established by intraperitoneal injections of thioacetamide (TAA) in WT and PU.1(+/-) mice respectively. Compared with the WT mice, PU.1(+/-) mice displayed a lower fibrotic score, less collagen content, better liver function, and lower levels of oxidative stress and inflammatory response. In conclusion, PU.1 suppresses Sirt1 translation via transcriptional promotion of miR-34a/-29c, thus promoting Sirt1-mediated HSC activation and TAA-induced hepatic fibrosis.

miR-335 inhibited cell proliferation of lung cancer cells by target Tra2β.

Accumulating evidence has suggested that the dysregulation of miRNAs is an important factor in the pathogenesis of lung cancer. Here, we demonstrate that miR-335 expression is reduced in non-small cell lung cancer (NSCLC) tumors relative to non-cancerous adjacent tissues, whilst the expression of Tra2β is increased. In addition, clinical data revealed that the increased Tra2β and decreased miR-335 expression observed in NSCLC cells was associated with poor patient survival rates. In-vitro experimentation showed that the overexpression of miR-335 inhibited the growth, invasion and migration capabilities of A459 lung cancer cells, by targeting Tra2β. In contrast, inhibition of miR-335 or overexpression of the Tra2β target gene stimulated the growth, invasion and migratory capabilities of A459 lung cancer cells in vitro. Furthermore, overexpression of miR-335 or inhibition of Tra2β decreased the phosphorylation of Rb-S780 and Rb-AKT. Overall, these findings suggest that the downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation by upregulation of Tra2β, mediated via activation of the AKT/mTOR signaling pathway, and suggest that miR-335 may have potential as a novel therapeutic target for NSCLC. This article is protected by copyright. All rights reserved.

The IL-21-mTOR axis blocks treg differentiation and function by suppression of autophagy in patients with systemic lupus erythematosus.

The mechanistic target of rapamycin (mTOR) has become a therapeutic target in systemic lupus erythematosus (SLE). mTOR regulates normal T-cell lineage specification, including development of regulatory cells (Tregs). Therefore, we investigated whether mTOR is activated within Tregs and causes their depletion and dysfunction in patients with SLE.

NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation.

Phospholipids, such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC), are the major components of cell membranes. Their exposure to reactive oxygen species creates oxidized phospholipids, which predispose to the development of chronic inflammatory diseases and metabolic disorders through endothelial activation and dysfunction. Although the effects of oxidized PAPC (oxPAPC) on endothelial cells have been previously studied, the underlying molecular mechanisms evoking biological responses remain largely unknown. Here, we investigated the molecular mechanisms of oxPAPC function with a special emphasis on NRF2-regulated microRNAs (miRNAs) in human umbilical vein endothelial cells (HUVECs) utilizing miRNA profiling, global run-on sequencing (GRO-seq), genome-wide NRF2 binding model, and RNA sequencing (RNA-seq) with miRNA overexpression and silencing. We report that the central regulators of endothelial activity, KLF2 for quiescence, PFKFB3 for glycolysis, and VEGFA, FOXO1 and MYC for growth and proliferation, are regulated by transcription factor NRF2 and the NRF2-regulated miR-106b∼25 cluster member, miR-93, in HUVECs. Mechanistically, oxPAPC was found to induce glycolysis and proliferation NRF2-dependently, and oxPAPC-dependent induction of the miR-106b∼25 cluster was mediated by NRF2. Additionally, several regulatory loops were established between NRF2, miR-93 and the essential regulators of healthy endothelium, collectively implying that NRF2 controls the switch between the quiescent and the proliferative endothelial states together with miR-93.

Pharmacological blockage of the CXCR4-CXCL12 axis in endometriosis leads to contrasting effects in proliferation, migration and invasion.

High levels of inflammatory factors including chemokines have been reported in peritoneal fluid and blood of women with endometriosis. CXCL12 mediates its action by interaction with its specific receptor, CXCR4, which has been reported to be elevated in human endometriosis lesions and in the rat model of endometriosis. Activation of the CXCR4-CXCL12 axis increases cell proliferation, migration and invasion of cancer cells. To obtain insights into the CXCR4 expression profile in lesions and endometrium, as well as functionality of the CXCR4-CXCL12 axis in endometriosis we analysed the expression of CXCR4 in tissues on a human tissue array and studied CXCL12-mediated activation of proliferation, invasion, and migration in vitro. We observed differences in levels of nuclear CXCR4 expression among lesion types, being higher in ovarian lesions. Endometriotic cell lines (12Z) showed higher levels of CXCR4, proliferative and migratory potential, and AKT phosphorylation/kinase activity compared to untreated control cells (EEC). CXCL12 and endometriotic stromal cell-enriched media increased proliferation of non-endometriotic epithelial cells. CXCL12 caused a significant increase in 12Z cell invasion but had no effect on migration; AMD3100, a CXCR4-specific inhibitor, significantly increased invasion of 12Z cells but decreased their migration. However, treatment with CXCL12 plus AMD3100 significantly decreased invasion and migration of 12Z cells. In conclusion, the CXCR4-CXCL12 axis is functional in endometriosis cells, but the expression of CXCR4 varies among lesions. CXCL12 promoted proliferation, migration, and invasion of endometriotic cells, while inducing AKT phosphorylation and activity, but pharmacologically blocking this axis in the absence of the ligand induced their invasiness.

The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.

Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K(+) channel modulators on colorectal cancer (CRC) cells.