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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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2
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Mushtaq U. EP1 receptor: Devil in emperors coat. J Cell Biochem 2023; 124:1105-1114. [PMID: 37450673 DOI: 10.1002/jcb.30436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/20/2023] [Accepted: 06/06/2023] [Indexed: 07/18/2023]
Abstract
EP1 receptor belongs to prostanoid receptors and is activated by prostaglandin E2. The receptor performs contrasting functions in central nervous system (CNS) and other tissues. Although the receptor is neurotoxic and proapoptotic in CNS, it has also been reported to act in an antiapoptotic manner by modulating cell survival, proliferation, invasion, and migration in different types of cancers. The receptor mediates its neurotoxic effects by increasing cytosolic Ca2+ levels, leading to the activation of its downstream target, protein kinase C, in different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and epilepsy. Antagonists ONO-8713, SC51089, and SC51322 against EP1 receptor ameliorate the neurotoxic effect by attenuating the neuroinflammation. The receptor also shows increased expression in different types of cancers and has been found to activate different signaling pathways, which lead to the development, progression, and metastasis of different cancers. The receptor stimulates the cell survival pathway by phosphorylating the AKT and PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways. Although there are limited studies about this receptor and not a single clinical trial has been targeting the EP1 receptor for different neurological disorders or cancer, the receptor is appearing as a potential candidate for therapeutic targets. The aim of this article is to review the recent progress in understanding the pathogenic roles of EP1 receptors in different pathological conditions.
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Affiliation(s)
- Umar Mushtaq
- Department of Biotechnology, Central University of Kashmir, Ganderbal, India
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3
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Buchholz A, Vattai A, Fürst S, Vilsmaier T, Zati Zehni A, Steger A, Kuhn C, Schmoeckel E, Dannecker C, Mahner S, Jeschke U, Heidegger HH. Prostaglandin E2 receptor EP1 expression in vulvar cancer. J Cancer Res Clin Oncol 2023; 149:5369-5376. [PMID: 36436093 PMCID: PMC10349743 DOI: 10.1007/s00432-022-04487-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/15/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic targets are essential. Chronic inflammation plays an important role in carcinogenesis and COX-2, and its product prostaglandin E2 and its receptors EP1-4 are known to be important mediators in cancer initiation and progression. METHODS EP1 expression in vulvar cancer specimens (n = 129) was investigated via immunohistochemistry and evaluated using the well-established immunoreactive score (IRS). Subsequently, the values were correlated with clinicopathological parameters. RESULTS Our analysis did not reveal EP1 expression as a negative prognostic factor in overall and disease-free survival. However, in the subgroup of patients with lymph-node metastasis, overall survival was significantly shorter in tumors with high EP1 expression. Moreover, EP1 expression correlated positively with good differentiation of the tumor, but not with p16 status or COX-2 expression. CONCLUSIONS This study shed first light on EP1 expression in vulvar carcinoma. EP1 expression correlated significantly with the grading of the tumor, suggesting that it influences cell differentiation. Further research on EP1 signaling may lead to a deeper understanding of the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Anna Buchholz
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Aurelia Vattai
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Sophie Fürst
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Theresa Vilsmaier
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alaleh Zati Zehni
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alexander Steger
- Klinik und Poliklinik für Innere Medizin I, University Hospital, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany
| | - Christina Kuhn
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Elisa Schmoeckel
- Department of Pathology, LMU Munich, Thalkirchner Str. 142, 80337, Munich, Germany
| | - Christian Dannecker
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany.
| | - Helene H Heidegger
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
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Chen C, Guan J, Gu X, Chu Q, Zhu H. Prostaglandin E2 and Receptors: Insight Into Tumorigenesis, Tumor Progression, and Treatment of Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:834859. [PMID: 35356289 PMCID: PMC8959932 DOI: 10.3389/fcell.2022.834859] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/07/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common primary liver cancer with ∼750,000 annual incidence rates globally. PGE2, usually known as a pro-inflammatory cytokine, is over-expressed in various human malignancies including HCC. PGE2 binds to EP receptors in HCC cells to influence tumorigenesis or enhance tumor progression through multiple pathways such as EP1-PKC-MAPK, EP2-PKA-GSK3β, and EP4-PKA-CREB. In the progression of hepatocellular carcinoma, PGE2 can promote the proliferation and migration of liver cancer cells by affecting hepatocytes directly and the tumor microenvironment (TME) through ERK/COX-2/PGE2 signal pathway in hepatic stellate cells (HSC). For the treatment of hepatocellular carcinoma, there are drugs such as T7 peptide and EP1 antagonist ONO-8711 targeting Cox-2/PGE2 axis to inhibit tumor progression. In conclusion, PGE2 has been shown to be a traditional target with pleiotropic effects in tumorigenesis and progression of HCC that could be used to develop a new potential clinical impact. For the treatment study focusing on the COX-PGE2 axis, the exclusive usage of non-steroidal anti-inflammatory agents (NSAIDs) or COX-2-inhibitors may be replaced by a combination of selective EP antagonists and traditional anti-tumoral drugs to alleviate severe side effects and achieve better outcomes.
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Wang Q, Morris RJ, Bode AM, Zhang T. Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy. Cancer Res 2021; 82:949-965. [PMID: 34949672 DOI: 10.1158/0008-5472.can-21-2297] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/27/2021] [Accepted: 12/17/2021] [Indexed: 11/16/2022]
Abstract
Because of profound effects observed in carcinogenesis, prostaglandins (PGs), prostaglandin-endoperoxide synthases, and PG receptors are implicated in cancer development and progression. Understanding the molecular mechanisms of PG actions has potential clinical relevance for cancer prevention and therapy. This review focuses on the current status of PG signaling pathways in modulating cancer progression and aims to provide insights into the mechanistic actions of PGs and their receptors in influencing tumor progression. We also examine several small molecules identified as having anticancer activity that target prostaglandin receptors. The literature suggests that targeting PG pathways could provide opportunities for cancer prevention and therapy.
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Affiliation(s)
- Qiushi Wang
- The Hormel Institute, University of Minnesota
| | | | - Ann M Bode
- The Hormel Institute, University of Minnesota
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El-Ashmawy NE, El-Zamarany EA, Khedr NF, Selim HM, Khedr EG. Inhibition of PKC/MEK pathway suppresses β1-integrin and mitigates breast cancer cells proliferation. Toxicol Rep 2021; 8:1530-1537. [PMID: 34408972 PMCID: PMC8361284 DOI: 10.1016/j.toxrep.2021.07.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
PGE2 enhanced β1- integrin expression via EP1 receptor, PKC, MEK and NfҡB. FOXC2, E2F1 and survivin play a role in PGE2 mediated effect in MCF7 cells. PGE2 enhances breast cancer cell cycle through E2F1, FOXC2, survivin and β integrin. Biochemical mediators of PKC/MEK pathway could be considered as targets for breast cancer treatment. Prostaglandin E2 (PGE2) and β1-integrin have been correlated with breast cancer, where both could enhance progression and metastasis. Protein kinase C (PKC) and MEK have played a vital role in breast cancer development. Our study was conducted to elucidate the effect of inhibition of E-prostanoid receptor 1 (EP1)/ PKC/ MEK/ β1-integrin pathway in mitigating breast cancer progression and to evaluate the role of the intermediate signals FOXC2, E2F1, NF-ҡB and survivin. MCF7 cells were treated with 17 -PT-PGE2, an EP1 agonist, for 24 h, and β1-integrin was measured. To MCF7 cells treated with 17-PT-PGE2, inhibitors of either EP1, MEK, PKC or NF-ҡB were added followed by measurement of β1-integrin gene expression and cell proliferation in each case. Addition of 17- PT-PGE2 to MCF7 cells showed enhancement of both cell proliferation, and cell cycle transition from G1 to S phase. In addition, activation of EP1 receptor increased β1-integrin expression. On the contrary, inhibition of EP1 receptor showed a decrease in the cell proliferation, β1-integrin expression and cells transition to S phase, but increased cell count in apoptotic phase. Selective inhibition of each of MEK, PKC, and NF-ҡB suppressed 17 -PT-PGE2-mediated β1-integrin expression as well as cell proliferation. Furthermore, FOXC2, phosphorylated NF-ҡB, E2F1, and survivin levels were upregulated with 17- PT-PGE2 and suppressed by MEK, PKC and NF-ҡB inhibitors. Targeting the biochemical mediators of PKC/MEK pathway may be of value in developing new chemical entities for cancer treatment.
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Affiliation(s)
| | - Enas A El-Zamarany
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt
| | - Naglaa F Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Hend M Selim
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - Eman G Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
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7
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Saito S, Ozawa H, Imanishi Y, Sekimizu M, Watanabe Y, Ito F, Ikari Y, Nakahara N, Kameyama K, Ogawa K. Cyclooxygenase-2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma. Oncol Lett 2021; 22:533. [PMID: 34084214 PMCID: PMC8161457 DOI: 10.3892/ol.2021.12794] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/20/2021] [Indexed: 01/05/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is associated with the progression in various types of cancer, and its expression has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX-2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX-2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX-2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resection with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX-2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX-2 expression with stemness property, the expression levels of CSC-associated genes after exposure to celecoxib were assessed by reverse transcription-quantitative PCR. A sphere formation assay was also performed using ultra-low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX-2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX-2 inhibition led to downregulation of CSC-associated gene expression and sphere formation. The present findings suggested that COX-2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX-2 may enhance chemo-sensitivity in HNSCC. Therefore, COX-2 may be an attractive target for the treatment of HNSCC.
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Affiliation(s)
- Shin Saito
- Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroyuki Ozawa
- Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yorihisa Imanishi
- Department of Otorhinolaryngology-Head and Neck Surgery, International University of Health and Welfare, Narita, Chiba 286-8582, Japan
| | - Mariko Sekimizu
- Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshihiro Watanabe
- Department of Otorhinolaryngology-Head and Neck Surgery, International University of Health and Welfare, Narita, Chiba 286-8582, Japan
| | - Fumihiro Ito
- Department of Otorhinolaryngology-Head and Neck Surgery, National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan
| | - Yuichi Ikari
- Department of Otorhinolaryngology-Head and Neck Surgery, Kawasaki Municipal Kawasaki Hospital, Kawasaki, Kanagawa 210-0013, Japan
| | - Nana Nakahara
- Department of Otorhinolaryngology-Head and Neck Surgery, Saitama City Hospital, Saitama 336-8522, Japan
| | - Kaori Kameyama
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kaoru Ogawa
- Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
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Fox EF, Lamb MC, Mellentine SQ, Tootle TL. Prostaglandins regulate invasive, collective border cell migration. Mol Biol Cell 2020; 31:1584-1594. [PMID: 32432969 PMCID: PMC7521797 DOI: 10.1091/mbc.e19-10-0578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
While prostaglandins (PGs), short-range lipid signals, regulate single cell migration, their roles in collective migration remain unclear. To address this, we use Drosophila border cell migration, an invasive, collective migration that occurs during Stage 9 of oogenesis. Pxt is the Drosophila cyclooxygenase-like enzyme responsible for PG synthesis. Loss of Pxt results in both delayed border cell migration and elongated clusters, whereas somatic Pxt knockdown causes delayed migration and compacted clusters. These findings suggest PGs act in both the border cells and nurse cells, the substrate on which the border cells migrate. As PGs regulate the actin bundler Fascin, and Fascin is required for on-time migration, we assessed whether PGs regulate Fascin to promote border cell migration. Coreduction of Pxt and Fascin results in delayed migration and elongated clusters. The latter may be due to altered cell adhesion, as loss of Pxt or Fascin, or coreduction of both, decreases integrin levels on the border cell membranes. Conversely, integrin localization is unaffected by somatic knockdown of Pxt. Together these data lead to the model that PG signaling controls Fascin in the border cells to promote migration and in the nurse cells to maintain cluster cohesion.
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Affiliation(s)
- Emily F Fox
- Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Maureen C Lamb
- Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Samuel Q Mellentine
- Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
| | - Tina L Tootle
- Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
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Niu JC, Ma N, Liu W, Wang PJ. EP1 receptor is involved in prostaglandin E2-induced osteosarcoma growth. Bosn J Basic Med Sci 2019; 19:265-273. [PMID: 30995899 DOI: 10.17305/bjbms.2019.4177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/30/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies showed that the activation of prostaglandin (PG) receptor EP1 promotes cell migration and invasion in different cancers. The aim of this study was to investigate the role of EP1 in the proliferation of osteosarcoma (OS) cells in vitro and in vivo. EP1 mRNA and protein levels were analyzed by real-time RT-PCR and Western blot, respectively in human OS cell lines MG63, OS732, U-2OS, and 143B compared to human fetal osteoblastic hFOB 1.19 cells. MG63 cells were treated with PGE2, EP1 specific agonist 17-PT-PGE2, 17-PT-PGE2 + EP1 specific antagonist SC51089, or DMSO (control). EP1R-siRNA or a non-silencing irrelevant RNA duplex (negative control) were used for the transfection of MG63 cells, followed by PGE2 treatment. Nude mice carrying MG63 xenografts were treated with SC51089 (2 mg/kg/day). MG63 cells/xenografts were analyzed by MTT assay, TUNEL assay, PKC enzyme activity assay, and Western blot (EP1 and apoptotic proteins), and tumor growth/volume was evaluated in mice. EP1 levels were significantly higher in OS cells compared to osteoblasts. PGE2 or 17-PT-PGE2 treatment increased the proliferation and decreased the apoptosis of MG63 cells. Inhibition of EP1 by SC51089 or siRNA markedly decreased the viability of MG63 cells. Similarly, SC51089 treatment significantly inhibited MG63 cell proliferation and promoted apoptosis in vivo. The silencing of EP1 receptor by siRNA or blockade of EP1 signaling by SC51089 activated extrinsic and intrinsic apoptotic pathways both in vivo and in vitro, as evidenced by increased levels of Bax, cyt c, cleaved caspase-3, caspase-8 and caspase-9. EP1 appears to be involved in PGE2-induced proliferative activity of MG63 cells. Antagonizing EP1 may provide a novel therapeutic approach to the treatment of OS.
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Affiliation(s)
- Jing-Cai Niu
- Department of Hand and Foot Surgery, Second Affiliated Hospital of Soochow University, Suzhou; Department of Orthopedics, Second Affiliated Hospital of Anhui Medical University, Hefei Anhui, China.
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Xu S, Zhou W, Ge J, Zhang Z. Prostaglandin E2 receptor EP4 is involved in the cell growth and invasion of prostate cancer via the cAMP‑PKA/PI3K‑Akt signaling pathway. Mol Med Rep 2018; 17:4702-4712. [PMID: 29328471 DOI: 10.3892/mmr.2018.8415] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 10/19/2017] [Indexed: 11/06/2022] Open
Abstract
Prostate cancer (PCa) is one of the most prevalent diagnosed malignancies globally. Previous studies have demonstrated that prostaglandin E2 (PGE2) is closely associated with the tumorigenesis and progression of PCa. However, the underlying molecular mechanisms remain unclear and require further investigation. Matrix metalloproteinases (MMPs), receptor activator of nuclear factor‑κB ligand (RANKL) and runt‑related transcription factor 2 (RUNX2), which are involved in cell growth and bone metastasis, are frequently activated or overexpressed in various types of cancer, including PCa. The present study was designed to investigate the associations between PGE2 and the PGE2 receptor EP4, and MMPs, RANKL and RUNX2 in PCa, and to define their roles in PCa cell proliferation and invasion in addition to understanding the molecular mechanisms. The results of western blotting and reverse transcription‑quantitative polymerase chain reaction demonstrated that the protein and the mRNA expression levels of MMP‑2, MMP‑9, RANKL and RUNX2 in PC‑3 cells were significantly upregulated by treatment with PGE2, respectively, and knockdown of these proteins blocked PGE2‑induced cell proliferation and invasion in PC‑3 cells, as determined by Cell Counting Kit‑8 and Matrigel invasion assays, respectively. The effect of PGE2 on the protein and mRNA expression levels was primarily regulated via the EP4 receptor. EP4 receptor signaling activates the cyclic (c)AMP‑protein kinase A (PKA) signaling pathway, and forskolin, an activator of adenylate cyclase (AC), exhibited similar effects to an EP4 receptor agonist on the protein expression, while SQ22536, an inhibitor of AC, inhibited the protein expression. These results confirmed that the AC/cAMP pathway may be involved in EP4 receptor‑mediated upregulation of protein expression. By using a specific inhibitor of PKA, it was also demonstrated that cAMP/PKA was also involved in the EP4 receptor‑mediated upregulation of protein expression. In addition to the signaling pathway involving PKA, the EP4 receptor also exerts activities through activation of Akt kinase. The results in the present study confirmed the hypothesis that EP4 receptor‑mediated protein expression in PCa cells that were pretreated with a specific inhibitor of phosphatidylinositol 3‑kinase (PI3K) was significantly inhibited. In conclusion, the results of the present study indicate that PGE2 significantly upregulated the mRNA and protein expression levels of the MMP‑2, MMP‑9, RANKL and RUNX2, and the EP4 receptor was involved in the cell proliferation and invasion of PCa via the cAMP‑PKA/PI3K‑Akt signaling pathway. These results may provide novel insight into potential therapeutic strategies for the prevention and treatment of PCa.
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Affiliation(s)
- Song Xu
- Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Wenquan Zhou
- Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingping Ge
- Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhengyu Zhang
- Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
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Yang HJ, Jiang JH, Yang YT, Yang XD, Guo Z, Qi YP, Zeng FH, Zhang KL, Chen NZ, Xiang BD, Li LQ. Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival. World J Gastroenterol 2016; 22:8798-8805. [PMID: 27818595 PMCID: PMC5075554 DOI: 10.3748/wjg.v22.i39.8798] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/15/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis.
METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.
RESULTS Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001).
CONCLUSION COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.
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Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway. Sci Rep 2016; 6:33823. [PMID: 27654511 PMCID: PMC5031967 DOI: 10.1038/srep33823] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 09/02/2016] [Indexed: 12/28/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) has been implicated in cell invasion in non-small-cell lung cancer (NSCLC). However, the mechanism is unclear. The present study investigated the effect of COX-2 on β1-integrin expression and cell invasion in NSCLC. COX-2 and β1-integrin were co-expressed in NSCLC tissues. COX-2 overexpression or Prostaglandin E2 (PGE2) treatment increased β1-integrin expression in NSCLC cell lines. β1-integrin silencing suppressed COX-2-mediated tumour growth and cancer cell invasion in vivo and in vitro. Prostaglandin E Receptor EP1 transfection or treatment with EP1 agonist mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. EP1 agonist treatment promoted Erk1/2, p38 phosphorylation and E2F-1 expression. MEK1/2 and p38 inhibitors suppressed EP1-mediated β1-integrin expression. E2F-1 silencing suppressed EP1-mediated FoxC2 and β1-integrin upregulation. ChIP and Luciferase Reporter assays identified that EP1 agonist treatment induced E2F-1 binding to FoxC2 promotor directly and improved FoxC2 transcription. FoxC2 siRNA suppressed β1-integrin expression and EP1-mediated cell invasion. Immunohistochemistry showed E2F-1, FoxC2, and EP1R were all highly expressed in the NSCLC cases. This study suggested that COX-2 upregulates β1-integrin expression and cell invasion in NSCLC by activating the MAPK/E2F-1 signalling pathway. Targeting the COX-2/EP1/PKC/MAPK/E2F-1/FoxC2/β1-integrin pathway might represent a new therapeutic strategy for the prevention and treatment of this cancer.
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Wang YY, Gu XL, Wang C, Wang H, Ni QC, Zhang CH, Yu XF, Yang LY, He ZX, Mao GX, Yang SY. The far-upstream element-binding protein 2 is correlated with proliferation and doxorubicin resistance in human breast cancer cell lines. Tumour Biol 2016; 37:9755-69. [DOI: 10.1007/s13277-016-4819-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 01/08/2016] [Indexed: 10/22/2022] Open
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14
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Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer. Oncogene 2015; 35:4021-35. [PMID: 26640151 DOI: 10.1038/onc.2015.467] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 11/02/2015] [Accepted: 11/02/2015] [Indexed: 12/18/2022]
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15
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O'Callaghan G, Houston A. Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? Br J Pharmacol 2015; 172:5239-50. [PMID: 26377664 DOI: 10.1111/bph.13331] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 08/06/2015] [Accepted: 09/14/2015] [Indexed: 12/28/2022] Open
Abstract
Elevated expression of COX-2 and increased levels of PGE2 are found in numerous cancers and are associated with tumour development and progression. Although epidemiological, clinical and preclinical studies have shown that the inhibition of PGE2 synthesis through the use of either non-steroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors (COXibs) has the potential to prevent and treat malignant disease, toxicities due to inhibition of COX-2 have limited their use. Thus, there is an urgent need for the development of strategies whereby COX-2 activity may be reduced without inducing any side effects. The biological effects of PGE2 are mediated by signalling through four distinct E-type prostanoid (EP) receptors - EP1 , EP2 , EP3 and EP4 . In recent years, extensive effort has gone into elucidating the function of PGE2 and the EP receptors in health and disease, with the goal of creating selective inhibitors as a means of therapy. In this review, we focus on PGE2 , and in particular on the role of the individual EP receptors and their signalling pathways in neoplastic disease. As knowledge concerning the role of the EP receptors in cancer grows, so does the potential for exploiting the EP receptors as therapeutic targets for the treatment of cancer and metastatic disease.
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Affiliation(s)
- G O'Callaghan
- Department of Medicine, University College Cork, Cork, Ireland.,HRB Clinical Research Facility, University College Cork, Cork, Ireland
| | - A Houston
- Department of Medicine, University College Cork, Cork, Ireland.,Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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16
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Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment. Clin Exp Metastasis 2015; 32:335-44. [PMID: 25749879 DOI: 10.1007/s10585-015-9710-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 02/28/2015] [Indexed: 12/19/2022]
Abstract
Breast cancer can reoccur, often as bone metastasis, many years if not decades after the primary tumor has been treated. The factors that stimulate dormant metastases to grow are not known, but bone metastases are often associated with skeletal trauma. We used a dormancy model of MDA-MB-231BRMS1, a metastasis-suppressed human breast cancer cell line, co-cultured with MC3T3-E1 osteoblasts in a long term, three dimensional culture system to test the hypothesis that bone remodeling cytokines could stimulate dormant cells to grow. The cancer cells attached to the matrix produced by MC3T3-E1 osteoblasts but grew slowly or not at all until the addition of bone remodeling cytokines, TNFα and IL-β. Stimulation of cell proliferation by these cytokines was suppressed with indomethacin, an inhibitor of cyclooxygenase and of prostaglandin production, or a prostaglandin E2 (PGE2) receptor antagonist. Addition of PGE2 directly to the cultures also stimulated cell proliferation. MCF-7, non-metastatic breast cancer cells, remained dormant when co-cultured with normal human osteoblast and fibroblast growth factor. Similar to the MDA-MB-231BRMS1 cells, MCF-7 proliferation increased in response to TNFα and IL-β. These findings suggest that changes in the bone microenvironment due to inflammatory cytokines associated with bone repair or excess turnover may trigger the occurrence of latent bone metastasis.
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Bai X, Wang J, Guo Y, Pan J, Yang Q, Zhang M, Li H, Zhang L, Ma J, Shi F, Shu W, Wang Y, Leng J. Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway. Sci Rep 2014; 4:6538. [PMID: 25289898 PMCID: PMC5377465 DOI: 10.1038/srep06538] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 09/05/2014] [Indexed: 02/07/2023] Open
Abstract
Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1–4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE2 (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE2 increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. 17-PT-PGE2 treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE2-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF-κB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE2/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.
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Affiliation(s)
- Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jie Wang
- Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, P. R. China
| | - Yan Guo
- Institute of Pediatrics, Fourth Clinical Medical College, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jinshun Pan
- The Center of Metabolic Disease Research, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Hai Li
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Feng Shi
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Wei Shu
- Department of Periodontal, Institute of Stomatology, The Stomatological Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P. R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P. R. China
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Yu Y, Zhang M, Zhang X, Cai Q, Zhu Z, Jiang W, Xu C. Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:85. [PMID: 25261977 PMCID: PMC4189590 DOI: 10.1186/s13046-014-0085-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 09/24/2014] [Indexed: 12/27/2022]
Abstract
Background We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer. Methods Expression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay. Results Our data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner. Conclusions The results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.
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Hu YJ, Li HY, Qiu KJ, Li DC, Zhou JH, Hu YH, Zhang FM. Downregulation of Notch1 inhibits the invasion of human hepatocellular carcinoma HepG2 and MHCC97H cells through the regulation of PTEN and FAK. Int J Mol Med 2014; 34:1081-6. [PMID: 25110169 DOI: 10.3892/ijmm.2014.1889] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 08/08/2014] [Indexed: 11/06/2022] Open
Abstract
Tumor invasion and metastasis are the main causes of mortality in patients with hepatocellular carcinoma (HCC). Thus, the effective inhibition of these tumorigenic processes is critical in order for HCC therapy to be effective. Previous studies have demonstrated that Notch1 is associated with metastasis in several human malignancies. However, the exact molecular mechanisms underlying the Notch1-mediated induction of the invasion of HCC cells remain poorly understood. In the present study, we demonstrate that, compared to the normal liver cell line, L02, Notch1 is highly expressed in the human HCC cell lines, HepG2 and MHCC97H. Using small interfering RNA (siRNA), we knocked down the expression of Notch1 in the cell lines. Notch1 expression in the HCC cell lines was also measured following transfection with siRNA using RT-PCR and western blot analysis. In addition, a migration and invasion assay was performed to determine the effects of Notch1 knockdown on cell migration and invasion. Our results demonstrated that the downregulation of Notch1 by small interfering RNA (siRNA) significantly inhibited the migration and invasion of both HCC cell lines. Additionally, we demonstrated that the knockdown of Notch1 in both HCC cell lines increased both the total expression of phosphatase and tensin homolog (PTEN) and its phosphorylated form. By contrast, focal adhesion kinase (FAK) and phospho-FAK expression was decreased following Notch1 depletion. Taken together, our data suggest that targeting Notch1 may be a useful therapeutic approach to inhibiting the metastasis of HCC cells.
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Affiliation(s)
- Yan-Jian Hu
- Department of Gastroenterology, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Hong-Ying Li
- Department of Biochemistry, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Kai-Jie Qiu
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Da-Chuan Li
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Jia-Hui Zhou
- Department of Applied Statistics, Liaoning University, Shenyang, Liaoning 110036, P.R. China
| | - Yan-Hua Hu
- Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Feng-Min Zhang
- Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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20
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Xia S, Ma J, Bai X, Zhang H, Cheng S, Zhang M, Zhang L, Du M, Wang Y, Li H, Rong R, Shi F, Yang Q, Leng J. Prostaglandin E2 promotes the cell growth and invasive ability of hepatocellular carcinoma cells by upregulating c-Myc expression via EP4 receptor and the PKA signaling pathway. Oncol Rep 2014; 32:1521-30. [PMID: 25109834 DOI: 10.3892/or.2014.3393] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 07/21/2014] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major health problem worldwide. Prostaglandin E2 (PGE2), the predominant product of cyclooxygenase-2, has been implicated in hepatocarcinogenesis. However, the underlying molecular mechanisms remain to be further elucidated. c-myc, a cellular proto-oncogene, is activated or overexpressed in many types of human cancer, including HCC. The present study was designed to investigate the internal relationship and molecular mechanisms between PGE2 and c-Myc in HCC, and to define its role in HCC cell growth and invasion. Our results showed that PGE2 significantly upregulated c-Myc expression at both the mRNA and protein levels, and knockdown of c-Myc blocked PGE2-induced HCC cell growth and invasive ability in human HCC Huh-7 cells. The effect of PGE2 on c-Myc expression was mainly through the EP4 receptor, and EP4 receptor-mediated c-Myc protein upregulation largely depended on de novo biosynthesis of c-Myc mRNA and its protein. EP4 receptor signaling activated GS/AC and increased the intracellular cAMP level in Huh-7 cells. The adenylate cyclase (AC) activator forskolin mimicked the effects of the EP4 receptor agonist on c-Myc expression, while the AC inhibitor SQ22536 reduced EP4 receptor-mediated c-Myc upregulation. These data confirm the involvement of the GS/AC/cAMP pathway in EP4 receptor-mediated c-Myc upregulation. Moreover, the phosphorylation levels of CREB protein were markedly elevated by EP4 receptor signaling, and by using specific inhibitor and siRNA interference, we demonstrated that PKA/CREB was also involved in the EP4 receptor-mediated c-Myc upregulation. In summary, the present study revealed that PGE2 significantly upregulates c-Myc expression at both mRNA and protein levels through the EP4R/GS/AC/cAMP/PKA/CREB signaling pathway, thus promoting cell growth and invasion in HCC cells. Targeting of the PGE2/EP4R/c-Myc pathway may be a new therapeutic strategy to prevent and cure human HCC.
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Affiliation(s)
- Shukai Xia
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hai Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Shanyu Cheng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Mingzhan Du
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hai Li
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Rong Rong
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Feng Shi
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Bai X, Yang Q, Shu W, Wang J, Zhang L, Ma J, Xia S, Zhang M, Cheng S, Wang Y, Leng J. Prostaglandin E2 upregulates β1 integrin expression via the E prostanoid 1 receptor/nuclear factor κ-light-chain-enhancer of activated B cells pathway in non-small-cell lung cancer cells. Mol Med Rep 2014; 9:1729-36. [PMID: 24584670 DOI: 10.3892/mmr.2014.2000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 02/13/2014] [Indexed: 11/06/2022] Open
Abstract
The prostaglandin E2 (PGE2) E prostanoid (EP)1 receptor shown to be associated with lung cancer cell invasion. However, the mechanism of EP1 receptor-mediated cell migration remains to be elucidated. β1 integrin is an essential regulator of the tumorigenic properties of non-small-cell lung carcinoma (NSCLC) cells. To date, little is known regarding the association between the EP1 receptor and β1 integrin expression. The present study investigated the effect of EP1 receptor activation on β1 integrin expression and cell migration in NSCLC cells. A total of 34 patients with clinical diagnosis of NSCLC and 10 patients with benign disease were recruited for the present study. The expression levels of the EP1 receptor and β1 integrin expression were studied in resected lung tissue using immunohistochemistry. A statistical analysis was performed using Stata se12.0 software. The effects of PGE2, EP1 agonist 17-phenyl trinor-PGE2 (17-PT-PGE2) and the nuclear factor κ-B (NF-κB) inhibitor on β1 integrin expression were investigated on A549 cells. The expression of β1 integrin and the phosphorylation of NF-κB‑p65 Ser536 was investigated by western blot analysis. Cell migration was assessed by a transwell assay. The results demonstrated that β1 integrin and EP1 receptor expression exhibited a positive correlation of evident significance in the 44 samples. The in vitro migration assay revealed that cell migration was increased by 30% when the cells were treated with 5 µM 17-PT-PGE2 and that the pre-treatment of β1 integrin monoclonal antibody inhibited 17-PT-PGE2‑mediated cell migration completely. PGE2 and 17-PT-PGE2 treatment increased β1 integrin expression. RNA interference against the EP1 receptor blocked the PGE2-mediated β1 integrin expression in A549 cells. Treatment with 17-PT-PGE2 induced NF-κB activation, and the selective NF-κB inhibitor pyrrolidinedithiocarbamate inhibited 17-PT-PGE2-mediated β1 integrin expression. In conclusion, the present study indicated that the PGE2 EP1 receptor regulates β1 integrin expression and cell migration in NSCLC cells by activating the NF-κB signaling pathway. Targeting the PGE2/EP1/β1 integrin signaling pathway may aid in the development of new therapeutic strategies for the prevention and treatment of this type of cancer.
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Affiliation(s)
- Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Wei Shu
- Department of Periodontal, Institute of Stomatology, The Stomatological Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jie Wang
- Department of Pathology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Shukai Xia
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Shanyu Cheng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Zhang H, Cheng S, Zhang M, Ma X, Zhang L, Wang Y, Rong R, Ma J, Xia S, Du M, Shi F, Wang J, Yang Q, Bai X, Leng J. Prostaglandin E2 promotes hepatocellular carcinoma cell invasion through upregulation of YB-1 protein expression. Int J Oncol 2013; 44:769-80. [PMID: 24378923 DOI: 10.3892/ijo.2013.2234] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 11/21/2013] [Indexed: 12/20/2022] Open
Abstract
Prostaglandin E2 (PGE2) has been implicated in hepatocellular carcinoma cell invasion. Recently, it was reported that Y box-binding protein 1 (YB-1) is closely correlated with malignancy. This study was designed to examine the mechanisms by which PGE2 increases YB-1 expression and promotes HCC cell invasion. PGE2 greatly enhanced HCC cell invasion through upregulation of the YB-1 protein, and the EP1 receptor is mainly responsible for this regulation. Src and EGFR were both activated by PGE2, which in turn increased the phosphorylation levels of p44/42 MAPK. Src, EGFR and p44/42 MAPK were all involved in PGE2-induced YB-1 expression. Chemical inhibitors and RNAi analysis all confirmed the role of mTOR complex 1 in YB-1 expression induced by PGE2. Furthermore, YB-1 was able to regulate the expression of a series of EMT-associated genes, which indicated that YB-1 could have the potential to control the epithelial-mesenchymal transition process in HCC cells. These findings reveal that PGE2 upregulated YB-1 expression through the EP1/Src/EGFR/p44/42 MAPK/mTOR pathway, which greatly enhanced HCC cell invasion. This study for the first time describes the mechanisms through which PGE2 regulates YB-1 expression and promotes HCC cell invasion.
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Affiliation(s)
- Hai Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Shanyu Cheng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Min Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xiuping Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Li Zhang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Yipin Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Rong Rong
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Juan Ma
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Shukai Xia
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Mingzhan Du
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Feng Shi
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Jie Wang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Qinyi Yang
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xiaoming Bai
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Jing Leng
- Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, P.R. China
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23
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Han S, Han L, Yao Y, Sun H, Zan X, Liu Q. Activated hepatic stellate cells promote hepatocellular carcinoma cell migration and invasion via the activation of FAK-MMP9 signaling. Oncol Rep 2013; 31:641-8. [PMID: 24284889 DOI: 10.3892/or.2013.2872] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 09/06/2013] [Indexed: 11/06/2022] Open
Abstract
Activated hepatic stellate cells (HSCs) are the major subtype of stromal cells in the liver tumor microenvironment which can promote the growth and migration of hepatocellular carcinoma (HCC) cells. However, the underlying mechanisms by which activated HSCs exert their oncogenic effects are not fully understood to date. In the present study, we investigated the number of activated HSCs and its clinicopathological significance in HCC and uncovered its correlation with focal adhesion kinase (FAK)-MMP9 signaling. A higher number of activated HSCs was associated with tumor invasion of the portal vein, advanced TNM stage and poorer tumor differentiation. The number of activated HSCs was positively correlated with the expression levels of p-FAK and MMP9 in HCC. Furthermore, we studied the effects of activated HSCs on the migration and invasion of HCC cells in vitro. Conditioned medium (CM) from activated HSCs or co-culture with activated HSCs significantly induced the migration and invasion of HCC cells. In addition, activation of FAK-MMP9 signaling in HCC was demonstrated in the presence of activated HSC-CM and of co-culture. Inhibition of FAK-MMP9 signaling in HCC cells with FAK short hairpin RNA (shRNA) abrogated the effects of activated HSCs on HCC cells. Taken together, our data suggest that activated HSCs in the tumor microenvironment promote HCC cell migration and invasion via activation of FAK-MMP9 signaling.
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Affiliation(s)
- Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Lei Han
- Department of Immunology and Pathogenic Biology, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Yingmin Yao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Hao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Xianfeng Zan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of the College of Medicine, Xi'an Jiaotong University, Xi'an 710061, P.R. China
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Duan CH, Tai S. Role of hepatitis B virus X protein in hepatocarcinogenesis. Shijie Huaren Xiaohua Zazhi 2013; 21:2397-2402. [DOI: 10.11569/wcjd.v21.i24.2397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for HCC. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the carcinogenesis of HCC. HBx is a multifunctional regulator that plays a key role in the occurrence, development, invasion and metastasis of cancers. Due to its important roles in the development of HCC, the research on the HBx protein has become a hot topic in recent years. This review describes the latest advances in understanding the role of the HBx protein in hepatocarcinogenesis.
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