[Show abstract][Hide abstract] ABSTRACT: We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-α induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-κB signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-κB/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.
Proceedings of the National Academy of Sciences 07/2015; 112(31). DOI:10.1073/pnas.1502068112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis.
Methods: CRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, ChIP, RNA pull-down assay, deletion mapping assay, LC-MS/MS and RNA immunoprecipitation to determine the mechanisms of MYC regulation of lncRNAs. Moreover, soft agar assay and in vivo xenograft experiments (four athymic nude mice per group) provided evidence of MYC-regulated lncRNAs in cancer cell transformation and tumorigenesis. The Kaplan-Meier method was used for survival analyses. All statistical tests were two-sided.
Results: We identified lncRNAs differentially expressed in CRC (P < .05, greater than two-fold) and verified four lncRNAs upregulated and two downregulated in CRC cells and tissues. We further identified MYC-regulated lncRNAs, named MYCLos. The MYC-regulated MYCLos may function in cell proliferation and cell cycle by regulating MYC target genes such as CDKN1A (p21) and CDKN2B (p15), suggesting new regulatory mechanisms of MYC-repressed target genes through lncRNAs. RNA binding proteins including HuR and hnRNPK are involved in the function of MYCLos by interacting with MYCLo-1 and MYCLo-2, respectively. Knockdown experiments also showed that MYCLo-2, differentially expressed not only in CRC but also in prostate cancer, has a role in cancer transformation and tumorigenesis.
Conclusions: Our results provide novel regulatory mechanisms in MYC function through lncRNAs and new potential lncRNA targets of CRC.
JNCI Journal of the National Cancer Institute 02/2015; 107(4):dju505. DOI:10.1093/jnci/dju505 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Based on three chloroplast markers (psbA-trnH, trnL-trnF, and trnT-trnL), we identified eight haplotypes in 23 samples of Litsea coreana collected from seven provinces across southern and southwestern China. The Hap6 was the most widely distributed haplotype. The genetic diversity was highest in Sichuan Province and its adjacent regions. Therefore, these regions should be areas of priority for conservation of L. coreana in the future. In addition, our molecular dating analyses indicated that the uplift of the Tibetan Plateau and past climate changes accounted for the diversification of L. coreana in China. Finally, we found that the chemical components of L. coreana were significantly affected by both collection time and postharvest handling methods.
[Show abstract][Hide abstract] ABSTRACT: The section Moutan of the genus Paeonia consists of eight species that are confined to a small area in China. A wide range of metabolites, including monoterpenoid glucosides, flavonoids, tannins, stilbenes, triterpenoids, steroids, paeonols, and phenols, have been found in the species belonging to section Moutan. However, although previous studies have analyzed the metabolites found in these species, the metabolic similarities that can be used for the chemotaxonomic distinction of section Moutan species are not yet clear. In this study, HPLC-DAD-based metabolic fingerprinting was applied to the classification of eight species: Paeoniasuffruticosa, Paeoniaqiui, Paeoniaostii, Paeoniarockii, Paeoniajishanensis, Paeoniadecomposita, Paeoniadelavayi, and Paeonialudlowii. In total, of the 47 peaks that exhibited an occurrence frequency of 75% in all 23 tree peony samples, 43 of these metabolites were identified according to their retention times and UV absorption spectra, together with combined HPLC-QTOF-MS. These data were compared with reference standard compounds. The 43 isolated compounds included 17 monoterpenoid glucosides, 11 galloyl glucoses, 5 flavonoids, 6 paeonols and 4 phenols. Principal component analysis (PCA), and hierarchical cluster analysis (HCA), showed a clear separation between the species based on metabolomics similarities and four groups were identified. The results exhibited good agreement with the classical classification based on the morphological characteristics and geographical distributions of the subsections Vaginatae F.C. Stern and Delavayanae F.C. Stern with the exception of P. decomposita, which was found to be a transition species between these two subsections. According to their metabolic fingerprinting characteristics, P. ostii and P. suffruticosa can be considered one species, and this result is consistent with the viewpoint of medicinal plant scientists but different from that of classical morphological processing. Significantly large variations were obtained in the metabolic profiles of P. delavayi, whereas no significant difference was found between P. delavayi and P. ludlowii. This indicates that these two species have a close genetic relationship. In conclusion, the combination of HPLC-DAD and multivariate analyses has great potential for guiding future chemotaxonomic studies to examine the potential pharmaceutical value of the effective constituents of tree peony species and appears to be able to clarify the confusion and skepticism associated with the reported morphology- and molecular phylogenetics-based taxonomy of tree peonies.
[Show abstract][Hide abstract] ABSTRACT: One hundred and forty-four samples of Chishao and Baishao, which represented six species of Paeonia L. were evaluated for their genetic variation, genetic differentiation and phylogenetic relationship, based on the nuclear ribosomal DNA internal transcribed spacer (ITS) region. Samples from representative of the population were then used to do a cultivation comparison experiment, and then to identify the contents of the active ingredients. The results showed there were differences in the haplotype distribution and frequency between populations of Chishao and Baishao. An analysis of molecular variance (AMOVA) indicated statistically significant (P<0.001) genetic differentiation between the populations of wild and cultivated Paeonia lactiflora Pall. The albiflorin content between Chishao and Baishao was also significant different (P<0.05). All the results clearly illustrate that currently cultivated P. lactiflora cannot be used as a substitute for Chishao.
[Show abstract][Hide abstract] ABSTRACT: Two new isoflavones, 6,8,4′-trihydroxy-7,3′-dimethoxyisoflavone (1) and 6,8,4′-trihydroxy-7-methoxyisoflavone (2), were isolated from the rhizomes of Iris dichotoma. The structures of the new compounds were elucidated by spectroscopic analyses including 2D NMR techniques.
[Show abstract][Hide abstract] ABSTRACT: Background
Single copy genes are common across angiosperm genomes. With the sufficiently high quality sequenced genomes, the identification of large-scale single copy genes among multiple species is possible. Although some characteristics have been reported, our study provides novel insights into single copy genes.
We identified single copy genes across 29 angiosperm genomes. A significant negative correlation was found between the number of duplicate blocks and the number of single copy genes. We found that a considerable number of single copy genes are located in organelles, showing a preference for binding and catalytic activity. The analysis of effective number of codons (Nc) illustrates that single copy genes have a stronger codon bias than non-single copy genes in eudicots. The relative high expression level of single copy genes was partially confirmed by the RNA-seq data, rather than the Codon Adaptation Index (CAI). Unlike in most other species, a strongly negatively correlation occurs between Nc and GC3 among single copy genes in grass genomes. When compared to all non-single copy genes, single copy genes indicate more conservation (as indicated by Ka and Ks values). But our alternative splicing (AS) results reveal that selective constraints are weaker in single copy genes than in low copy family genes (1–10 in-paralogs) and stronger than high copy family genes (>10 in-paralogs). Using concatenated shared single copy genes, we obtained a well-resolved phylogenetic tree. With the addition of intron sequences, the branch support is improved, but striking incongruences are also evident. Therefore, it is noteworthy that inclusion of intron sequences seems more appropriate for the phylogenetic reconstruction at lower taxonomic levels.
Our analysis provides insight into the evolutionary characteristics of single copy genes across 29 angiosperm genomes. The results suggest that there are key differences in evolutionary constraints between single copy genes and non-single copy genes. And to some extent, these evolutionary constraints show some species-specific differences, especially between eudicots and monocots. Our preliminary evidence also suggests that the concatenated shared single copy genes are well suited for use in resolving phylogenetic relationships.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-504) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: Our goal is to test if CS1 could be targeted by CAR T cells to treat MM.
We generated a retroviral construct of a CS1-specific CAR and engineered primary human T cells expressing the CAR. We then tested the capacity of CS1-CAR T cells to eradicate human multiple myeloma tumor cells in vitro, ex vivo and in vivo using orthotopic MM xenograft mouse models.
In vitro, compared to mock-transduced T cells, upon recognizing CS1 positive MM cells, CS1-CAR-tranduced T cells secreted more IFN-γ as well as IL-2, expressed higher levels of the activation marker CD69, showed higher capacity for degranulation, and displayed enhanced cytotoxicity. Ectopically forced expression of CS1 in MM cells with low CS1 expression enhanced recognition and killing by CAR T cells. Ex vivo, CS1-CAR T cells also showed similarly enhanced activities when responding to primary MM cells. More importantly, in orthotopic MM xenograft mouse models, adoptive transfer of human primary T cells expressing CS1-CAR efficiently suppressed the growth of human MM.1S and IM9 myeloma cells and significantly prolonged mouse survival.
CS1 is a promising antigen that can be targeted by CAR-expressing T cells for treatment of MM.
Clinical Cancer Research 03/2014; 20(15). DOI:10.1158/1078-0432.CCR-13-2510 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.
Proceedings of the National Academy of Sciences 03/2014; 111(11). DOI:10.1073/pnas.1400350111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The tribe Chelidonieae comprises 23 species of eight genera with an extensive distribution and a long medicinal usage history both in China and Western countries. A large number of chemical constituents have been isolated and identified from the species in tribe Chelidonieae, such as alkaloids, organic acids, and their derivatives, aromatics, triterpenoids, sterols, essential oils, and proteins, most of which possess a variety of bioactivities, especially for the antibacterial, anti-inflammation, antitumor, analgesia, anti-oxidation, and antiparasitic activity. Meanwhile, potential toxicities have been discovered in some constituents. Therefore, the species in tribe Chelidonieae have become a rich source for new drug discovery, biologic study, and mechanism research. This paper presents comprehensive information of the chemical constituents, pharmacological and toxicological research on the plants in tribe Chelidoieae, which is a reference for the plants in this tribe for further development.
[Show abstract][Hide abstract] ABSTRACT: A rapid and accurate ultra-performance liquid chromatography-photo-diode array (UPLC-PDA) detection method was established for simultaneous determination of 5 compounds including polydatin, resveratrol, emodin-8-glucoside, emodin, and physcion in Polygonum cuspidatum. Twenty-six batches of samples were collected from different areas and markets in China. The compounds were separated in less than 12min using a C18 column with acetonitrile and water containing 0.5% acetic acid as the mobile phase at a flow rate of 0.3mL/min. The precision (intra-day and inter-day assay), stability, limits of detection and quantitation, linearity, and recovery were evaluated for this method. RSD for intra-day precision, inter-day precision, and stability were less than 2.5%, 3.5%, and 2.19%, respectively. Recovery ranged from 96.78% to 104.58% (RSD<2.71%). The content range of polydatin, resveratrol, emodin-8-glucoside, emodin, and physcion were 13.45-34.55, 0.97-13.12, 3.34-17.62, 6.53-13.69, and 1.71-4.23mg/g, respectively. By applying principal component analysis and hierarchical cluster analysis, the quality of 26 specimens can be divided into 3 groups according to contents of compounds. This indicates the need to strengthen the quality control of P. cuspidatum. This is the first report to provide an effective UPLC method and related statistical methods to evaluate the quality of P. cuspidatum from different areas.
Journal of Liquid Chromatography & Related Technologies 12/2013; 36(20). DOI:10.1080/10826076.2012.723096 · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rhubarb is an important Chinese medicinal herb with a long history of over 2000 years and has been commonly used as a laxative. It is the radix and rhizome of Rheum officinale Baill., R. palmatum L. and R. tanguticum Maxim, all of which are mainly distributed in a broad region in the Tibetan plateau. Anthraquinone glycosides are a series of major active ingredients found in all three species. They are key intermediates in the anthraquinone secondary metabolism and the sennnoside biosynthesis. The variation of the anthraquinone glycoside content in rhubarb in response to specific factors remains an attractive topic.
A simple and sensitive Ultra Performance Liquid Chromatography with Photo-Diode Array (UPLC-PDA) detector was developed for the simultaneous determination of six anthraquinone glycosides in rhubarb, i.e., aloeemodin-8-O-glucoside, rhein-8-O-glucoside, chrysophanol-1-O-glucoside, emodin-1-O-glucoside, chrysophanol-8-O-glucoside, emodin-8-O-glucoside. Nine batches of R. tanguticum Maxim, five batches of Rheum officinale Baill and thirteen batches of R. palmatum L. were submitted to the multi-component analysis. The results showed that the anthraquinone glycoside content varied significantly even within the same species. The data of the anthraquinone glycoside content in rhubarb were assessed by correlational analysis, principal component analysis, spatial analysis, vertical slice analysis through SPSS and Geographic Information System (ArcGis) to determine the correlations of the anthraquinone glycoside content with plant species, geographical distribution and altitude. The results showed that the anthraquinone glycoside content varied significantly within the same species but not between different species. The PCA and content analysis results confirmed that the plant species has no obvious effect on the content variation. Neither was any significant correlation observed between the anthraquinone glycoside content and the geographic distribution of the rhubarb. Through correlational analysis, altitude was found to be the main factor that affects the anthraquinone glycoside content in rhubarb. Rhubarb grown at higher altitude has higher anthraquinone glycoside content.
This work provides a rapid, sensitive and accurate UPLC-PDA method for the simultaneous determination of six anthraquinone glycosides in rhubarb. The anthraquinone glycoside content varied significantly within the same species. The relationship of the anthraquinone glycoside content with plant species, geographic distribution and altitude were studied using correlational analysis, principal component analysis and spatial autocorrelation analysis through SPSS and ArcGIS. Plant species and geographic distribution were found not to affect the content of the six anthraquinone glycosides in rhubarb. The variations in the anthraquinone glycoside content were primarily due to the different altitude where the plant was grown.
Chemistry Central Journal 10/2013; 7(1):170. DOI:10.1186/1752-153X-7-170 · 2.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insect tea, listed in the “Compendium of Materia Medica” by Li Shizhen, is not only a traditional drink for the ethnic minority in southwest China, but also one of China's traditional export commodities. Insect tea is made of the feces of insects that feed on plants, and characterized by minimal dose, enjoyable tea flavor, few tea-residues, and superb transparency. Insect tea has been used to clear summer heat, protect the spleen and stomach, and facilitate digestion. Modern research has suggested that insect tea is safe and nutritional, and it has blood lipid lowering, antihypertensive and hypoglycemic effects. At present, due to the household production of insect tea, there are a variety of species of tea-producing insects and feeding plants. In the present review, we summarized the types, civilian applications, nutritional value, pharmacological activity and safety of insect tea, in an effort to provide scientific knowledge for future study.
Food Research International 10/2013; 53(2):629-635. DOI:10.1016/j.foodres.2013.01.005 · 2.82 Impact Factor