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  • MLL family has served as the

    2019-07-24

    MLL family has served as the oncogene in many cancers [8,27,28]. MLL3 has also usually served as a member of MLL/COMPASS complex in the enhancer region. However, the role of MLL3 in the prostate cancer has been less understood. In the present study, we observed that MLL3 was located in the enhancer of PD-L1 and regulated the H3K4me1 level in the enhancer. This regulation continuously promoted PD-L1 RNA and protein expression. Furthermore, the expressions of MLL3 and PD-L1 were positively correlated in the clinical prostate cancer tissues in different clinical database. It was noted that both of MLL3 and PD-L1 were highly expressed in metastasis prostate cancer tissues compared to primary prostate cancer tissues. In tumor tolerating model of mice, MLL3 depletion increased the offense of T cell to the tumor in mice. When the T AMG-176 were increased, the tumor growths were decreased and survivors of mice were increase. When shRNA control and MLL3 depletion tumors were used anti-PD-L1 treatment, both groups' growths of them were blocked. The RNA and protein levels of PD-L1 were downregulated by MLL3 in xenografts. Therefore, these data demonstrated that MLL3 regulated the tumor evasion from immune through the PD-L1 pathway.
    Methods and material
    Statistical analysis Experiments in the paper were carried out with three replicates. Statistical analyses were performed using Student's t-test for most comparisons. The P < 0.05 is statistically significance.
    Conflict of interest
    Introduction Acute pancreatitis (AP) is a sudden inflammation of the pancreas initiated in acinar cells by mechanisms not yet completely understood. Most patients suffer a mild and self-limiting disease that resolves without serious complications, but approximately 20% of patients develop a severe AP with multiple organ dysfunction syndrome associated with high mortality rate. The clinical course and severity of AP can fluctuate fast and unpredictably and unfortunately there is no specific therapy for the disease [1]. Despite numerous studies over the past years, the inner aspects of AP pathogenesis remain elusive, and although different theories have been proposed, they only explain certain aspects of the pathogenesis. Most studies support that premature trypsinogen activation and NF-κB activation are independent and parallel key events in the initiation of the disease [2]. However other factors like oxidative stress, impaired autophagy, mitochondrial injury, aberrant calcium signals, and endoplasmic reticulum (ER) stress, have also been shown to early injure pancreatic acinar cells and contribute to the pathogenesis of the disease [[3], [4], [5], [6]]. A crosstalk between inflammation and ER stress is supported by the observation that the responses of the ER stress stimulate NF-kB activation, a key event in the early stages of AP [3,7]. The ER is critical for the proper folding, maturation and secretion of transmembrane and secreted proteins. When correct folding fails, proteins are targeted for degradation in the cytosol through ubiquitination by the ER-associated degradation (ERAD) and lysosome-mediated protein degradation via autophagy [7,8]. Factors like calcium depletion, oxidative imbalance or high cellular protein demand, perturb the ER causing accumulation of unfolded or misfolded proteins in the lumen, a situation known as ER stress. In this context the ER triggers a well conserved adaptative cellular mechanism known as the unfolded protein response (UPR) [9]. In the early phase of the UPR the adaptative response aims to restore protein folding homeostasis, but if cells fail to recover from ER stress, apoptosis is initiated [10]. Three ER transmembrane proteins orchestrate the UPR: protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6) which under non-stressed situations are associated with the chaperone binding immunoglobulin protein (BiP). Under ER stress BiP preferentially binds unfolded proteins so the stress sensor proteins become active and trigger the UPR [11]. However, some studies also suggest that unfolded proteins directly activate IRE1 [12].