Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence. hepatocellular carcinoma | MRI | MDR2 -/-mice | genomic instability
Abstract-While protease-activated receptors (PARs) play a traditional role in vascular biology, they emerge with surprisingly new assignments in tumor biology. PAR1 expression correlates with the invasion properties of breast carcinoma, whereas human PAR1 antisense reduces their ability to migrate through Matrigel. Part of the molecular mechanism of PAR1 invasion involves the formation of focal contact complexes on PAR1 activation. PAR1 induces angiogenesis in animal models in vivo and exhibits an oncogenic phenotype of enhanced ductal complexity when overexpressed in mouse mammary glands. Key Words: PAR1 Ⅲ epithelia Ⅲ invasion Ⅲ metastasis Ⅲ angiogenesis I n addition to its central role in hemostasis and thrombosis, the serine protease thrombin is a potent mitogen of vascular endothelial and smooth muscle cells. 1,2 Along with endothelial dysfunction, massive proliferation of vascular smooth muscle cells (VSMCs) is one of the prominent characteristics of atherosclerosis, suggesting a role for thrombin in the etiology of the disease. While vascular proliferation, inflammation, apoptosis, and extracellular matrix alterations all contribute to the pathobiology of atherosclerosis, the precise role of each of these processes is poorly understood. In this review, we will consider the role of the thrombin receptor in cell proliferation and invasiveness, which is likely to be relevant to atherosclerotic VSMC proliferation.Most thrombin-regulated cellular events are mediated via the protease activated receptors PAR1, PAR3, and PAR 4. 3 The PARs are a family of seven transmembrane G-protein coupled receptors activated via proteolytic cleavage. This unique mode of activation appears to involve exposure of autoligated sites present on the receptor themselves. 4 -7 While the full repertoire of protease signaling through PARs remains to be determined, this family plays a distinct role in epithelial cell biology. Analysis of PAR1 in the context of normal epithelial function as well as under pathological conditions highlights a new function for this gene (and possibly other members of the PAR family) in normal development and in tumor progression (Figure).Epithelial cells associate into intact polarized sheets and communicate through an intricate network of cell-cell junctions and cell-extracellular matrix (ECM) interactions. This architectural restraint of cell-cell junctions underlined by a basement membrane serves as extra-strict boundaries to maintain normal cellular behavior. A critical event in malignant tumor development is the acquisition of the ability to invade through basement membranes, enter the circulatory system, and re-emerge from blood vessels to establish metastatic colonies at distant sites. This task is accomplished via a well orchestrated set of events including the recruitment of enzymes to remodel targeted locations of the basement membrane microenvironment. We have shown that PAR1 has central roles in breast carcinoma invasion and metastasis 8 as well as in other types of carcinomas (eg, bladder, ov...
BackgroundPopulation genetics predicts that tight linkage between new and/or pre-existing beneficial and deleterious alleles should decrease the efficiency of natural selection in finite populations. By decoupling beneficial and deleterious alleles and facilitating the combination of beneficial alleles, recombination accelerates the formation of high-fitness genotypes. This may impose indirect selection for increased recombination. Despite the progress in theoretical understanding, interplay between recombination and selection remains a controversial issue in evolutionary biology. Even less satisfactory is the situation with crossover interference, which is a deviation of double-crossover frequency in a pair of adjacent intervals from the product of recombination rates in the two intervals expected on the assumption of crossover independence. Here, we report substantial changes in recombination and interference in three long-term directional selection experiments with Drosophila melanogaster: for desiccation (~50 generations), hypoxia, and hyperoxia tolerance (>200 generations each).ResultsFor all three experiments, we found a high interval-specific increase of recombination frequencies in selection lines (up to 40–50 % per interval) compared to the control lines. We also discovered a profound effect of selection on interference as expressed by an increased frequency of double crossovers in selection lines. Our results show that changes in interference are not necessarily coupled with increased recombination.ConclusionsOur results support the theoretical predictions that adaptation to a new environment can promote evolution toward higher recombination. Moreover, this is the first evidence of selection for different recombination-unrelated traits potentially leading, not only to evolution toward increased crossover rates, but also to changes in crossover interference, one of the fundamental features of recombination.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0206-5) contains supplementary material, which is available to authorized users.
Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking B-catenin stabilization. Nuclear localization of B-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces B-catenin nuclear localization also in established epithelial tumor cell lines of intact B-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated B-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced B-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced B-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface ( forming a neutralizing complex of ''Receptors-SFRP-Wnt ''). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PAR1-induced Wnt-4. The striking stabilization of B-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated B-catenin stabilization. This link between PAR1 and B-catenin may bear substantial implications both in developmental and tumor progression processes. (Cancer Res 2006; 66(10): 5224-33)
Human protease-activated receptor-1 (hPar1) plays a role in malignant and physiological invasion processes. We have identified a functional androgen response element (ARE) located in the hPar1 promoter upstream of the transcription start site at -1791 to -1777. Dihydrotestosterone treatment of the prostate cancer cell line LNCaP increased endogenous hPar1 mRNA levels, consistent with the threefold increase in promoter activity of hPar1-luciferase reporter construct. Specific binding of the hPar1-derived ARE to LNCaP nuclear extracts was demonstrated by electrophoretic mobility shift assay. This binding was abrogated by antiandrogen receptor (anti-AR) antibodies or excess cold oligonucleotide but not by a mutated oligonucleotide. Moreover, using chromatin immunoprecipitation assays, we confirm the in vivo interaction between the AR and ARE domain of the hPar1 promoter. In parallel, we show that hormone ablation therapy markedly reduces the otherwise high hPar1 expression levels in prostate cancer biopsy specimens. We suggest that the hPar1 gene is regulated transcriptionally by androgens, representing one of several target genes effectively reduced during hormone ablation therapy. A major limitation of hormonal deprivation is that it causes only a temporary remission, and the cancer eventually reappears in a more malignant, androgen-independent form. hPar1 is also overexpressed in CL1 cells, an aggressively metastasizing, hormone-independent subclone of LNCaP, and in PC3 prostate adenocarcinoma lacking AR in a mechanism yet to be fully elucidated. These data may imply that hPar1 expression correlates with prostate cancer progression in androgen-dependent and -independent phases and therefore, provides an instrumental, therapeutic target for treatment in prostate cancer.
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