S100A4 promotes the progression of lipopolysaccharide-induced acute epididymitis in mice†

2020 ◽  
Vol 102 (6) ◽  
pp. 1213-1224 ◽  
Author(s):  
Yingjie Wu ◽  
Haoran Li ◽  
Yinghe Qin
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Mrna Levels ◽  
Ki 67 ◽  
Tnf Α ◽  
Proliferation And Apoptosis ◽  
Sperm Membrane ◽  
Marked Cell ◽  
Acute Epididymitis

Abstract S100A4 has been suggested to be a critical regulator of tumor metastasis and is implicated in the progression of inflammation. The aim of this study is to investigate the expression and possible role of S100A4 in epididymitis. Using a mouse model of epididymitis induced by the injection of lipopolysaccharide (LPS) in the deferent duct, we found that LPS administration induced an upregulation of S100a4 transcription (P < 0.05) and a recruitment of S100A4 positive cells in the epididymal interstitium of wild type (WT) mice. Co-immunofluorescence showed that S100A4 was mainly expressed by granulocytes, CD4 lymphocytes, and macrophages. Deficiency of S100A4 reduced epididymal pathological reaction and the mRNA levels of the pro-inflammatory cytokines IL-1β and TNF-α (P < 0.01), suggesting that S100A4 promotes the progression of epididymitis. Furthermore, S100A4 deficiency alleviated the decline of sperm motility and rectified the abnormal expression of sperm membrane protein AMAD3, which suggested that in the progression of epididymitis, S100A4 aggravates the damage to sperm vitality. In addition, both Ki-67 marked cell proliferation and transferase-mediated dUTP-biotin nick end labeling detected cell apoptosis were reduced in S100a4−/− mice compared with WT mice after LPS treatment, indicating that S100A4 promotes both cell proliferation and cell apoptosis in epididymitis. Overall, these results demonstrate that S100A4 promotes the progression of LPS-induced epididymitis and facilitates a decline in sperm vitality, and its function may be related to the process of cell proliferation and apoptosis during inflammation.

scholarly journals Dexamethasone can attenuate the pulmonary inflammatory response via regulation of the lncH19/miR-324-3p cascade

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Ye Chen ◽  
Chao Zhang ◽  
Chang-xue Xiao ◽  
Xiao-dong Li ◽  
Zhi-li Hu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Cell Apoptosis ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Inflammatory Genes ◽  
Functional Studies ◽  
Tnf Α ◽  
Pulmonary Inflammatory Response

Abstract Objective To investigate lncRNAs and their roles in regulating the pulmonary inflammatory response under dexamethasone (Dex) treatment. Methods IL-1β (10 ng/mL) and LPS (1 μg/mL) was used to construct inflammatory cell models with A549 cells; IL-1β performed better against LPS. Different concentrations of Dex were used to attenuate the inflammation induced by IL-1β, and its effect was assessed via RT-PCR to detect inflammatory cytokine-related mRNA levels, including those of IKβ-α, IKKβ, IL-6, IL-8, and TNF-α. Furthermore, ELISA was used to detect the levels of the inflammatory cytokines TNF-α, IL-6, and IL-8. RT-PCR was used to quantify the levels of lncRNAs, including lncMALAT1, lncHotair, lncH19, and lncNeat1. LncH19 was most closely associated with the inflammatory response, which was induced by IL-1β and attenuated by Dex. Among the lncRNAs, the level of lncH19 showed the highest increase following treatment with 1 and 10 μM Dex. Therefore, lncH19 was selected for further functional studies. LncH19 expression was inhibited by shRNA transduced with lentivirus. Cell assays for cell proliferation and apoptosis as well as RT-PCR, western blot, and ELISA for inflammatory genes were conducted to confirm the functions of lncH19. The predicted target miRNAs of lncH19 were hsa-miR-346, hsa-miR-324-3p, hsa-miR-18a-3p, hsa-miR-18b-5p, hsa-miR-146b-3p, hsa-miR-19b-3p, and hsa-miR-19a-3p. Following estimation via RT-PCR, hsa-miR-346, hsa-miR-18a-3p, and hsa-miR-324-3p showed consistent patterns in A549 NC and A549 shlncH19. An miRNA inhibitor was transfected into A549 NC and A549 shlncH19 cells, and the expression levels were determined via RT-PCR. hsa-miR-324-3p was inhibited the most compared with hsa-miR-346 and hsa-miR-18a-3p and was subjected to further functional studies. RT-PCR, ELISA, and western blotting for inflammatory gene detection were conducted to validate the functions of the target hsa-miR-324-3p. Results Treatment with 1 and 10 μM Dex could effectively attenuate the inflammatory response. During this process, lncH19 expression significantly increased (P < 0.05). Therefore, treatment with 1 μM Dex was used for further study. Under IL-1β treatment with or without Dex, lncH19 inhibition led to an increase in cell proliferation; a decrease in cell apoptosis; an increase in the protein levels of inflammatory genes; phosphorylation of P65, ICAM-1, and VCAM-1; and increase inflammatory cytokines. Prediction of the targets of lncH19 and validation via RT-PCR revealed that miR-346, miR-18a-3p, and miR-324-3p negatively correlate with lncH19. Additionally, Dex increased the lncH19 expression but reduced that of the miRNAs. Among the miRNAs, miR-324-3p was the most markedly downregulated miRNA following treatment of miRNA inhibitors. The MTS assay and cell apoptosis assay showed that the miR-324-3p inhibitor inhibited cell proliferation and induced cell apoptosis, thereby significantly attenuating the inflammatory response, which reversed the effect of lncH19 in regulating cell proliferation and the secretion of inflammatory cytokines (P < 0.05). Therefore, lncH19 might regulate miR-324-3p in pulmonary inflammatory response under Dex treatment. Conclusion Dex can attenuate the pulmonary inflammatory response by regulating the lncH19/miR-324-3p cascade.

miR-338-3p inhibits HIF-1α to Attenuate Nucleus Pulposus Cell Proliferation and Promote Apoptosis Through the Hippo-YAP Pathway

2021 ◽  
Author(s):  
Daolu Zhan ◽  
Jian Liu ◽  
Mingxia Lin ◽  
Jian Chen ◽  
Yehan Fang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nucleus Pulposus ◽  
Intervertebral Disc Degeneration ◽  
Nucleus Pulposus Cell ◽  
Luciferase Assay ◽  
Ki 67 ◽  
Pathway Activation ◽  
Proliferation And Apoptosis ◽  
Related Proteins

Abstract The proliferation and apoptosis of nucleus pulposus (NP) cells (NPCs) play a crucial role in intervertebral disc degeneration (IDD). we aimed to discover the role of miRNA-induced IDD. We analyzed the miRNA expression of three NP tissues from IDD patients and three normal NP samples using the GEO2R tool, and The results revealed that miR-338-3p was upregulated in NPCs from IDD patients. miR-338-3p suppressed NPCs proliferation, and the related proteins PCNA and Ki-67 were downregulated, as demonstrated via western blotting. miR-338-3p promoted apoptosis. Furthermore, we predicted that HIF-1α was targeted by miR-338-3p, using the miRDB database, and this target was validated via dual luciferase assay. HIF-1α reversed miR-338-3p-induced NPCs proliferation and apoptosis. The Hippo-YAP pathway activation proteins YAP, CTGF, and PCNA were upregulated, unlike the inhibitory YAP phosphorylation. In conclusions, our results suggestive that miR-338-3p inhibited HIF-1α/ Hippo-YAP pathway to attenuate NPCs proliferation and apoptosis.

Regular Voluntary Running Inhibits Androgen-Independent Prostate Cancer Growth in Mice

2021 ◽  
pp. 1-7
Author(s):  
Mário Esteves ◽  
Carina Silva ◽  
Sofia S. Pereira ◽  
Tiago Morais ◽  
Ângela Moreira ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Study Groups ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Voluntary Running ◽  
Proliferation And Apoptosis ◽  
Phosphate Buffered Saline ◽  
Androgen Independent

Introduction: Benefits of regular physical exercise were demonstrated as preventive and coadjuvant nonpharmacological anticancer therapy. However, the role of exercise in modulating prostate cancer behavior has yet to be established. Methods: Prostate tumors were induced in C57BL/6 male mice (n = 28) by subcutaneous inoculation of a suspension of murine androgen-independent RM1 cells (1.5 × 105 cells/500 μL phosphate-buffered saline) in the dorsal region. Mice were randomly allocated into 2 study groups: sedentary tumor-induced (n = 14) and exercised tumor-induced (n = 14). Exercise consisted of voluntary running in wheeled cages. Mice (n = 7 per group) were sacrificed either 14 or 28 days after cell inoculation to evaluate tumor weight and percentage of area occupied by immunohistochemistry stained cells for Ki-67 and TdT-mediated dUTP-biotin nick end labeling, used as surrogate markers of cell proliferation and apoptosis, respectively. Results: Compared with sedentary tumor-induced mice, the tumors developed by exercised tumor-induced mice were significantly smaller at 14 days (0.17 [0.12] g vs 0.48 [0.24] g, P < .05) and at 28 days (0.92 [0.73] g vs 2.09 [1.31] g, P < .05), with smaller Ki-67 and greater TdT-mediated dUTP-biotin nick end-labeling stained areas (P < .05). Conclusion: These results suggest that regular voluntary running inhibits prostate cancer cell growth by reducing cell proliferation and enhancing apoptosis.

microRNA-939 Promotes the Vitality of Human Breast Cancer Cells via Inhibition of E2F1/P73 Signaling

2021 ◽  
Vol 11 (5) ◽  
pp. 832-840
Author(s):  
Shuaibing Wang ◽  
Xiuheng Qi ◽  
Hong Liu
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Target Gene ◽  
Disease Free Survival ◽  
Luciferase Assay ◽  
Clinical Samples ◽  
Mrna Levels ◽  
Ki 67 ◽  
Proliferation And Apoptosis

We assessed miR-939’s role in breast cancer (BC) and its molecular mechanism. PCR was performed to detect miRNA levels. Correlations between miR-939 and patients’ pathological information were analyzed. After transfection of E2F1 plasmid, P73 plasmid, si-E2F1, si-P73, miR-939 mimic or si-miR-939, cell proliferation and apoptosis were measured. The miR-939 target gene was proved by a luciferase assay. Protein and mRNA levels of E2F1 and P73 were detected by immunoblotting and PCR, and corresponding proliferation or apoptosis were assessed. MiR-939 expression was significantly increased in BC and associated with TNM staging, Ki-67 enhancement, and shorter disease-free survival time. In BC clinical samples, E2F1 expression is negatively correlated with miR-939 expressions. Overexpressing miR-939 stimulated growth but suppressed cell apoptosis. Functional analysis indicated E2F1 is the target gene of miR-939, and overexpression of miR-939 significantly downregulated E2F1 and P73. Silencing of E2F1 or P73 significantly promoted MDA-MB-231 cell proliferation and inhibited apoptosis. Overexpression of E2F1 plasmid or P73 plasmid significantly inhibited MDA-MB-231 cell proliferation but induced apoptosis. Transfection of P73 or E2F1 plasmid abolished miR-939’s effects on proliferation and apoptosis. miR-939 promotes breast cancer progression by downregulation of E2F1 to inhibit P73 pathway, thereby promoting proliferation and inhibiting apoptosis.

scholarly journals LINC00221 suppresses the malignancy of children acute lymphoblastic leukemia

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Man Huang ◽  
Jiajia Zheng ◽  
Yongya Ren ◽  
Jingjing Zhu ◽  
Linbing Kou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Ki 67 ◽  
Protein Coding ◽  
Proliferation And Apoptosis ◽  
Rna Immunoprecipitation ◽  
Non Coding Rnas

Abstract As the most common malignant disease in childhood, children acute lymphoblastic leukemia (ALL) is a heterogeneous disease caused by the accumulated genetic alterations. Long non-coding RNAs (lncRNAs) are reported as critical regulators in diseases. GEPIA database indicated that long intergenic non-protein coding RNA 221 (LINC00221) was conspicuously down-regulated in acute myeloid leukemia. However, its expression pattern in ALL has not been revealed. This work was carried out to study the role of LINC00221 in ALL cells. Quantitative real-time PCR (qRT-PCR) quantified LINC00221 expression in ALL cells. The function of LINC00221 in ALL was determined by ki-67 immunofluorescence staining, EdU, TUNEL, JC-1, and caspase-3/8/9 activity assays. RNA pull down and Ago2-RNA immunoprecipitation (RIP) assays investigated the interaction between miR-152-3p and LINC00221 or ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (ATP2A2). Our study revealed the low expression of LINC00221 in ALL cells. Subsequently, LINC00221 was verified to bind with miR-152-3p. Moreover, functional assays pointed out that LINC00221 overexpression posed anti-proliferation and pro-apoptosis effects in ALL cells, and these effects could be separately reversed by miR-152-3p up-regulation. Afterward, LINC00221 was revealed to regulate ATP2A2 expression via sponging miR-152-3p. Additionally, ATP2A2 was verified to involve in regulating LINC00221-mediated ALL cell proliferation and apoptosis. In conclusion, LINC00221 suppressed ALL cell proliferation and boosted ALL cell apoptosis via sponging miR-152-3p to up-regulate ATP2A2.

scholarly journals Dexamethasone can attenuate the pulmonary inflammatory response via regulation of the lncH19/miR-324-3p cascade

2020 ◽  
Author(s):  
Ye Chen ◽  
Chao Zhang ◽  
Chang-xue Xiao ◽  
Xiao-dong Li ◽  
Zhi-li Hu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Cell Apoptosis ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Inflammatory Genes ◽  
Functional Studies ◽  
Tnf Α ◽  
Pulmonary Inflammatory Response

Abstract Objective: To investigate lncRNAs and their roles in regulating the pulmonary inflammatory response under dexamethasone (Dex) treatmentMethods: IL-1β (10 ng/mL) and LPS (1 μg/mL) was used to construct inflammatory cell models with A549 cells; IL-1β performed better against LPS. Different concentrations of Dex were used to attenuate the inflammation induced by IL-1β, and its effect was assessed via RT-PCR to detect inflammatory cytokine-related mRNA levels, including those of IKβ-α, IKKβ, IL-6, IL-8, and TNF-α. Furthermore, ELISA was used to detect the levels of the inflammatory cytokines TNF-α, IL-6, and IL-8. RT-PCR was used to quantify the levels of lncRNAs, including lncMALAT1, lncHotair, lncH19, and lncNeat1. LncH19 was most closely associated with the inflammatory response, which was induced by IL-1β and attenuated by Dex. Among the lncRNAs, the level of lncH19 showed the highest increase following treatment with 1 and 10 μM Dex. Therefore, lncH19 was selected for further functional studies. LncH19 expression was inhibited by shRNA transduced with lentivirus. Cell assays for cell proliferation and apoptosis as well as RT-PCR, western blot, and ELISA for inflammatory genes were conducted to confirm the functions of lncH19. The predicted target miRNAs of lncH19 were hsa-miR-346, hsa-miR-324-3p, hsa-miR-18a-3p, hsa-miR-18b-5p, hsa-miR-146b-3p, hsa-miR-19b-3p, and hsa-miR-19a-3p. Following estimation via RT-PCR, hsa-miR-346, hsa-miR-18a-3p, and hsa-miR-324-3p showed consistent patterns in A549 NC and A549 shlncH19. An miRNA inhibitor was transfected into A549 NC and A549 shlncH19 cells, and the expression levels were determined via RT-PCR. hsa-miR-324-3p was inhibited the most compared with hsa-miR-346 and hsa-miR-18a-3p and was subjected to further functional studies. RT-PCR, ELISA, and western blotting for inflammatory gene detection were conducted to validate the functions of the target hsa-miR-324-3p.Results: Treatment with 1 and 10 μM Dex could effectively attenuate the inflammatory response. During this process, lncH19 expression significantly increased (P < 0.05). Therefore, treatment with 1 µM Dex was used for further study. Under IL-1β treatment with or without Dex, lncH19 inhibition led to an increase in cell proliferation; a decrease in cell apoptosis; an increase in the protein levels of inflammatory genes; phosphorylation of P65, ICAM-1, and VCAM-1; and increase inflammatory cytokines. Prediction of the targets of lncH19 and validation via RT-PCR revealed that miR-346, miR-18a-3p, and miR-324-3p negatively correlate with lncH19. Additionally, Dex increased the lncH19 expression but reduced that of the miRNAs. Among the miRNAs, miR-324-3p was the most markedly downregulated miRNA following treatment of miRNA inhibitors. The MTS assay and cell apoptosis assay showed that the miR-324-3p inhibitor inhibited cell proliferation and induced cell apoptosis, thereby significantly attenuating the inflammatory response, which reversed the effect of lncH19 in regulating cell proliferation and the secretion of inflammatory cytokines (P < 0.05). Therefore, lncH19 might regulate miR-324-3p in pulmonary inflammatory response under Dex treatment.Conclusion: Dex can attenuate the pulmonary inflammatory response by regulating the lncH19/miR-324-3p cascade.

scholarly journals miR-149 inhibits cell proliferation and enhances chemosensitivity by targeting CDC42 and BCL2 in neuroblastoma

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Fengxia Mao ◽  
Ju Zhang ◽  
Xinru Cheng ◽  
Qianya Xu
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Colony Formation ◽  
Luciferase Activity ◽  
B Cell Lymphoma ◽  
Mrna Levels ◽  
Poor Survival ◽  
Rna Immunoprecipitation ◽  
Polymerase Chain

Abstract Background Neuroblastoma (NB) is one of most common childhood tumors with high mortality among children worldwide. microRNAs (miRNAs) have been reported to play essential roles in the pathogenesis and therapeutics of NB. However, the role of miR-149 and its mechanism remain poorly understood. Main methods The expression levels of miR-149, cell division cycle 42 (CDC42) and B-cell lymphoma 2 (BCL2) were measured in NB tissues or cells by quantitative real-time polymerase chain reaction or western blot. Cell proliferation was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and colony formation assays. Cell apoptosis was detected by flow cytometry. Chemosensitivity of NB cells to doxorubicin (Dox) was analyzed by MTT assay. The interaction between miR-149 and CDC42 or BCL2 was explored by luciferase activity and RNA immunoprecipitation analyses. Results Our data indicated that low expression of miR-149 was displayed in NB tissues and cells and associated with poor survival rate. Overexpression of miR-149 inhibited cell proliferation and colony formation but promoted cell apoptosis and chemosensitivity to Dox in NB cells. Moreover, CDC42 and BCL2 were targeted by miR-149. Additionally, CDC42 and BCL2 mRNA levels were elevated in NB tissues and cells and restoration of CDC42 or BCL2 reversed the regulatory effect of miR-149 on NB progression. Conclusion Our data suggested that miR-149 suppressed cell proliferation and improved Dox chemosensitivity by regulating CDC42 and BCL2 in NB, providing a novel avenue for treatment of NB.

LncRNA LINC00858 enhances cervical cancer cell growth through miR-3064-5p/ VMA21 axis

2021 ◽  
pp. 1-11
Author(s):  
Min Wei ◽  
Youguo Chen ◽  
Wensheng Du
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Luciferase Reporter ◽  
Cancer Cell Growth ◽  
Protein Coding ◽  
Gynecological Malignancy ◽  
Promising Therapeutic Target ◽  
Proliferation And Apoptosis ◽  
Reporter Assays

BACKGROUND: Cervical cancer (CC) is the most common form of gynecological malignancy. Long intergenic non-protein coding RNA 858 (LINC00858) has been identified to participate in multiple cancers. However, the role and mechanism of LINC00858 in CC cells are still elusive. AIM: The aim of this study is to explore the biological functions and mechanisms of LINC00858 in CC cells. METHODS: RT-qPCR analysis was used to examine the expression of LINC00858 in CC cells. EdU and colony formation assay were utilized to assess cell proliferation. TUNEL assay and flow cytometry assay were conducted to assess cell apoptosis. The mechanism regarding LINC00858 was certified through RNA pull down, RIP and luciferase reporter assays. RESULTS: The up-regulated LINC00858 was detected in CC cells. Reduction of LINC00858 effectively subdued CC cells proliferation and stimulated cell apoptosis. LINC00858 was determined to bind with miR-3064-5p and up-regulate VMA21 in CC cells. In rescue assays, miR-3064-5p down-regulation and VMA21 up-regulation were able to counteract the effect caused by LINC00858 decrease on CC cell proliferation and apoptosis. CONCLUSION: LINC00858 enhances cell proliferation, while restraining cell apoptosis in CC through targeting miR-3064-5p/VMA21 axis, implying that LINC00858 may serve as a promising therapeutic target for CC.

scholarly journals Expression of miR-195 and its target gene Bcl-2 in human intervertebral disc degeneration and their effects on nucleus pulposus cell apoptosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xue-Lin Lin ◽  
Zhao-Yun Zheng ◽  
Qing-Shan Zhang ◽  
Zhen Zhang ◽  
You-Zhi An
Keyword(s):  
Cell Proliferation ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Rat Model ◽  
Cell Apoptosis ◽  
Intervertebral Disc Degeneration ◽  
Target Gene ◽  
Blank Group ◽  
Tnf Α

Abstract Objective To investigate the expression of miR-195 and its target gene Bcl-2 in intervertebral disc degeneration (IVDD) and its effect on nucleus pulposus (NP) cell apoptosis. Methods The expressions of miR-195 and Bcl-2 in NP tissues of IVDD patients were quantified by qRT-PCR and western blotting, respectively. NP cells were divided into blank group, TNF-α group, TNF-α + miR-NC group, TNF-α + siBcl-2 group, and TNF-α + miR-195 inhibitors + siBcl-2 group. Cell proliferation was detected by MTT assay, cell apoptosis evaluated by flow cytometry, and mitochondrial membrane potential (MMP) tested by JC-1 staining. Moreover, the function of miR-195 on IVDD in vivo was investigated using a puncture-induced IVDD rat model. Results IVDD patients had significantly increased miR-195 expression and decreased Bcl-2 protein expression in NP tissues. The expression of miR-195 was negatively correlated with the expression of Bcl-2 in IVDD patients. Dual-luciferase reporter gene assay indicated that Bcl-2 was a target gene of miR-195. In comparison with blank group, TNF-α group showed decreased cell proliferation and MMP, increased cell apoptosis, upregulated expression of miR-195, Bax, and cleaved caspase 3, and downregulated Bcl-2 protein, while these changes were attenuated by miR-195 inhibitors. Additionally, siBcl-2 can reverse the protective effect of miR-195 inhibitors on TNF-α-induced NP cells. Besides, inhibition of miR-195 alleviated IVDD degeneration and NP cell apoptosis in the rat model. Conclusion MiR-195 was significantly upregulated in NP tissues of IVDD patients, and inhibition of miR-195 could protect human NP cells from TNF-α-induced apoptosis via upregulation of Bcl-2.

scholarly journals Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

2021 ◽  
Vol 22 (4) ◽  
pp. 2047
Author(s):  
Nina Schmid ◽  
Kim-Gwendolyn Dietrich ◽  
Ignasi Forne ◽  
Alexander Burges ◽  
Magdalena Szymanska ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Drug Targets ◽  
Growth Regulation ◽  
Sirtuin 1 ◽  
Ki 67 ◽  
Granulosa Cell Tumors ◽  
Novel Drug

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

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