An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development

Background SETD1A, a member of SET1/MLL family H3K4 methyltransferases, is involved in the tumorigenesis of numerous cancers. However, the biological role and mechanism of SETD1A in non-small cell lung cancer (NSCLC) remain to be elucidated. Methods The expression of SETD1A, NEAT1, EZH2, and β-catenin in NSCLC tissues and cell lines was detected by qRT-PCR, immunohistochemistry and western blotting. The regulatory mechanisms were validated by chromatin immunoprecipitation, co-immunoprepitation and luciferase reporter assay. The self-renewal, cisplatin sensitivity and tumorigenesis of NSCLC cells were analyzed using sphere formation, CCK-8, colony formation assays and xenograft tumor models. Results SETD1A expression was significantly increased in NSCLC and its overexpression predicted a poor prognosis of patients with NSCLC. Functional experiments showed that SETD1A positively regulated cancer stem cell property and negatively regulated cisplatin sensitivity in NSCLC cells via the Wnt/β-catenin pathway. Next, we found that SETD1A positively regulated the Wnt/β-catenin pathway via interacting with and stabilizing β-catenin. The SET domain is dispensable for the interaction between SETD1A and β-catenin. Furthermore, we identified that SETD1A bound to the promoters of NEAT1 and EZH2 to activate gene transcription by inducing H3K4me3 enrichment. Rescue experiments showed that SETD1A promoted the Wnt/β-catenin pathway and exerted its oncogenic functions in NSCLC, at least, partly through NEAT1 and EZH2 upregulation. In addition, SETD1A was proven to be a direct target of the Wnt/β-catenin pathway, thus forming a positive feedback loop in NSCLC cells. Conclusion SETD1A and Wnt/β-catenin pathway form a positive feedback loop and coordinately contribute to NSCLC progression.

NOVEL IMMUNOTHERAPEUTIC TARGETED GRANZYME DELIVERY SYSTEMS IN TREATMENT OF MALIGNANT TUMORS

Cytotoxicity is the main human killer cell property. The cytotoxicity reaction of human killer cells is achieved through a complex of molecules, including perforins, granzyme, cathepsin and others. However, only one molecule is enough for target cell death: granzyme. Other molecules are intended for granzyme activation and its delivery to the target cell cytoplasm. Granzymes are a whole family of serine proteases that perform their function in the human body as integral cytolytic effectors during programmed cell death of cancer and pathogen-infected cells. Secreted mainly by cytotoxic T-lymphocytes and NK-cells, granzymes initiate apoptosis via caspase-dependent and caspase-independent pathways. These natural properties make granzymes one of the most promising human enzymes for use in the development of targeted therapeutic strategies in the treatment of various types of cancer.The most promising is granzyme B, because it has the most powerful effector properties. Due to the initiation of cascade reactions that activate apoptosis, granzyme is attractive as a basis for the development of medicines applicable in clinical oncology. At this time, several approaches have been developed for delivering granzyme molecules to tumor cells and facilitating its penetration through the cell membrane. Moreover, some solutions are proposed to overcome the resistance of target cells to granzyme-mediated apoptosis. These approaches are discussed in this review.The purpose of this review was to systematize information on the use of granzyme B as a nanostructured drug delivery system in the treatment of solid and hematological malignancies. In addition, this review discusses ways to overcome the resistance of granzyme penetration into target cells.

Prom1 expression does not mark a stem/progenitor population in the mouse oviduct epithelium

SummaryThe oviduct or fallopian tube is the site of fertilization and preimplantation embryonic development. The epithelium lining the oviduct consists of multiciliated and secretory cells, which support fertilization and preimplantation development, however, its homeostasis still remains poorly understood. CD133/Prom1 has been used to identify adult stem cell populations in various organs and often associated with cancer stem cell property. Using a Cre-recombinase based lineage tracing strategy, we found that CD133/Prom1 expression was not associated with a stem/progenitor population in the oviduct but marked a sub population of multiciliated and secretory cells which did not propagate. Interestingly, Prom1 expressing secretory cells rapidly transition to multiciliated cells and progressively migrate to the tips of epithelial folds in the ampulla. Our results show that CD133/Prom1 expression cannot be used as a progenitor/stem cell marker in the mouse oviduct.

Controlled neighbor exchanges drive glassy behavior, intermittency and cell streaming in epithelial tissues

Cell neighbor exchanges are integral to tissue rearrangements in biology, including development and repair. Often these processes occur via topological T1 transitions analogous to those observed in foams, grains and colloids. However, in contrast to in non-living materials the T1 transitions in biological tissues are rate-limited and cannot occur instantaneously due to the finite time required to remodel complex structures at cell-cell junctions. Here we study how this rate-limiting process affects the mechanics and collective behavior of cells in a tissue by introducing this important biological constraint in a theoretical vertex-based model as an intrinsic single-cell property. We report in the absence of this time constraint, the tissue undergoes a motility-driven glass transition characterized by a sharp increase in the intermittency of cell-cell rearrangements. Remarkably, this glass transition disappears as T1 transitions are temporally limited. As a unique consequence of limited rearrangements, we also find that the tissue develops spaitally correlated streams of fast and slow cells, in which the fast cells organize into stream-like patterns with leader-follower interactions, and maintain optimally stable cell-cell contacts. The predictions of this work is compared with existing in-vivo experiments in Drosophila pupal development.