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    • The purpose of this study is to

    2020-09-18

    The purpose of this study is to investigate KDM1B expression and its functional significance in PC. We used lentivirus-mediated shRNA to down-regulate KDM1B expression in PC cell lines in vitro and detected the changes of cell proliferation and apoptosis. These studies provided a novel insight into the functional role of KDM1B in PC progression.
    Materials and methods
    Results
    Disscusion The Multidisciplinary Pancreatic Cancer Clinic developed a pancreatic cancer treatment plan based on the unique needs of the patient, only approximately 20% of the tumors were found to be operable or resectable. Therefore, it is necessary for us to look for the specific indicator and diagnosis of pancreatic cancer in the early stage. Previous studies have proven that epigenetic modifications play an important role in pancreatic cancer [33,34]. In the present study, we evaluated the functional significance of KDM1B in PC and its potential as a therapeutic target or a biomarker. We demonstrated that overexpression of KDM1B was a frequent event in PC. Next, we used lentivirus-mediated shRNA to silence KDM1B expression in PC cells. Knockdown of KDM1B significantly reduced cell proliferation in PANC-1 and SW1990 silibinin as suggested by both MTT and Celigo tests. Moreover, KDM1B knockdown increased the activity of Caspase3/7, indicating that KDM1B may decrease the apoptosis trend of PC cells. Flow cytometry also identified the inhibition effect of KDM1B on apoptosis of PANC-1 and SW1990 cells. These results suggested that KDM1B might play a critical role in promoting PC cell proliferation. Our data were in accordance with a previous report showing the knockdown of KDM1B in breast cancer cells, which led to a significant reduction in cell proliferation [35]. Furthermore, to illuminate the molecular mechanisms by which KDM1B affects PC cell growth, we detected modifications of some molecules associated with cell apoptosis, growth and survival control in PANC-1 cells after KDM1B knockdown. It may be logical to consider that higher levels of apoptosis in a tumor could lead to a better prognosis. Apoptosis mediated by either the intrinsic or extrinsic pathways results in cleavage of Caspase-3, Caspase-7. Caspase-3 is rarely mutated in pancreatic cancer and is therefore an ideal marker for measuring apoptosis in these tumors [36]. Our studies have validated the use of active caspase-3 staining as a marker for apoptosis. To further validate apoptosis within the tumor, cleavage of the poly (ADP-ribose) polymerase (PARP) catalyzed by caspase-3 was also measured. The activations of all these three apoptosis-related molecules were increased by KDM1B knockdown, which strongly confirmed that KDM1B plays a key role in PC apoptosis in vitro. To the best of our knowledge, this is the first in vitro study concerning the effects of KDM1B against PC cell growth. Previous studies reviewed the anti-apoptotic effect of NF-κB [37]. In the present study, when shKDM1B was used to interfere with the expression of KDM1B, the IkBa was greatly down-regulated. These results suggested that the inhibition of NF-κB signaling served a critical role in the inhibitory effect of KDM1B against apoptosis in PANC-1 cells. Previous studies demonstrated that survivin was a small molecular, acting as a genuine apoptosis inhibitor [38], which contradicted our results in the antibody chip. In our studies, the expression of survivin was up-regulated, accompanying the activation of p-ERK/eIF2a signaling pathway, whereas the apoptosis was increased. On the contrary, high level of p-ERK/eIF2a contributes to the occurrence and development of hepatocyte cell apoptosis in alcoholic liver injury rats [39]. Therefore, further verification of p-ERK/eIF2a signaling pathway should be taken. The antibody chip brought up another hint that KDM1B knockdown induced up-regulation of p-p53 and p-Smad2. The p53 pathway is targeted for inactivation in most human cancers either directly or indirectly, highlighting its critical function as a tumor suppressor gene. Upon activation, p53 mediates a growth-suppressive effect on cells by blocking the cell cycle or it can lead cells to undergo programmed cell death primarily by binding to particular DNA sequences and activating transcription of specific genes. Furthermore, previous study has demonstrated that TGF-β/Smad signaling is operational in PC [40]. We for the first time found that KDM1B suppressed apoptosis in PC cells probably via p53/Smad signaling.