The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development ...strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8
and CD4
T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor. The combination treatment also produced synergistic increase in P-ERK1/2 level in spleen. Immunohistochemistry shown that SEP induced the PD-L1 expression in melanoma tissue possibly by promoting IFN-γ excretion, which led to the synergistic anti-tumor effects of aPD-L1 and SEP. Furthermore, in the purified T lymphocyte from the naive mice, the combination of SEP and αPD-L1 had more potent than SEP or αPD-L1 in promoting T lymphocyte proliferation and cytokines secretion including IL-2 and IFN-γ, at least partially by activating MEK/ERK pathway. Our study provides the scientific basis for a clinical trial that would involve combination of anti-PD-L1 mAb and SEP for sustained melanoma control.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co-regulate each other's expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is ...implicated in cancer progression. However, we found that a higher CCR2 mRNA level is remarkably associated with prolonged survival of breast cancer patients. These conflicting results prompted us to study the non-coding function of CCR2 mRNA. We found that the CCR2 3′ untranslated region (UTR) inhibited MDA-MB-231 and MCF-7 cell metastasis by repressing epithelial–mesenchymal transition (EMT) in vitro, and suppressed breast cancer metastasis in vivo. Mechanistically, the CCR2 3′UTR modulated the expression of the RhoGAP protein STARD13 via acting as a STARD13 ceRNA in a microRNA-dependent and protein coding-independent manner. The CCR2 3′UTR blocked the activation of RhoA–ROCK1 pathway, which is the downstream effector of STARD13, and thus decreased the phosphorylation level of myosin light chain 2 (MLC2) and formation of F-actin. Additionally, the function of the CCR2 3′UTR was dependent on STARD13 expression. In conclusion, our results confirmed that the CCR2 3′UTR acts as a metastasis suppressor by acting as a ceRNA for STARD13 and thus inhibiting RhoA–ROCK1–MLC–F-actin pathway in breast cancer cells. This article has an associated First Person interview with the first author of the paper.
Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting ...the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3′UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3′UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3′UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3′UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3′UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.
•A new critical role of ceRNAs in ER + breast cancer is proposed.•We examine the relationship of CYP4Z2P, CYP4Z1 and CDK3 in breast cancer.•The roles of CYP4Z2P and CYP4Z1 in TAM resistance were further studied.•The novel mechanism provides new insights for TAM resistance.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Competing endogenous RNAs (ceRNAs) network has been correlated with the initiation and development of cancer. Here, we identify CDH5, HOXD1, and HOXD10 as putative STARD13 ceRNAs and they display ...concordant patterns with STARD13 in different metastatic potential breast cancer cell lines and tissues. Notably, 3'UTRs of these genes suppress breast cancer metastasis via inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo, which are activated through the crosstalk between STARD13 and its ceRNAs in 3'UTR- and miRNA-dependent manners. In addition, Kaplan-Meier survival analysis reveals that mRNA level of STARD13 and its ceRNAs is remarkably associated with survival of breast cancer patients. These results suggest that 3'UTRs of CDH5, HOXD1, and HOXD10 inhibit breast cancer metastasis via serving as STARD13 ceRNAs.
MicroRNA-125b (miR-125b) has been reported to be upregulated in several kinds of leukemia, suggesting that miR-125b plays a role in Leukemia development. In this study, it was shown that miR-125b ...expression level decreased in response to 1α, 25-dihydroxy-vitamin D3 (1,25D3) in a dose- and time-dependent manner and miR-125b blocked 1,25D3-induced monocytic differentiation of U937 cells. In addition, miR-125b decreased mRNA expression of myelomonocytic differentiation markers, including CD11c, CD18 and CD64 and arrested the cell cycle at the S phase in U937 and HL60 cells. Fes was identified as a novel direct target of miR-125b and miR-125b could also reduce the expression levels of PU.1 and macrophage colony-stimulating factor receptor (MCSFR). Furthermore, Fes was found to be involved in monocytic differentiation via upregulation of PU.1 and MCSFR and Fes siRNA could also inhibit 1,25D3-induced monocytic differentiation of U937 and HL60 cells and decrease mRNA expression of CD11c, CD18 and CD64. Importantly, the inhibition of Fes siRNA on 1,25D3-induced monocytic differentiation could be rescued by transfection with miR-125b inhibitor. Our data highlights an important role of miR-125b in AML progression, implying the potential application of miR-125b in AML therapy.
•MiR-125b blocks monocytic differentiation of AML cells.•Fes is a novel direct target of miR-125b.•MiR-125b reduces expression level of PU.1 and MCSFR.•MiR-125b is a potential target in AML therapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In the pathogenesis of rheumatoid arthritis (RA), rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) have tumor-like characteristics, mainly manifested by hyperproliferation and resistance to ...apoptosis and then it will erode the bone and cartilage, eventually leading to joint destruction. Paris saponin VII (PS VII) is an active compound derived from a traditional herbal medicine named
Trillium tschonoskii
Maxim, which has anti-tumor, analgesic, and immunomodulatory effects. However, its anti-RA effect has not yet been reported. This study was to investigate the effect of PS VII on two rheumatoid arthritis fibroblast-like synoviocytes lines (RA-FLS and MH7A) and adjuvant-induced arthritis (AIA) in rats.
In vitro
, the effects of PS VII on the proliferation, cell cycle, and apoptosis of RA-FLS and MH7A cells were detected by MTT, flow cytometry, and western blot analysis.
In vivo
, the effect of PS VII on the weight of the rat, paw swelling, ankle joint diameter, arthritis index, serum inflammatory cytokines (TNF-α, IL-6, and IL-1β), histopathological assessment and apoptosis proteins in the synovial tissues were evaluated in AIA rats. The
in vitro
studies showed that PS VII inhibited the proliferation of RA-FLS and MH7A cells, induced S phase arrest and triggered cell apoptosis mainly through the mitochondrial apoptotic pathway and the regulation of JNK and p38 MAPK pathways. The
in vivo
studies revealed that PS VII could improve ameliorate body weight, paw swelling, ankle joint diameter, reduce the spleen and thymus index, suppress the production of TNF-α, IL-6 and IL-1β, improve histopathological changes and regulate the expressions of apoptosis proteins in AIA Rats. In conclusion, PS VII could inhibit the proliferation and trigger apoptosis of RA-FLS and MH7A cells by regulating the mitochondrial apoptosis pathway and the JNK and p38 MAPK pathways, and alleviate the symptoms of RA, signifying it to be one of the potential anti-RA therapeutics.
First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their ...papers. Jinhang Hu is the first author on 'CCR2 3'UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis', published in Journal of Cell Science. Jinhang conducted the work in this article in Tao Xi's lab at China Pharmaceutical University, Nanjing, China. She is now a research associate with Zhishu Tang at the Shaanxi University of Chinese Medicine in Xian Yang, China, investigating the bioactive constituents and anti-tumour mechanisms of the active ingredients in traditional Chinese medicine.
MiR-424 plays an important role via promoting the monocytic differentiation in many human leukemia cell lines. Here, we report that miR-424 decreased miR-125b expression to 36 % by directly targeting ...caudal type homeobox 2. However, miR-424 also decreased expression of Fes, PU.1 and colony-stimulating factor receptor (MCSFR). As Fes, PU.1 and MCSFR were down-regulated by over-expression of miR-125b (unpublished work), a similar effect of miR-424 and Fes siRNA on CD64, Egr-1, Egr-2 and CEBPA indicates that Fes may be an important downstream target of miR-424. We hypothesize that miR-424 promotes monocytic differentiation by regulating other critical factors and miR-424 has high affinity for these factors. For the first time, the molecular mechanism of miR-424 during monocytic differentiation of U937 cells has been elucidated in this study.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Competitive endogenous messenger RNAs (ceRNAs) affect other RNAs transcription through competitively binding common microRNAs (miRNAs). In this study we identified long non-coding RNA (lncRNA) MALAT1 ...can function as a ceRNA of cell division cycle 42 (cdc42) 3′UTR in inducing migration and invasion of breast cancer cells via miR-1. We found that miR-1 bound both MALAT1 and cdc42 3′UTR directly. Further study showed that MALAT1 induced migration and invasion of breast cancer cells while reduced the level of cdc42. Our results suggest that MALAT1 regulated migration and invasion of breast cancer cells via affecting cdc42 through binding miR-1 competitively.
•Verifying MALAT1 does promote migration and invasion of breast cancer cells.•MiR-1 plays an important role in MALAT1 and cdc42 regulating network.•MALAT1 competitively binds miR-1 with cdc42 to promote migration and invasion of breast cancer cells.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Green synthesis of silver nanoparticles (AgNPs) has been extensively studied by using a variety of plant extracts for applications in biomedical sciences and engineering. However, there are no ...reports on the synthesis of AgNPs by utilizing the berry extract of Sea Buckthorn , which is a traditional Chinese medicine and exhibits a wide spectrum of antioxidant, anti-inflammatory and anticancer activities. In this paper, we report an easy and eco-friendly technique for the preparation of AgNPs using the Sea Buckthorn berry extract under ultrasonic radiation at ambient temperature and the evaluation of both biosynthesis parameters and biological activities. The UV-visible spectrum and dynamic light scattering (DLS) analysis showed that the size of AgNPs was sensitive to the biosynthesis parameters, such as the pH of the extract, material proportion and reaction time, offering a size-controlled synthetic method for AgNPs. The X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED) and DLS studies showed that the AgNPs (pH 10.0; material proportion 1 : 1; 4 h) had a face-centered cubic (fcc) structure and spherical shape with an average particle size of 27.3 ± 0.2 nm covered by anions, and existed in a monodispersed form with a polydispersity index (PDI) of 0.213. The biosynthesized AgNPs showed potent anticancer activity against human colorectal cancer (HCT116 and SW620), hepatoma cancer (HepG2), breast cancer (MCF-7) and cervical cancer (HeLa) cell lines as well as strong antioxidant activity. The IC 50 values for these five cell lines were 8.77, 4.61, 14.59, 16.05 and 27.98 μg mL −1 , respectively. However, the biosynthesized AgNPs revealed poor inhibition activities for the growth of E . coli and S . aureus . These results confirmed that the Sea Buckthorn could be a low-cost, nontoxic and eco-friendly natural resource for the synthesis of AgNPs, which might be useful for the development of new alternative antioxidant and anticancer agents in biomedicine.
PDF
