RNA sequencing can simultaneously identify exonic polymorphisms and quantitate gene expression. Here we report RNA sequencing of developing maize kernels from 368 inbred lines producing 25.8 billion reads and 3.6 million single-nucleotide polymorphisms. Both the MaizeSNP50 BeadChip and the Sequenom MassArray iPLEX platforms confirm a subset of high-quality SNPs. Of these SNPs, we have mapped 931,484 to gene regions with a mean density of 40.3 SNPs per gene. The genome-wide association study identifies 16,408 expression quantitative trait loci. A two-step approach defines 95.1% of the eQTLs to a 10-kb region, and 67.7% of them include a single gene. The establishment of relationships between eQTLs and their targets reveals a large-scale gene regulatory network, which include the regulation of 31 zein and 16 key kernel genes. These results contribute to our understanding of kernel development and to the improvement of maize yield and nutritional quality.
Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1 À/À mice or in response to CD4 þ or CD8 þ T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumorspecific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the coregulatory molecule LAG-3, the blockade of which restored IFNg secretion that was reduced by melanomaderived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. Cancer Res; 74(13); 3418-28. Ó2014 AACR.
CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors and endothelial cells. However, the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking. Recent evidence revealed that CD146 is not merely an adhesion molecule, but also a cellular surface receptor of miscellaneous ligands, including some growth factors and extracellular matrixes. Through the bidirectional interactions with its ligands, CD146 is actively involved in numerous physiological and pathological processes of cells. Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers, especially vascular and lymphatic metastasis. Thus, immunotherapy against CD146 would provide a promising strategy to inhibit metastasis, which accounts for the majority of cancer-associated deaths. Therefore, to deepen the understanding of CD146, we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.
Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTV-PyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumor-infiltrating CD4+ T cells and macrophages. An IL-25 neutralization antibody, while not affecting primary tumor growth, substantially reduced lung metastasis. Inhibition of IL-25 resulted in decreased type 2 T cells and macrophages in the primary tumor microenvironments, both reported to enhance breast tumor invasion and subsequent metastasis to the lung. Taken together, our data suggest IL-25 blockade as a novel treatment for metastatic breast tumor.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0345-7) contains supplementary material, which is available to authorized users.
Maize transformation is highly based on the formation of embryonic callus, which is mainly derived from scutellum cells of the immature maize embryo. However, only a few genes involved in callus induction have been identified in maize. To reveal the potential genes involved in the callus induction of maize, we carried out a high-throughput RNA sequencing on embryos that were cultured for 0, 1, 2, 4, 6, and 8 days, respectively, on a medium containing or lacking 2,4-dichlorophenoxyacetic acid. In total, 7,525 genes were found to be induced by 2,4-dichlorophenoxyacetic acid and categorized into eight clusters, with clusters 2 and 3 showing an increasing trend related to signal transmission, signal transduction, iron ion binding, and heme binding. Among the induced genes, 659 transcription factors belong to 51 families. An AP2 transcription factors, ZmBBM2, was dramatically and rapidly induced by auxin and further characterization showed that overexpression of ZmBBM2 can promote callus induction and proliferation in three inbred maize lines. Therefore, our comprehensive analyses provide some insight into the early molecular regulations during callus induction and are useful for further identification of the regulators governing callus formation.
Abstract. Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm composed of myofibroblastic and fibroblastic spindle cells, accompanied by the inflammatory infiltration of plasma cells, lymphocytes and/or eosinophils. Epithelioid inflammatory myofibroblastic sarcoma (EIMS), which primarily consists of cells with a round or epithelioid morphology, is associated with a poor prognosis and rapid development of local recurrence, and has been recognized to be a variant of IMT. Diagnosis of EIMS is difficult owing to its close resemblance to malignant mesothelioma, anaplastic large cell lymphoma, gastrointestinal stromal tumor and other malignant diseases. In the present study, a case of this rare tumor was evaluated in a 26-year-old male who was admitted to hospital after experiencing abdominal pain for ~18 days and abdominal distention for 1 week. The patient's tumor was examined by imaging, gross examination, histology, immunohistochemistry and fluorescence in situ hybridization (FISH). The magnetic resonance imaging enhanced-scanning image revealed that the morphology of the tumor was irregular, and signal was medley consisting of high and low hybrid reinforcement. Tumors were located in the bladder and rectal pit, in the lower part of the lower abdomen, indicating the presence of malignancy and involvement of the small intestine and rectum. Enhanced-scanning imaging revealed notable inhomogeneous enhancement. Gross examination revealed that the tumor was solid and had a variegated appearance with alternating fleshy and mucoid areas in the cut surface. Microscopically, the tumors were dominated by sheets of epithelioid-to-round cells with a prominent inflammatory infiltrate. The majority of the stroma was myxoid. Immunohistochemically, the tumor cells exhibited diffuse strong staining for ALK receptor tyrosine kinase (hereafter ALK), vimentin, tumor protein P53, desmin, Wilms' tumor 1 and programmed death-ligand 1. FISH analysis also revealed the existence of ALK rearrangement. The expression of PD-L1 in EIMS indicates that the immune checkpoint blockade could represent a novel therapy for the treatment of EIMS.
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