Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

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Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating the microRNA-34a-5p/NOTCH1 signaling pathway

Open Life Sciences ◽

10.1515/biol-2020-0025 ◽

2020 ◽

Vol 15 (1) ◽

pp. 284-295

Author(s):

Yongtian Zhang ◽

Dandan Zhao ◽

Shumei Li ◽

Meng Xiao ◽

Hongjing Zhou ◽

...

Keyword(s):

Multiple Myeloma ◽

Signaling Pathway ◽

Notch Receptor ◽

Cell Counting ◽

Luciferase Reporter ◽

Notch1 Signaling ◽

Non Coding Rna ◽

Notch1 Signaling Pathway ◽

Long Non Coding Rna

AbstractMultiple myeloma (MM) is a serious health issue in hematological malignancies. Long non-coding RNA taurine-upregulated gene 1 (TUG1) has been reported to be highly expressed in the plasma of MM patients. However, the functions of TUG1 in MM tumorigenesis along with related molecular basis are still undefined. In this study, increased TUG1 and decreased microRNA-34a-5p (miR-34a-5p) levels in MM tissues and cells were measured by the real-time quantitative polymerase reaction assay. The expression of relative proteins was determined by the Western blot assay. TUG1 knockdown suppressed cell viability, induced cell cycle arrest and cell apoptosis in MM cells, as shown by Cell Counting Kit-8 and flow cytometry assays. Bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay indicated that miR-34a-5p was a target of TUG1 and directly bound to notch receptor 1 (NOTCH1), and TUG1 regulated the NOTCH1 expression by targeting miR-34a-5p. The functions of miR-34a-5p were abrogated by TUG1 upregulation. Moreover, TUG1 loss impeded MM xenograft tumor growth in vivo by upregulating miR-34a-5p and downregulating NOTCH1. Furthermore, TUG1 depletion inhibited the expression of Hes-1, Survivin, and Bcl-2 protein in MM cells and xenograft tumors. TUG1 knockdown inhibited MM tumorigenesis by regulating the miR-34a-5p/NOTCH1 signaling pathway in vitro and in vivo, deepening our understanding of the TUG1 function in MM.

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STAT1-mediated inhibition of FOXM1 enhances gemcitabine sensitivity in pancreatic cancer

Clinical Science ◽

10.1042/cs20180816 ◽

2019 ◽

Vol 133 (5) ◽

pp. 645-663 ◽

Cited By ~ 10

Author(s):

Chao Liu ◽

Jiaqi Shi ◽

Qingwei Li ◽

Zhiwei Li ◽

Changjie Lou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Immunohistochemical Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Luciferase Reporter ◽

Pancreatic Cancer Cells ◽

Foxm1 Expression

Abstract Forkhead box protein M1 (FOXM1) was identified as an oncogenic transcription factor and master regulator of tumor progression and metastasis. FOXM1 expression often correlates with poor prognosis and chemotherapy resistance. In the present study, we investigated the association of FOXM1 expression and chemoresistance in pancreatic cancer. Elevated FOXM1 protein levels were associated with gemcitabine chemoresistance in patients with pancreatic cancer. In gemcitabine resistance cell line models of pancreatic cancer, FOXM1 expression increased, which induced gemcitabine chemoresistance in vitro. In pancreatic cancer cells treated with gemcitabine, FOXM1 affected nuclear factor κB (NF-κB) signaling activity. Immunohistochemical analysis demonstrated a negative association of FOXM1 expression and the level of phosphorylated signal transducer and activator of transcription 1 (pSTAT1) in human pancreatic cancer tissues. Dual-luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that pSTAT1 directly binds to the FOXM1 promoter to down-regulate its transcription. Interferon γ (IFNγ) promoted gemcitabine-induced cell apoptosis and inhibited cell proliferation in vitro and in vivo by FOXM1 inhibition. These data suggested that FOXM1 enhances chemoresistance to gemcitabine in pancreatic cancer. IFNγ could be used to down-regulate the expression of FOXM1 through STAT1 phosphorylation, thereby increasing the sensitivity of pancreatic cancer cells to gemcitabine. These studies suggested the sensitization by IFNγ in pancreatic ductal adenocarcinoma (PDAC) chemotherapy, which requires further clinical studies.

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Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.628209 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yaqin Sun ◽

Jing Ji ◽

Zheng Zha ◽

Hui Zhao ◽

Bing Xue ◽

...

Keyword(s):

Multiple Sclerosis ◽

Signaling Pathway ◽

Blue Staining ◽

Neuroprotective Effects ◽

Notch1 Signaling ◽

Transmission Electron ◽

Proliferation And Differentiation ◽

Notch1 Signaling Pathway

Promoting the differentiation of oligodendrocyte precursor cells (OPCs) is important for fostering remyelination in multiple sclerosis. Catalpol has the potential to promote remyelination and exert neuroprotective effects, but its specific mechanism is still unclear. Recent studies have shown that the NOTCH1 signaling pathway is involved in mediating OPC proliferation and differentiation. In this study, we elucidated that catalpol promoted OPC differentiation in vivo and vitro and explored the regulatory role of catalpol in specific biomolecular processes. Following catalpol administration, better and faster recovery of body weight and motor balance was observed in mice with cuprizone (CPZ)-induced demyelination. Luxol fast blue staining (LFB) and transmission electron microscopy (TEM) showed that catalpol increased the myelinated area and improved myelin ultrastructure in the corpus callosum in demyelinated mice. In addition, catalpol enhanced the expression of CNPase and MBP, indicating that it increased OPC differentiation. Additionally, catalpol downregulated the expression of NOTCH1 signaling pathway-related molecules, such as JAGGED1, NOTCH1, NICD1, RBPJ, HES5, and HES1. We further demonstrated that in vitro, catalpol enhanced the differentiation of OPCs into OLs and inhibited NOTCH1 signaling pathway activity. Our data suggested that catalpol may promote OPC differentiation and remyelination through modulation of the NOTCH1 pathway. This study provides new insight into the mechanism of action of catalpol in the treatment of multiple sclerosis.

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In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568210204916170096 ◽

2010 ◽

Vol 999 (999) ◽

pp. 1-11

Author(s):

P. Ulivi ◽

C. Arienti ◽

W. Zoli ◽

M. Scarsella ◽

S. Carloni ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Antitumor Efficacy ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

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Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22041985 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1985

Author(s):

Xiaohe Li ◽

Ling Ma ◽

Kai Huang ◽

Yuli Wei ◽

Shida Long ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Kinase Inhibitor ◽

In Vivo Experiments ◽

Age Related ◽

And Migration ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽

10.3390/cancers13092017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2017

Author(s):

Lital Sharvit ◽

Rinat Bar-Shalom ◽

Naiel Azzam ◽

Yaniv Yechiel ◽

Solomon Wasser ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Liquid ◽

Human Pancreatic Cancer ◽

P53 Signaling ◽

Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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Porcine Milk-Derived Small Extracellular Vesicles Promote Intestinal Immunoglobulin Production through pIgR

Animals ◽

10.3390/ani11061522 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1522

Author(s):

Bin Zeng ◽

Hailong Wang ◽

Junyi Luo ◽

Meiying Xie ◽

Zhengjiang Zhao ◽

...

Keyword(s):

Small Intestine ◽

Extracellular Vesicles ◽

Immunoglobulin A ◽

Luciferase Reporter ◽

Epithelial Cell Line ◽

Intestinal Immunity ◽

In Vivo Experiments ◽

Porcine Milk

Secretory immunoglobulin A (SIgA) plays an important role in gut acquired immunity and mucosal homeostasis. Breast milk is the irreplaceable nutritional source for mammals after birth. Current studies have shown the potential functional role of milk-derived small extracellular vesicles (sEVs) and their RNAs cargo in intestinal health and immune regulation. However, there is a lack of studies to demonstrate how milk-derived sEVs affect intestinal immunity in recipient. In this study, through in vivo experiments, we found that porcine milk small extracellular vesicles (PM-sEVs) promoted intestinal SIgA levels, and increased the expression levels of polymeric immunoglobulin receptor (pIgR) both in mice and piglet. We examined the mechanism of how PM-sEVs increased the expression level of pIgR in vitro by using a porcine small intestine epithelial cell line (IPEC-J2). Through bioinformatics analysis, dual-luciferase reporter assays, and overexpression or knockdown of the corresponding non-coding RNAs, we identified circ-XPO4 in PM-sEVs as a crucial circRNA, which leads to the expression of pIgR via the suppression of miR-221-5p in intestinal cells. Importantly, we also observed that oral administration of PM-sEVs increased the level of circ-XPO4 and decreased the level of miR-221-5p in small intestine of piglets, indicating that circRNAs in milk-derived sEVs act as sponge for miRNAs in recipients. This study, for the first time, reveals that PM-sEVs have a capacity to stimulate intestinal SIgA production by delivering circRNAs to receptors and sponging the recipient’s original miRNAs, and also provides valuable data for insight into the role and mechanism of animal milk sEVs in intestinal immunity.

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Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210201095613 ◽

2021 ◽

Vol 21 ◽

Author(s):

Huiming Chen ◽

Junfeng Zhao ◽

Ningning Jiang ◽

Zheng Wang ◽

Chang Liu

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Precancerous Lesions ◽

Clinical Specimen ◽

Ductal Adenocarcinoma ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

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Radiation activates the NORAD expression to promote ESCC radioimmunotherapy resistance via EEPD1/ATR/Chk1 signaling by inhibiting the pri-miR-199 processing and exosomal transfer of miR-199a-5p

10.21203/rs.3.rs-516399/v1 ◽

2021 ◽

Author(s):

Yuchen Sun ◽

Jizhao Wang ◽

Xuanzi Sun ◽

Jing Li ◽

Xu Zhao ◽

...

Keyword(s):

Its Region ◽

Luciferase Reporter ◽

In Vivo Experiments ◽

Cycle Arrest ◽

Non Coding Rna ◽

Irradiation Treatment ◽

Recombination Repair ◽

Reporter Assays

Abstract Background Radioresistance, a poorly understood phenomenon, results in the failure of radiotherapy and consequent local recurrence, threatening a large proportion of ESCC patients. To date, lncRNAs have been found to be involved in diverse biological processes, including radioresistance.Methods ELISA was used to evaluated the H3 modifications in radio-resistant ESCC cells. FISH and qRT-PCR were adopted to examine the expression and localization of lncRNA-NORAD, pri-miR-199a and miR-199a. Electron microscopy and Nanoparticle tracking analysis (NTA) was conducted to observe and identify exosomes. High-throughput RNA sequencing and TMT mass spectrometry were performed to identify the functional lncRNAs and proteins involved in ESCC radioresistance. A series of in vitro and in vivo experiments were performed to investigate the biological effect of NORAD. CHIP, qPCR-RIP, co-IP and dual-luciferase reporter assays were used to explore the interaction of related RNAs and proteins. Results We show here that a DNA damage activated non-coding RNA-NORAD, which is critical for ESCC radio-resistance. NORAD was highly expressed in radio-resistant ESCC cells and tissues. Irradiation treatment promotes NORAD expression via enhancing H3K4me2 enrichment on its region. NORAD knockdown cells exhibit significantly hypersensitivity to irradiation in vivo and in vitro. NORAD is required for initiating repair and restart of stalled forks, G2 cycle arrest and homologous recombination repair upon irradiation treatment. Mechanistically, NORAD inhibits miR-199a expression by competitively binding PUM1 from pri-miR-199a, inhibiting the process of pri-miR-199a. Mature miR-199a in NORAD-knockdown cells can be packaged into exosomes; miR-199a restores the radiosensitivity of radioresistant cells by targeting EEPD1, then inhibiting ATR/Chk1 signaling pathway. Simultaneously, NORAD knockdown blocks the ubiquitination of PD-L1, leads to the better response for radiation and anti-PD-1 treatment in mouse model.Conclusion This study raises the possibility that LncRNA-NORAD could be a potential treatment target for improving the efficiency of immunotherapy in combination with radiation in ESCC.

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