scholarly journals LINC00893 Inhibits The Progression of Prostate Cancer Through miR-3173-5p/SOCS3/JAK2/STAT3 Pathway

2021 ◽  
Author(s):  
Chuigong Yu ◽  
Yu Fan ◽  
Yu Zhang ◽  
Lupeng Liu ◽  
Gang Guo
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 inhibits the proliferation and metastasis of papillary thyroid cancer (PTC) cells, but its role in PCa has not been reported. Our study aims to clarify the role and underlying mechanism of LINC00893 in regulating the progression of PCa.Methods: We analyzed LINC00893 expression through TCGA database. We also collected 66 paires of PCa tissues and matched para-cancerous tissues as well as cell lines and assessed LINC00893 expression. Subsequently, we conducted gain-of-function assays to confirm the role of LINC00893 in PCa. CCK-8, EdU, colony information and transwell assays were implemented to detect cell proliferation, colony formation and metastasis abilities, respectively. RT-qPCR and western blot assays were used to quantify the expression of mRNA and protein. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull down assays were conducted to evaluate the interaction of molecules. Spearman correlation coefficient analysis was conducted to detect the correlation between molecules.Results: We found that the LINC00893 expression in PCa tissues and cell lines was upregulated compared with matched controls, and patients with low expression of LINC00893 suffered a low overall survival rate. Overexpression of LINC00893 hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as metastasis of PCa cells in vitro and in vivo. In terms of mechanism, suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway occupied a central position in the regulation of PCa progression by LINC00893. LINC00893 weakened the inhibition role of miR-3173-5p on SOCS3 expression through functioning as a miR-3173-5p sponge, which inhibited the JAK2/STAT3 signaling pathway. Conclusions: LINC00893 suppresses the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway. our data uncovers a novel mechanism by which LINC00893 hinders the progression of PCa, which enriches the molecular network of LINC00893 regulating the PCa progression and laies a theoretical foundation for PCa targeted therapy.

scholarly journals Krupple-Like Factor 5 is a Potential Therapeutic Target and Prognostic Marker in Epithelial Ovarian Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Abdul K. Siraj ◽  
Poyil Pratheeshkumar ◽  
Sasidharan Padmaja Divya ◽  
Sandeep Kumar Parvathareddy ◽  
Khadija A. Alobaisi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. Krupple-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in a variety of cancer types. However, its role and expression in EOC is not fully illustrated. Immunohistochemical analysis was performed to assess KLF5 protein expression in 425 primary EOC samples using tissue microarray. We also addressed the function of KLF5 in EOC and its interaction with signal transducer and activator of transcription 3 (STAT3) signaling pathway. We found that KLF5 overexpressed in 53% (229/425) of EOC samples, and is associated with aggressive markers. Forced expression of KLF5 enhanced cell growth in low expressing EOC cell line, MDAH2774. Conversely, knockdown of KLF5 reduced cell growth, migration, invasion and progression of epithelial to mesenchymal transition in KLF5 expressing cell lines, OVISE and OVSAHO. Importantly, silencing of KLF5 decreased the self-renewal ability of spheroids generated from OVISE and OVSAHO cell lines. In addition, downregulation of KLF5 potentiated the effect of cisplatin to induce apoptosis in these cell lines. These data reveals the pro-tumorigenic role of KLF5 in EOC and uncover its role in activation of STAT3 signaling pathway, suggesting the importance of KLF5 as a potential therapeutic target for EOC therapy.

scholarly journals Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway

2020 ◽  
Vol 21 (2) ◽  
pp. 438 ◽  
Author(s):  
Abdul Q. Khan ◽  
Eiman I. Ahmed ◽  
Noor Elareer ◽  
Hamna Fathima ◽  
Kirti S. Prabhu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
Papillary Thyroid Cancer ◽  
Cell Lines ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Cytotoxic Effects ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705–STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study’s findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.

Lipopolysaccharide induces epithelial–mesenchymal transition of alveolar epithelial cells cocultured with macrophages possibly via the JAK2/STAT3 signaling pathway

2019 ◽  
Vol 39 (2) ◽  
pp. 224-234 ◽  
Author(s):  
Y Qin ◽  
P Zhao ◽  
Y Chen ◽  
X Liu ◽  
H Dong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Markers ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Epithelial–mesenchymal transition (EMT) plays a key role in the process of pulmonary fibrosis (PF). Increasing evidences have shown that exaggerated EMT in recurrent pulmonary injury mediates the early pathogenesis of PF. This study aimed to evaluate EMT of human alveolar epithelial cells (A549) when cocultured with human macrophages Tohoku hospital pediatrics-1 (THP-1) induced by lipopolysaccharide (LPS) and investigate the role of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Firstly, we detected the inflammatory and EMT biomarkers in A549 cells monoculture and A549/THP-1 cells coculture in the presence or absence of LPS. Then, the activation of JAK2/STAT3 signaling pathway was determined in coculture. Interestingly, inflammatory markers, such as interleukin (IL)-6, matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)- β, and collagen type 1 (COL-1), were enhanced in LPS treated coculture. Besides, the expression of E-cadherin decreased but α-smooth muscle actin expression increased, indicating the presence of EMT in A549 cells when cocultured with THP-1 macrophages. However, these phenotypes could not be observed in LPS-treated A549 cells monoculture. Meanwhile, JAK2/STAT3 signaling pathway was activated, and the STAT3 DNA-binding and inflammatory markers were inhibited by Stattic. Together, these findings demonstrate the key role of JAK2/STAT3 signaling pathway in LPS promoted EMT of A549 in the presence of THP-1 macrophages as an in vitro PF model.

5,7,3′-Triacetyl Hesperetin Suppresses Adjuvant-Induced Arthritis in Rats through Modulating JAK2/STAT3 Pathway

2013 ◽  
Vol 41 (03) ◽  
pp. 601-614 ◽  
Author(s):  
Dan Yang Ren ◽  
Tao Xu ◽  
Rong Li ◽  
Cheng Huang ◽  
Yan Huang ◽  
...  
Keyword(s):  
Janus Kinase ◽  
Rt Pcr ◽  
Signal Transducers ◽  
Stat3 Pathway ◽  
Immune Organs ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Index Index ◽  
Synovial Tissues

This work was designed to identify the effect of 5,7,3′-triacetyl hesperetin (TAHP) on rat adjuvant arthritis (AA) and further clarify the possible role of TAHP on modulating Janus kinase signal transducers and activators (JAK/STAT in this process. Freund's complete adjuvant was used to induce AA in rats. TAHP (33, 66, 132 mg/kg) was administered intragastrically. Secondary paw swelling, polyarthritis index, index of immune organs and histopathological assessment were used to evaluate the effects of TAHP on AA in rats. IL-6 in serum and in synovial tissues was examined with ELISA and RT-PCR. In addition, JAK2/STAT3 pathway-related key molecules mRNA expression in synovial tissues of AA rats were detected by RT-PCR and western blot respectively. It was found that TAHP (66, 132 mg/kg) could significantly inhibit secondary paw swelling, restore the index of immune organs and reduce polyarthritis index. Results of histopathological assessment showed that TAHP clearly ameliorated the pathological changes in AA rats. TAHP could downregulate the level of IL-6 in serum and in synovial tissues of AA rats. Besides, treatment with TAHP could decrease mRNA expressions of STAT3 and JAK2, as well as the ratio of p-JAK2/JAK2 protein and p-STAT3/STAT3 protein from synovial tissues. Thus, the paper demonstrated that TAHP had a therapeutic effect on AA in rats and the mechanisms were partly associated with modulating proinflammatory cytokine IL-6 production in serum and in synovial tissues and inhibiting excessive activation of JAK2/STAT3 signaling pathway which might play a crucial role in the pathogenesis of AA.

scholarly journals The long non-coding RNA LINC00473 contributes to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2 axis in prostate cancer

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Zengshu Xing ◽  
Sailian Li ◽  
Zhenxiang Liu ◽  
Chong Zhang ◽  
Meijiang Meng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Stat3 Signaling ◽  
Non Coding Rna ◽  
Stat3 Signaling Pathway ◽  
High Incidence ◽  
Long Non Coding Rna

Abstract Prostate cancer is a kind of male malignant tumor, which has brought tremendous health threat to men. Prostate cancer is difficult to be cured because of high incidence and metastasis rate. Thereby, it is of great urgency to elucidate the underlying molecular mechanism of prostate cancer for the treatment of this cancer. LINC00473 dysregulation has been observed in many cancers. However, the role of LINC00473 was unknown in prostate cancer. In the present study, we discovered that prostate cancer cells presented high expression of LINC00473, and LINC00473 inhibition limited cell proliferation and the expression of proteins in JAK-STAT3 signaling pathway. Additionally, LINC00473 acted as an up-stream factor for miR-195-5p to negatively modulate miR-195-5p expression. Moreover, SEPT2 interacted with miR-195-5p in prostate cancer and SEPT2 expression was positively modulated by LINC00473 and negatively regulated by miR-195-5p. Last, the inhibitory effect of LINC00473 knockdown on cell proliferation and expression of proteins of JAK-STAT3 signaling pathway was restored by SEPT2 overexpression. All in all, LINC00473 contributed to cell proliferation via JAK-STAT3 signaling pathway by regulating miR-195-5p/SEPT2 axis in prostate cancer, which provided a novel therapeutic tactic for prostate cancer patients.

scholarly journals STEAP1 facilitates metastasis and epithelial–mesenchymal transition of lung adenocarcinoma via the JAK2/STAT3 signaling pathway

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Shu-fen Huo ◽  
Wen-li Shang ◽  
Min Yu ◽  
Xiao-ping Ren ◽  
Hong-xia Wen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Janus Kinase ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a relatively newly identified gene target from prostate cancer, breast cancer, and gastric cancer. However, functions of STEAP1 in lung adenocarcinoma (LUAD) are still unknown. In the present study, we explored the molecular and cellular mechanisms of STEAP1 in LUAD. Western blot and Q-PCR were conducted to detect the protein and mRNA expressions respectively. The cell proliferation was tested by CCK8 assay. The effects of STEAP1 on the metastasis and epithelial–mesenchymal transition (EMT) of LUAD were evaluated by EdU assay, wound healing assay, and transwell migratory assay. H1650, H358, HCC827, H1299, H23, A549, H1693 were selected as human LUAD cell lines in the study. Results have shown that STEAP1 expression was up-regulated in LUAD cells compared with normal lung epithelial cells. Knockdowning of STEAP1 suppressed the proliferation, migration, and invasion of LUAD epithelial cells. Importantly, after comparing the proliferation, migration, and invasion of LUAD to the corresponding control groups treated in STAT3 inhibitor ADZ1480, we found that STEAP1 regulates EMT via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. In conclusion, STEAP1 can serve as a therapeutic target, and it may have important clinical implications for LUAD treatment.

scholarly journals Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 217 ◽  
Author(s):  
Wook Jin
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Signaling Pathway ◽  
Essential Role ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial–mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.

scholarly journals Central Nervous System Inflammation Induced by Lipopolysaccharide Up-Regulates Hepatic Hepcidin Expression by Activating the IL-6/JAK2/STAT3 Pathway in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Fali Zhang ◽  
Peng Zhao ◽  
Zhongming Qian ◽  
Mingkang Zhong
Keyword(s):  
Iron Metabolism ◽  
Transferrin Saturation ◽  
Janus Kinase ◽  
Stat3 Pathway ◽  
Hepcidin Expression ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Transcription 3 ◽  
The Brain

It is known that lipopolysaccharide (LPS) triggers inflammatory response after intracerebroventricular (ICV) injection and elevates the expression of hepcidin through the interleukin 6/janus kinase 2/transducer and activator of the transcription 3 (IL-6/JAK2/STAT3) signaling pathway in the brain. This study was conducted to determine whether LPS ICV injection can regulate peripheral hepatic hepcidin expression and iron metabolism. Here, we studied the hepcidin expression in the liver, as well as serum iron and transferrin saturation, after LPS ICV injection. We also demonstrated the role of the IL-6/JAK2/STAT3 pathway in hepcidin expression in the livers of IL-6 knockout (IL-6–/– mice) and IL-6+/+ mice. AG490 was used to verify the effect of the IL-6/JAK2/STAT3 pathway on hepatic hepcidin expression. Our present study demonstrated that LPS ICV injection up-regulated hepatic hepcidin expression. This finding provides further evidence for highlighting the importance of the central inflammation on hepatic hepcidin expression and peripheral iron metabolism.

Panobinostat Inhibits JAK2/STAT3 Pathway in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2849-2849
Author(s):  
Giulia Perrone ◽  
Elisabetta Calabrese ◽  
Teru Hideshima ◽  
Gullu Gorgun ◽  
Ikeda Hiroshi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Nuclear Translocation ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation

Abstract Abstract 2849 Poster Board II-825 Histone deacetylase inhibitors (HDACi) are emerging as a potential therapy for Multiple Myeloma (MM). Their antineoplastic activity depends not only on nucleosomal histone acetylation, but also on direct modulation of non-histone proteins, including p53 or HSP90. Previous studies suggest that histone deacetylases inhibitors modulate Jak2/Stat3 signaling pathway, a cascade mediating tumor cell survival. Here we examine how Panobinostat, a class I-HDAC inhibitor currently in phase I/II clinical trial, can modulate the function of the Jak2/ Stat3 pathway in MM. We first observed that Panobinostat inhibited IL6-induced Stat3 phosphorylation (Tyr705) and Jak2 phosphorylation (Tyr 1007/1008) in MM cell lines ( MM1S and INA6) in a dose- and time- depend fashion, associated with induction of Stat3 acetylation (Lys 685). Since acetylation of Stat3 alters the distribution rather than the functional status of Stat3, we next examined whether Panobinostat altered the nuclear versus cytoplasmic localization of Stat3 in MM cell lines. Although total STAT3 protein level did not change, Panobinostat treatment did trigger decreased nuclear Stat3 phosphorylation, suggesting that Panobinostat blocks Stat3 transcriptional activity. We showed by western blot analysis that the down stream pathway induced by Stat3 (Survivin, Bcl XL, c-Myc) was also down regulated after Panobinostat treatment, further confirming inhibition of STAT3 activity. Take together, our results suggest that Panobinostat inhibits the Jak2/Stat3 pathway by inhibiting STAT3 binding to DNA consensus region, rather than modulating nuclear translocation. To establish the molecular mechanism whereby Panobinostat regulates this pathway, we examined IL6/gp130 receptor, which is upstream in the Jak2 /Stat3 pathway. Panobinostat decreased both cell surface and intracellular gp130 protein expression. Interestingly, Panobinostat also inhibited IL6-induced phosphorylation of gp130, suggesting that it can directly inhibit gp130 activation. Our study therefore suggests a dual mechanism of inhibition of the JAK2/Stat3 pathway induced by Panobinostat via modulation of STAT 3 transcriptional function and gp130 -induced STAT3 activation. Finally, we observed upregulation of the MEK/ERK signaling pathway associated with HDAC inhibition, suggesting that combined blockade of these cascades may be useful. Indeed our preliminary data demonstrate enhanced cytotoxicity in MM cell lines (MM1S and INA6) induced by treatment with combined Panobinostat and MEK inhibitors, even in the presence of bone marrow stromal cells or survival cytokines ( IL6 or IGF). Our study therefore suggests a novel mechanism of action of HDAC inhibitors that provides the rationale for clinical evaluation of novel combinations based upon targeting STAT3 signaling pathway. Disclosures: Anderson: Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding.

scholarly journals Dihydroartemisinin inhibits IL-6-induced epithelial–mesenchymal transition in laryngeal squamous cell carcinoma via the miR-130b-3p/STAT3/β-catenin signaling pathway

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110094
Author(s):  
Yajing Sun ◽  
Xiuying Lu ◽  
Hui Li ◽  
Xiaoming Li
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Objective To explore whether dihydroartemisinin (DHA) can block interleukin (IL)-6-induced epithelial–mesenchymal transition (EMT) in laryngeal squamous cell carcinoma (LSCC). Methods The expression of SLUG, signal transducer and activator of transcription 3 (STAT3), and microRNA (miR)-130b-3p was measured. In addition, a dual-luciferase reporter assay was performed to examine the interaction of miR-130b-3p with STAT3. Results We found that IL-6 can promote EMT and invasion in LSCC cells, whereas DHA can inhibit these two processes. However, DHA alone does not influence EMT and cancer invasion. Furthermore, DHA upregulated miR-130b-3p, which can downregulate STAT3 and β-catenin protein expression and decrease the activity of the IL-6/STAT3 signaling pathway. Moreover, we found that miR-130b-3p can target STAT3 directly. Conclusions DHA can block IL-6-triggered EMT and invasion in LSCC, and during these processes, DHA increases miR-130b-3p expression to decrease the activation of the IL-6/STAT3 and β-catenin signaling pathways. These findings may provide new insights into strategies for suppressing and even preventing LSCC metastasis.

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