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Li S, Liu W, Wang TT, Chen TQ, Guo JC. Identification of peanut skin components for treating hepatocellular carcinoma via network pharmacology and in vitro experiments. Chem Biol Drug Des 2024; 103:e14428. [PMID: 38230768 DOI: 10.1111/cbdd.14428] [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: 07/27/2023] [Revised: 10/17/2023] [Accepted: 12/11/2023] [Indexed: 01/18/2024]
Abstract
Peanut skin (PS) contains various flavonoids and phenols that have antitumor and antioxidant effects. However, no research has been conducted on PS and hepatocellular carcinoma (HCC). Therefore, this study sought to explore the potential mechanism of PS in treating HCC. PS was searched for in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SYMMAP databases. HCC targets were searched for in five major databases. Protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were performed. Molecular docking and molecular dynamics simulation were used for verification. Furthermore, in vitro experiments were used to verify the regulation of PS on human HCC (HepG2) cells. Ten ingredients and 95 common targets were identified for PS and HCC, respectively. The key targets of ingredients mainly relate to pathways such as hepatitis B, lipid and atherosclerosis, advanced glycation end products (AGEs)-AGE receptors (RAGEs) signaling pathway in diabetic complications, interleukin-17 (IL-17) signaling pathway, mitogen activated kinase-like protein (MAPK) signaling pathway, the PI3K-Akt signaling pathway. In addition, the molecular docking and molecular dynamics simulation analysis indicated the ingredients had strong binding ability with the targets. Moreover, in vitro experiments confirmed that luteolin can promote the apoptosis of HepG2 cells by controlling the expression of phosphorylated protein-tyrosine kinase (p-AKT). This study provides preliminary evidence that PS produces a marked effect in regulating multiple signaling pathways in HCC through multiple ingredients acting on multiple core genes, including AKT serine/threonine kinase 1 (AKT1), MYC, caspase 3 (CASP3), estrogen receptor 1 (ESR1), epidermal growth factor receptor (EGFR), jun proto-oncogene(JUN), and provides the basis for follow-up research to verify the mechanism of action of PS in treating HCC.
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Affiliation(s)
- Sha Li
- Department of Pharmacy, Changsha Stomatological Hospital, Changsha, China
| | - Wen Liu
- Department of Pharmacy, Hunan Provincial People's Hospital, Changsha, China
| | - Tong-Tong Wang
- Department of Pharmacy, The First Hospital of Changsha, Changsha, China
| | - Tong-Qiang Chen
- Hunan provincial institute of product and goods quality inspection, Changsha, China
| | - Jin-Cai Guo
- Department of Pharmacy, Changsha Stomatological Hospital, Changsha, China
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Dai L, Mugaanyi J, Cai X, Dong M, Lu C, Lu C. Comprehensive bioinformatic analysis of MMP1 in hepatocellular carcinoma and establishment of relevant prognostic model. Sci Rep 2022; 12:13639. [PMID: 35948625 PMCID: PMC9365786 DOI: 10.1038/s41598-022-17954-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/03/2022] [Indexed: 12/17/2022] Open
Abstract
Matrix metalloproteinase 1 (MMP1) encodes endopeptidases associated with degradation of multiple components of the extracellular matrix. This function has increasingly been considered to play a major proteolysis role in tumor invasion and metastasis. However, the relationship between MMP1 gene expression, tumor-immune microenvironment and prognosis in hepatocellular carcinoma patients remains mostly unclear. This study focused on a comprehensive analysis of MMP1 in hepatocellular carcinoma, specifically the prognosis and tumor-immune microenvironment. MMP1 expression was analyzed using TCGA database and clinical samples. MMP1 associated mechanisms, pathways, mutations and prognosis in hepatocellular carcinoma were evaluated. We also analyzed the tumor-immune microenvironment and corresponding treatments. Our research demonstrated that MMP1 expression was upregulated in patients with hepatocellular carcinoma and correlated with poor survival. A prognostic model was established and its performance evaluated. We also found and report various correlations between MMP1 and immune-related cells/genes, as well the potential therapeutic agents. These findings indicate that MMP1 can potentially be a promising prognostic biomarker and indicator of the tumor-immune microenvironment status in hepatocellular carcinoma.
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Affiliation(s)
- Lei Dai
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Joseph Mugaanyi
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Xingchen Cai
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Mingjun Dong
- Department of Emergency, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Caide Lu
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China.
| | - Changjiang Lu
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China.
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Li L, Ye T, Zhang Q, Li X, Ma L, Yan J. The expression and clinical significance of TPM4 in hepatocellular carcinoma. Int J Med Sci 2021; 18:169-175. [PMID: 33390785 PMCID: PMC7738955 DOI: 10.7150/ijms.49906] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/07/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is known as the fifth most common cancer in the world for its poor prognosis. New diagnostic markers and treatments are urgent to discover. To evaluate the protein expression of Tropomyosin4 (TPM4) and investigate its prognostic value in HCC, we collected 110 patients with different degrees of HCC and 10 patients with normal hepatic tissues and performed immunohistochemistry. Western bot was used to evaluate the expression of TPM4 in three HCC cell lines (HepG2, Huh7, SMMC-7721) and normal liver cell line LO2, as well as 7 HCC tissues and 7 normal hepatic tissues. The results of TPM4 staining revealed that TPM4 expression in HCC was higher than that in normal hepatic tissues, which was positive in 51.8% (n=57) and negative in 48.2% (n=53) while in normal hepatic tissues positive staining was in 10% (n=1) and negative staining was in 90% (n=9) (P=0.011). And the expression of TPM4 was related to pT status, grade and stage (P<0.001, P=0.015 and P<0.001, respectively). Western blot results indicated that TPM4 was high expressed in HCC cell line and HCC tissues. In conclusion, we believe that TPM4 can be applied as a diagnostic and prognostic marker to assist the management of HCC.
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Affiliation(s)
- Linjing Li
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Tao Ye
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China, 510515
| | - Qingyan Zhang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510080
| | - Xin Li
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China, 510515
| | - Li Ma
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou 730000, P.R. China
| | - Jing Yan
- Department of Clinical Laboratory Center, The Second Hospital of Lanzhou University, Lanzhou 730000, P.R. China
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4
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López-Cánovas JL, Del Rio-Moreno M, García-Fernandez H, Jiménez-Vacas JM, Moreno-Montilla MT, Sánchez-Frias ME, Amado V, L-López F, Fondevila MF, Ciria R, Gómez-Luque I, Briceño J, Nogueiras R, de la Mata M, Castaño JP, Rodriguez-Perálvarez M, Luque RM, Gahete MD. Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma. Cancer Lett 2021; 496:72-83. [PMID: 33038489 DOI: 10.1016/j.canlet.2020.10.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022]
Abstract
Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.
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Affiliation(s)
- Juan L López-Cánovas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Mercedes Del Rio-Moreno
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Helena García-Fernandez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Juan M Jiménez-Vacas
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - M Trinidad Moreno-Montilla
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marina E Sánchez-Frias
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain
| | - Víctor Amado
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Fernando L-López
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Marcos F Fondevila
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Rubén Ciria
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Irene Gómez-Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Javier Briceño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Unit of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Cordoba, 14004, Spain
| | - Rubén Nogueiras
- CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Manuel de la Mata
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Justo P Castaño
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel Rodriguez-Perálvarez
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Hepatic and Digestive Diseases (CIBERehd), Córdoba, 14004, Spain
| | - Raúl M Luque
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain
| | - Manuel D Gahete
- Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, 14004, Spain; Reina Sofía University Hospital, Córdoba, 14004, Spain; CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), Córdoba, 14004, Spain.
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Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21020496. [PMID: 31941025 PMCID: PMC7013925 DOI: 10.3390/ijms21020496] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 12/31/2019] [Accepted: 01/08/2020] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is initiated and promoted by chronic inflammation. Inflammatory mediators are transcriptionally regulated by several inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). cJun N-terminal kinase (JNK), a member of the MAPK family, plays a central role in HCC pathogenesis. Pathogen-associated molecular patterns (PAMPs) activate JNK and other MAPK upon recognition by toll-like receptors (TLRs). Apart from TLRs, PAMPs are sensed by several other pattern recognition receptors, including cytosolic NOD-like receptors (NLRs). In a recent study, we demonstrated that the NLR member NLRP12 plays a critical role in suppressing HCC via negative regulation of the JNK pathway. This article briefly reviews the crosstalk between NLRP12 and JNK that occurs during HCC.
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Ando W, Kikuchi K, Uematsu T, Yokomori H, Takaki T, Sogabe M, Kohgo Y, Otori K, Ishikawa S, Okazaki I. Novel breast cancer screening: combined expression of miR-21 and MMP-1 in urinary exosomes detects 95% of breast cancer without metastasis. Sci Rep 2019; 9:13595. [PMID: 31537868 PMCID: PMC6753125 DOI: 10.1038/s41598-019-50084-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Serum and tissue miR-21 expression in patients with breast cancer (BC) is a useful biomarker for cancer diagnosis, progression, and treatment. Matrix metalloproteinase-1 (MMP-1) is also important in breast cancer carcinogenesis. However, miR-21 and MMP-1/CD63 in urine exosomes in these patients have not been examined. Urine samples were collected from patients with BC and 26 healthy females. Urinary exosomes were isolated and confirmed by western blotting with anti-CD63 antibody and electron microscopy observation. MiR-21 and MMP-1/CD63 expression was examined by quantitative RT-PCR and western blotting, respectively. Patients with very early stage breast cancer were evaluated. MiR-21 expression in the patients was 0.26 [95% CI: 0.20–0.78], which was significant lower than in the 26 controls (1.00 [95% CI: 1.01–3.37], p = 0.0947). MMP-1/CD63 expression in patients was significantly higher than in controls (1.74 [95% CI: 0.86–5.08] vs 0.535 [95% CI: −0.01–2.81], p = 0.0001). Sensitivity and specificity were 0.708 and 0.783 for miR-21 and 0.792 and 0.840 for MMP-1/CD63, respectively. Sensitivity and specificity of combined expression were 95% and 79%, respectively. The sensitivity of MMP-1/CD63 expression in urinary exosomes was better than that of miR-21 expression. Thus, miR-21 and MMP/CD63 may be useful markers for BC screening.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, Kitasato University School of Pharmacy, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Kiyoshi Kikuchi
- Department of Surgery, Sanno Hospital, International University of Health and Welfare, 8-10-16 Akasaka, Minato-ku, Tokyo, 107-0052, Japan
| | - Takayuki Uematsu
- Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, 6-100 Arai, Kitamoto City, Saitama, 364-8501, Japan
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, 6-100 Arai, Kitamoto City, Saitama, 364-8501, Japan
| | - Takashi Takaki
- Division of Electron microscopy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Masaya Sogabe
- Department of General Thoracic Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Yutaka Kohgo
- Department of Internal Medicine, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan.,Health Care Center, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, Kitasato University School of Pharmacy, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Shigemi Ishikawa
- Department of Chest Surgery, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan
| | - Isao Okazaki
- Department of Internal Medicine, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan. .,Health Care Center, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan. .,Department of Internal Medicine, Sanno Hospital, International University of Health and Welfare, 8-10-16 Akasaka, Minato-ku, Tokyo, 107-0052, Japan.
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Zhang MH, Niu H, Li Z, Huo RT, Wang JM, Liu J. Activation of PI3K/AKT is involved in TINAG-mediated promotion of proliferation, invasion and migration of hepatocellular carcinoma. Cancer Biomark 2018; 23:33-43. [PMID: 29991125 DOI: 10.3233/cbm-181277] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is a highly aggressive malignancy that has a poor prognosis. Through the literatures, TINAG significantly participated in the processes of the renal-associated diseases, but there were no studies about the roles of TINAG in the HCC development. Hence, we attempted to use the HCC samples collected by ourselves to reveal the clinical significance and prognostic impact of TINAG in HCC. METHODS We first measured the expression level of TINAG in HCC on the basis of TCGA database. Then, real time quantitative reverse transcription PCR (RT-qPCR) was used to examine the expression level of TINAG in 100 pairs of HCC tissues and corresponding adjacent non-tumor tissues, as well as HCC cell lines (HepG2, HB611, HHCC, and Hep3B). Moreover, Kaplan-Meier method and COX's proportional hazards model were utilized to perform the survival and prognosis analyses using the clinical data collected by ourselves. After knockdown of TINAG, the cell proliferation, invasion and migration capacities of HepG2 and Hep3B cells were evaluate by counting kit-8 (CCK-8) assay (24 h, 48 h, 72 h, and 96 h post-cultivation), clone formation experiment, would-healing, and invasion as well as migration assays. To further explore whether the dys-regulated TINAG expression regulates the HCC progression and prognosis, protein biomarkers of PI3K signaling pathway, including AKT, p-AKT, PI3K, p-PI3K, p70S6K, and p-p70S6K were measured based on western blotting analysis. RESULTS According to the data of TCGA database, clinical patients, and HCC cell lines, TINAG was highly expressed in HCC compared with normal. Relationship of TINAG expression level with the clinicopathological factors implicated that the high expression of TINAG was significantly associated with pathologic stage, pathologic-node, and pathologic-metastasis. Univariate as well as multivariate COX analysis indicated that TINAG expression and pathologic metastasis can serve as the independent prognostic factor for overall survival of HCC. After TINAG knockdown in HepG2 and Hep3B cells, cell proliferation rate, the colony numbers, and the invasive and migratory capacity were found to be suppressed. Remarkably, western blot results showed that reduction of TINAG remarkably decreased p-AKT, p-PI3K, and p-p70S6K expression level in HepG2 and Hep3B cells. CONCLUSION Collectively, our results underscore the significance of TINAG in HCC progression and prognosis, and TINAG might be a novel candidate oncogene in HCC. These results propose that targeting TINAG might offer future clinical utility in HCC.
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Affiliation(s)
- Meng-Hui Zhang
- Department of Hepatobiliary, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China.,Department of General Surgery, The Fourth People's Hospital of Jinan, Jinan 250031, Shandong, China
| | - Hu Niu
- Department of General Surgery, The Fourth People's Hospital of Jinan, Jinan 250031, Shandong, China
| | - Zheng Li
- Department of General Surgery, The Fourth People's Hospital of Jinan, Jinan 250031, Shandong, China
| | - Ren-Tao Huo
- Department of General Surgery, The Fourth People's Hospital of Jinan, Jinan 250031, Shandong, China
| | - Jun-Mei Wang
- Heze Traditional Chinese Medicine Hospital, Heze 274035, Shandong, China
| | - Jun Liu
- Department of Hepatobiliary, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China
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Guan PP, Guo JW, Yu X, Wang Y, Wang T, Konstantopoulos K, Wang ZY, Wang P. The role of cyclooxygenase-2, interleukin-1β and fibroblast growth factor-2 in the activation of matrix metalloproteinase-1 in sheared-chondrocytes and articular cartilage. Sci Rep 2015; 5:10412. [PMID: 25992485 PMCID: PMC4438667 DOI: 10.1038/srep10412] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 04/13/2015] [Indexed: 12/13/2022] Open
Abstract
MMP-1 expression is detected in fluid shear stress (20 dyn/cm(2))-activated and osteoarthritic human chondrocytes, however, the precise mechanisms underlying shear-induced MMP-1 synthesis remain unknown. Using primary chondrocytes and T/C-28a2 chondrocytic cells as model systems, we report that prolonged application of high fluid shear to human chondrocytes induced the synthesis of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and fibroblast growth factor-2 (FGF-2), which led to a marked increase in MMP-1 expression. IL-1β, COX-2-dependent PGE2 activated the PI3-K/AKT and p38 signaling pathways, which were in turn responsible for MMP-1 synthesis via NF-κB- and c-Jun-transactivating pathways. Prolonged shear stress exposure (>12 h) induced 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) synthesis. Although 15d-PGJ2 suppressed PI3-K/AKT and p38 signaling pathways, it stimulated MMP-1 expression via activating heme oxygenase 1 (HO-1). The critical role of COX-2 in regulating MMP-1 expression in articular cartilage in vivo was demonstrated using COX-2(+/-) transgenic mice in the absence or presence of rofecoxib oral administration. These findings provide novel insights for developing therapeutic strategies to combat OA.
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Affiliation(s)
- Pei-Pei Guan
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Jing-Wen Guo
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Xin Yu
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Yue Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Tao Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Konstantinos Konstantopoulos
- Department of Chemical and Biomolecular Engineering
- Johns Hopkins Institute for NanoBioTechnology
- Johns Hopkins Physical Sciences-Oncology Center
- Center of Cancer Nanotechonology Excellence, The Johns Hopkins University, Baltimore, Maryland, United States of America, 21218
| | - Zhan-You Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
| | - Pu Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China, 110819
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Okazaki I, Noro T, Tsutsui N, Yamanouchi E, Kuroda H, Nakano M, Yokomori H, Inagaki Y. Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs). Cancers (Basel) 2014; 6:1220-55. [PMID: 24978432 PMCID: PMC4190539 DOI: 10.3390/cancers6031220] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 04/24/2014] [Accepted: 05/15/2014] [Indexed: 01/18/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC.
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Affiliation(s)
- Isao Okazaki
- Department of Internal Medicine, Sanno Hospital, International University of Health and Welfare, Tokyo 107-0052, Japan.
| | - Takuji Noro
- Department of Surgery, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan.
| | - Nobuhiro Tsutsui
- Department of Surgery, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan.
| | - Eigoro Yamanouchi
- Department of Radiology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan.
| | - Hajime Kuroda
- Department of Pathology, International University of Health and Welfare Hospital, Tochigi 329-2763, Japan.
| | - Masayuki Nakano
- Department of Pathology, Ofuna Chuo Hospital, Kanagawa 247-0056, Japan.
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama 364-8501, Japan.
| | - Yutaka Inagaki
- Department of Regenerative Medicine, Tokai University School of Medicine and Institute of Medical Sciences, Isehara 259-1193, Japan.
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Yeh CB, Yu YL, Lin CW, Chiou HL, Hsieh MJ, Yang SF. Terminalia catappa attenuates urokinase-type plasminogen activator expression through Erk pathways in Hepatocellular carcinoma. Altern Ther Health Med 2014; 14:141. [PMID: 24886639 PMCID: PMC4012530 DOI: 10.1186/1472-6882-14-141] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 04/25/2014] [Indexed: 01/31/2023]
Abstract
Background The survival rate of malignant tumors, and especially hepatocellular carcinoma (HCC), has not improved primarily because of uncontrolled metastasis. In our previous studies, we have reported that Terminalia catappa leaf extract (TCE) exerts antimetastasis effects on HCC cells. However, the molecular mechanisms of urokinase-type plasminogen activator (u-PA) in HCC metastasis have not been thoroughly investigated, and remain poorly understood. Methods The activities and protein levels of u-PA were determined by casein zymography and western blotting. Transcriptional levels of u-PA were detected by real-time PCR and promoter assays. Results We found that treatment of Huh7 cells with TCE significantly reduced the activities, protein levels and mRNA levels of u-PA. A chromatin immunoprecipitation (ChIP) assay showed that TCE inhibited the transcription protein of nuclear factors SP-1 and NF-κB. TCE also did inhibit the effects of u-PA by reducing the phosphorylation of ERK1/2 pathway. Conclusions These results show that u-PA expression may be a potent therapeutic target in the TCE-mediated suppression of HCC metastasis.
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Brassesco MS, Pezuk JA, de Oliveira JC, Valera ET, de Oliveira HF, Scrideli CA, Umezawa K, Tone LG. Activator protein-1 inhibition by 3-[(dodecylthiocarbonyl)methyl]-glutamaride impairs invasion and radiosensitizes osteosarcoma cells in vitro. Cancer Biother Radiopharm 2013; 28:351-8. [PMID: 23350896 DOI: 10.1089/cbr.2012.1305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor. Despite advances in neoadjuvant multi-agent chemotherapy, the outcome of patients has not significantly improved in the last decades, making the search for more effective therapeutic agents imperative. In the present study, we explored the possibility of using activator protein-1 inhibition by 3-[(dodecylthiocarbonyl)methyl]-glutarimide (DTCM-g) as a new therapeutic strategy in two OS cell lines, HOS and MG-63. Our results showed that low concentrations (2.5, 5, 10, and 20 μg/mL) of the drug significantly decreased cell proliferation and clonogenic capacity, albeit it did not significantly induce cell death. DTCM-g also decreased cell invasiveness, and inhibited PDPN, MMP-2, TIMP1, and TIMP2 expressions. Moreover, our results showed that DTCM-g synergized with ionizing radiation in both cell lines while chemosensitized MG-63 cells to doxorubicin treatment. Even though additional laboratorial and preclinical tests are still needed to support our data, we demonstrate that DTCM-g inhibits growth in OS cells, increases the cytotoxicity of other commonly used agents, and may possess antimetastatic activity.
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Affiliation(s)
- María Sol Brassesco
- 1 Division of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto, Brazil
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12
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Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World J Hepatol 2012; 4:342-55. [PMID: 23355912 PMCID: PMC3554798 DOI: 10.4254/wjh.v4.i12.342] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 11/17/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.
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Affiliation(s)
- Denis Selimovic
- Denis Selimovic, Youssef Haikel, Mohamed Hassan, Institut National de la Santé et de la Recherche Médicale, U 977, 67000 Strasbourg, France
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13
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Castro AF, Campos T, Babcock JT, Armijo ME, Martínez-Conde A, Pincheira R, Quilliam LA. M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells. J Cell Biochem 2012; 113:1253-64. [PMID: 22121046 DOI: 10.1002/jcb.23458] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector-binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as phosphatidylinositol 3 kinase (PI3K)/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf/M-Ras interaction and Ral/JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK, and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors.
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Affiliation(s)
- Ariel F Castro
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
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Nakagawa H, Maeda S. Molecular mechanisms of liver injury and hepatocarcinogenesis: focusing on the role of stress-activated MAPK. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:172894. [PMID: 22666632 PMCID: PMC3361329 DOI: 10.1155/2012/172894] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 02/26/2012] [Accepted: 02/28/2012] [Indexed: 01/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH(2)-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.
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Affiliation(s)
- Hayato Nakagawa
- Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, La Jolla, CA 92093, USA
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
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Yoon JH, Choi YJ, Lee SG. Ginsenoside Rh1 suppresses matrix metalloproteinase-1 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathway in human hepatocellular carcinoma cells. Eur J Pharmacol 2012; 679:24-33. [PMID: 22314224 DOI: 10.1016/j.ejphar.2012.01.020] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 01/18/2012] [Accepted: 01/21/2012] [Indexed: 12/28/2022]
Abstract
Invasion and metastasis are the major causes of treatment failure in patients with cancer. Here, we investigated the effects of ginsenoside Rh1 on tumor invasion and metastasis in human hepatocellular carcinoma HepG2 cells and its possible mechanism of action. Rh1 showed concentration- and time-dependent inhibition of HepG2 cell migration and invasion. Matrix metalloproteinase-1 (MMP-1) gene expression and its promoter activity were also concentration-dependently inhibited by Rh1 treatment. The inhibitory effect of Rh1 on MMP-1 expression was due to inactivation of the mitogen-activated protein kinases (MAPKs) ERK, JNK, and p38 MAPK. By transient transfection analysis with the MMP-1 promoter (-2846 to -29 nt) and AP-1 promoter, MMP-1 and AP-1 promoter activities were induced by phorbol myristate acetate (PMA) but were significantly inhibited by PD98059 (ERK1/2 inhibitor) or SP600125 (JNK inhibitor). The induction of MMP-1 and AP-1 promoters by PMA was attenuated by Rh1, and both promoter activities were synergistically inhibited by co-treatment with PD98059. To evaluate the effects of Rh1 on AP-1 dimers, expression analysis and electrophoretic mobility shift (EMSA) assay using radiolabeled AP-1-specific oligomers at proximal site (-73 nt) and distal site (-1600 nt) of the MMP-1 promoter were performed. The results showed that Rh1 inhibited the expression of c-Jun and c-Fos but did not affect the DNA binding ability of AP-1-specific oligomers. However, Rh1 attenuated the stability of c-Jun. Therefore, Rh1 has potential for development of novel chemotherapeutic agents for treatment of malignant cancers, including early hepatocellular carcinoma related to MMP-1 expression.
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Affiliation(s)
- Ji-Hae Yoon
- Department of Biotechnology, Bio-Energy Research Center, Chonnam National University, Gwangju 500-757, South Korea
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16
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Wu M, Li X, Li X, Li G. Signaling Transduction Network Mediated by Tumor Suppressor/Susceptibility Genes in NPC. Curr Genomics 2011; 10:216-22. [PMID: 19949542 PMCID: PMC2709932 DOI: 10.2174/138920209788488481] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Revised: 03/04/2009] [Accepted: 03/06/2009] [Indexed: 11/26/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a polygenetic disease. SPLUNC1, UBAP1, BRD7, NAG7, NOR1, NGX6 and LTF genes were found to be tumor suppressor/susceptibility genes in different stages of NPC. SPLUNC1, an early warning molecular diagnosis marker, inhibits the bacteria clone formation, and is an innated immune molecule. SPLUNC1 can negatively regulate the ERK/MAPK signaling transduction pathway to inhibit NPC cell proliferation and induce apoptosis. BRD7, a transcript regulation factor, interacts with BRD2, and promotes apoptosis induced by BRD2. Its promoter is regulated by c-Myc and SP1. BRD7 inhibits NPC cell cycle progression, preventing passage through G0/G1 by suppressing ras/MEK/ERK, Rb/E2F and Wnt signaling pathways. Abnormal activation of BRD7 is crucial to cell cycle turbulence in NPC. NGX6, a metastasis-associated protein, can negative-regulate the EGF/Ras/MAPK signaling transduction pathway, and interacts with ezrin protein to inhibit NPC cell invasion and metastasis. LTF, also a metastasis-associated protein, can negatively regulate MAPK signal transduction pathways, such as JNK2 and ERK, to inhibit NPC cell proliferation and growth. Taken together, it was found that these tumor suppressor/susceptibility genes can regulate key molecules involved in cell signal pathways such as ras/MEK/ERK, Rb/E2F and EGFR ras/MEK/MAPK, and can regulate the expression of some adhesion molecules such as ezrin, nm23 and α-catenin. According to functional genomics and signaling transduction pathways, we have described a signaling cross-talk network between the tumor suppressor/susceptibility genes involved in NPC. These tumor suppressor/susceptibility genes may be potential treatment targets for NPC in the future.
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Affiliation(s)
- Minghua Wu
- Cancer Research Institute, Central South University, Hunan, the People's Republic of China
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17
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Kimura R, Ishikawa C, Rokkaku T, Janknecht R, Mori N. Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2011; 1813:1543-53. [PMID: 21640141 DOI: 10.1016/j.bbamcr.2011.04.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 04/26/2011] [Accepted: 04/26/2011] [Indexed: 12/23/2022]
Abstract
Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. Despite the advances in surgical and medical management, the mechanisms underlying human osteosarcoma progression and metastasis remain to be elucidated. Gene expression profiles were compared by the cDNA microarray technique between two different human osteosarcoma sublines, MNNG/HOS and 143B, which differ greatly in spontaneous pulmonary metastatic potential. Here we report an enhanced expression of matrix metalloproteinase (MMP)-1 in the highly metastatic human osteosarcoma cell line 143B. Moreover, the in vitro invasion activity of 143B cells was MMP-1-dependent. The activator protein (AP)-1 binding site in the MMP-1 gene promoter was required for the constitutive expression of MMP-1 in 143B cells. Two AP-1 components, c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells. Mitogen-activated protein kinase pathways including the c-Jun NH(2)-terminal kinase and the extracellular signal-regulated kinase activate c-Jun and Fra-1 and thereby regulate c-Jun/Fra-1 mediated events, establishing the mitogen-activated protein kinase/AP-1/MMP-1 axis as important in 143B cells. These data suggest that MMP-1 plays a central role in osteosarcoma invasion. Accordingly, MMP-1 might be a biomarker and therapeutic target for invasive osteosarcomas and pulmonary metastases.
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Affiliation(s)
- Ryuichiro Kimura
- Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan
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Mitogen-activated protein kinases in hepatocellular carcinoma development. Semin Cancer Biol 2011; 21:10-20. [DOI: 10.1016/j.semcancer.2010.10.011] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 10/05/2010] [Accepted: 10/13/2010] [Indexed: 12/22/2022]
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Huang C, Wu M, Tang Y, Li X, Ouyang J, Xiao L, Li D, Li G. NAG7 promotes human nasopharyngeal carcinoma invasion through inhibition of estrogen receptor alpha and up-regulation of JNK2/AP-1/MMP1 pathways. J Cell Physiol 2009; 221:394-401. [PMID: 19591174 DOI: 10.1002/jcp.21867] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The NAG7, an estrogen receptor repressor, is a negative regulator of nasopharyngeal carcinoma cell growth. Here, we report that NAG7 promotes human nasopharyngeal carcinoma invasion, and we identify the mechanisms underlying this function. As a consequence of elevated NAG7 expression, the adhesion, migration, and invasive capabilities of HNE1 cells in vitro and in vivo were enhanced. NAG7 was a significant negative regulator of protein expression of estrogen receptor alpha (ERalpha), and activated both the JNK2/AP-1/MMP1 and the upstream H-Ras/p-c-Raf pathways. None of these effects induced by NAG7 over-expression could be counteracted by estrogen. These observations indicate that NAG7 plays a potential role in promoting nasopharyngeal carcinoma invasion by regulation of ERalpha and the H-ras/p-c-Raf and JNK2/AP-1/MMP1 signaling pathways.
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Affiliation(s)
- Chen Huang
- Cancer Research Institute, Central South University, Changsha, Hunan, PR China
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20
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Nagata H, Hatano E, Tada M, Murata M, Kitamura K, Asechi H, Narita M, Yanagida A, Tamaki N, Yagi S, Ikai I, Matsuzaki K, Uemoto S. Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma. Hepatology 2009; 49:1944-53. [PMID: 19418558 DOI: 10.1002/hep.22860] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.
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Affiliation(s)
- Hiromitsu Nagata
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Endo H, Sugioka Y, Nakagi Y, Saijo Y, Yoshida T. A novel role of the NRF2 transcription factor in the regulation of arsenite-mediated keratin 16 gene expression in human keratinocytes. ENVIRONMENTAL HEALTH PERSPECTIVES 2008; 116:873-879. [PMID: 18629308 PMCID: PMC2453154 DOI: 10.1289/ehp.10696] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2007] [Accepted: 03/06/2008] [Indexed: 05/26/2023]
Abstract
BACKGROUND Inorganic sodium arsenite (iAs) is a ubiquitous environmental contaminant and is associated with an increased risk of skin hyperkeratosis and cancer. OBJECTIVES We investigated the molecular mechanisms underlying the regulation of the keratin 16 (K16) gene by iAs in the human keratinocyte cell line HaCaT. METHODS We performed reverse transcriptase polymerase chain reaction, luciferase assays, Western blots, and electrophoretic mobility shift assays to determine the transcriptional regulation of the K16 gene by iAs. We used gene overexpression approaches to elucidate the nuclear factor erythroid-derived 2 related factor 2 (NRF2) involved in the K16 induction. RESULTS iAs induced the mRNA and protein expression of K16. We also found that the expression of K16 was transcriptionally induced by iAs through activator protein-1-like sites and an antioxidant response element (ARE) in its gene promoter region. Treatment with iAs also enhanced the production and translocation of the NRF2 transcription factor, an ARE-binding protein, into the nucleus without modification of its mRNA expression. In addition, iAs elongated the half-life of the NRF2 protein. When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. CONCLUSIONS Our data clearly indicate that the K16 gene is a novel target of NRF2. Furthermore, our findings also suggest that NRF2 has opposing roles in the cell--in the activation of detoxification pathways and in promoting the development of skin disorders.
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Affiliation(s)
| | | | | | | | - Takahiko Yoshida
- Address correspondence to T. Yoshida, Department of Health Science, Asahikawa Medical College, E2–1-1–1, Midorigaoka, Asahikawa, Hokkaido, 078–8510 Japan. Telephone: 81-166-68-2400/2402. Fax: 81-166-68-2409. E-mail:
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Shin MH, Moon YJ, Seo JE, Lee Y, Kim KH, Chung JH. Reactive oxygen species produced by NADPH oxidase, xanthine oxidase, and mitochondrial electron transport system mediate heat shock-induced MMP-1 and MMP-9 expression. Free Radic Biol Med 2008; 44:635-45. [PMID: 18036352 DOI: 10.1016/j.freeradbiomed.2007.10.053] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2007] [Revised: 10/19/2007] [Accepted: 10/25/2007] [Indexed: 12/18/2022]
Abstract
In addition to ultraviolet radiation, human skin is also exposed to infrared radiation (IR) from natural sunlight. IR typically increases the skin temperature. This study examined whether or not heat shock-induced ROS stimulates MMPs in keratinocyte HaCaT cells. In HaCaT cells, heat shock was found to increase the intracellular ROS levels, including hydrogen peroxide and superoxide. The heat shock treatment induced MMP-1 and MMP-9, but not MMP-2, at the mRNA and protein levels. Moreover, heat shock caused the rapid activation of the three distinct MAPKs, ERK, JNK, and p38 kinase. The heat shock-induced expression of MMP-1 and MMP-9 was significantly suppressed by a pretreatment with the antioxidant NAC or catalase. On the other hand, SOD inhibited heat shock-induced activity of MMP-9 induction, but not MMP-1. A pretreatment with NAC or catalase, but not SOD, attenuated the phosphorylation of ERK, JNK, and p38 kinase by heat shock. The potential sites of ROS generation by heat shock along with its role in the heat shock-induced expression of MMP-1 and MMP-9 were next analyzed. These results indicate that heat shock-induced ROS is promoted via NADPH oxidase, xanthine oxidase, and mitochondria. Indeed, the NADPH oxidase and xanthine oxidase activities were increased by heat shock. Overall, the ROS produced by heat shock may play an important role in the heat shock-induced activation of MAPKs, which can induce MMP-1 and-9 expressions.
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Affiliation(s)
- Mi Hee Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul National University, Seoul, Korea
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Page-McCaw A. Remodeling the model organism: matrix metalloproteinase functions in invertebrates. Semin Cell Dev Biol 2008; 19:14-23. [PMID: 17702617 PMCID: PMC2248213 DOI: 10.1016/j.semcdb.2007.06.004] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Accepted: 06/23/2007] [Indexed: 11/17/2022]
Abstract
The matrix metalloproteinase (MMP) family of extracellular proteases is conserved throughout the animal kingdom. Studies of invertebrate MMPs have demonstrated they are involved in tissue remodeling. In Drosophila, MMPs are required for histolysis, tracheal growth, tissue invasion, axon guidance, and dendritic remodeling. Recent work demonstrates that MMPs also participate in Drosophila tumor invasion. In Caenorhabditis elegans an MMP is involved in anchor cell invasion; a Hydra MMP is important for regeneration and maintaining cell identity; and a sea urchin MMP degrades matrix to allow hatching. In worms and in flies, MMPs are regulated by the JNK pathway.
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Affiliation(s)
- Andrea Page-McCaw
- Center for Biotechnology and Interdisciplinary Studies and Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
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Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, Kaibori M, Kamiyama Y, Nishizawa M, Fujisawa J, Okazaki K, Seki T. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007; 46:48-57. [PMID: 17596875 DOI: 10.1002/hep.21672] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
UNLABELLED Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF-beta) activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Whereas the TbetaRI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21(WAF1) transcription, JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI-1). We studied the domain-specific Smad3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV-infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI-1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21(WAF1) decreased. Of 14 patients with chronic hepatitis C with strong hepatocytic pSmad3L positivity, 8 developed HCC within 12 years; only 1 of 12 showing little pSmad3L positivity developed HCC. We further sought molecular mechanisms in vitro. JNK activation by the pro-inflammatory cytokine interleukin-1beta stimulated the pSmad3L/PAI-1 pathway in facilitating hepatocytic invasion, in the meantime reducing TGF-beta-dependent tumor-suppressive activity by the pSmad3C/p21(WAF1) pathway. CONCLUSION These results indicate that chronic inflammation associated with HCV infection shifts hepatocytic TGF-beta signaling from tumor-suppression to fibrogenesis, accelerating liver fibrosis and increasing risk for HCC.
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Affiliation(s)
- Koichi Matsuzaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan.
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Hsieh YH, Wu TT, Huang CY, Hsieh YS, Hwang JM, Liu JY. p38 mitogen-activated protein kinase pathway is involved in protein kinase Calpha-regulated invasion in human hepatocellular carcinoma cells. Cancer Res 2007; 67:4320-7. [PMID: 17483345 DOI: 10.1158/0008-5472.can-06-2486] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Protein kinase Calpha (PKCalpha) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKCalpha in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKCalpha-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKCalpha-SK) expressing DNA-based small interfering RNA (siRNA) PKCalpha was established and was then characterized by cell growth, migration, and invasion. The expression of PKCalpha was decreased in siPKCalpha-SK, and cell growth, migration, and invasion were reduced. These changes were associated with the decrease in p38 MAPK phosphorylation level, but not in c-jun-NH(2)-kinase-1/2 (JNK-1/2) and extracellular signal-regulated kinase-1/2 (ERK-1/2). This phenomenon was confirmed in the SK-Hep-1 cells treated with antisense PKCalpha olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKCalpha-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SK-Hep-1 cells treated with the SB203580 or DN-p38, but not with ERK-1/2 inhibitor PD98059 or JNK-1/2 inhibitor SP600125. Overexpression of constitutively active MKK6 or PKCalpha may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKCalpha-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKCalpha. This study provides new insight into the role of p38 MAPK in PKCalpha-mediated malignant phenotypes, especially in PKCalpha-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKCalpha-overexpressing cancers.
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Affiliation(s)
- Yi-Hsien Hsieh
- Institute of Biochemistry and Biotechnology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China
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Goda S, Inoue H, Umehara H, Miyaji M, Nagano Y, Harakawa N, Imai H, Lee P, Macarthy JB, Ikeo T, Domae N, Shimizu Y, Iida J. Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:445-58. [PMID: 16877347 PMCID: PMC1698790 DOI: 10.2353/ajpath.2006.050676] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Natural killer (NK) cells play a key role in inflammation and tumor regression through their ability to migrate into tissues. CXCL12 is a chemokine that promotes lymphocyte invasion and migration into tissues; however, the mechanism for this process remains incompletely understood. In this study, we show that CXCL12 significantly enhanced CD16(+)CD56(+) human peripheral NK-cell invasion into type I collagen by the catalytic activity of matrix metalloproteinase-1 (MMP-1). Confocal immunofluorescence and co-immunoprecipitation studies suggest that MMP-1 colocalized with alpha(2)beta(1) integrin on CXCL-12-stimulated NK-cell surface. The binding of pro-MMP-1 with alpha(2)beta(1) integrin required activation of G(i)-coupled pathway. However, the production of MMP-1 from CXCL12-stimulated NK cells was mediated by p38 and mitogen-activated or extracellular signal-regulation protein kinase kinase 1/2 in a manner independent of the G(i)-coupled pathway. These results suggest that CXCL12/CXCR4 interaction transduces the two signaling pathways to promote NK-cell invasion, which stimulates pericellular degradation of extracellular matrix proteins by membrane-associated MMP-1. The mechanisms would thus play a role in facilitating lymphocyte trafficking and accumulation in tissues during physiological and pathological processes.
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Affiliation(s)
- Seiji Goda
- Department of Biochemistry, Osaka Dental University, 8-1 Kuzuhahanazono-cho, Hirakata-shi, Osaka 573-1121, Japan.
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Cui X, Kim HJ, Kuiatse I, Kim H, Brown PH, Lee AV. Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration. Cancer Res 2006; 66:5304-13. [PMID: 16707456 DOI: 10.1158/0008-5472.can-05-2858] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The epidermal growth factor (EGF) and insulin-like growth factor (IGF) signaling pathways are critically involved in cancer development and progression. However, how these two signals cross-talk with each other to regulate cancer cell growth is not clearly understood. In this study, we found that EGF remarkably induced expression of major IGF signaling components, insulin receptor substrate (IRS)-1 and IRS-2, an effect that could be blocked by EGF receptor (EGFR) tyrosine kinase inhibitors. Although both extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase (JNK) signaling pathways were involved in the EGF up-regulation of IRS-1, the IRS-2 induction by EGF was specifically mediated by JNK signaling. Consistent with this, EGF increased IRS-2 promoter activity, which was associated with recruitment of activator protein-1 (AP-1) transcription factors and was inhibited by blocking AP-1 activity. Moreover, EGF treatment enhanced IGF-I and integrin engagement-elicited tyrosine phosphorylation of IRS and their downstream signaling, such as binding to phosphatidylinositol 3'-kinase regulatory subunit p85. Finally, repressing the induction of IRS-2 levels abolished the EGF enhancement of cell motility, suggesting that increased IRS-2 is essential for the EGF regulation of breast cancer cell migration. Taken together, our results reveal a novel mechanism of cross-talk between the EGF and IGF signaling pathways, which could have implications in therapeutic applications of targeting EGFR in tumors. Because AP-1 activity is involved in breast cancer progression, our work may also suggest IRS-2 as a useful marker for aggressive breast cancer.
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Affiliation(s)
- Xiaojiang Cui
- Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine and Methodist Hospital, Houston, Texas 77030, USA.
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Cheng JCH, Chou CH, Kuo ML, Hsieh CY. Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene 2006; 25:7009-18. [PMID: 16732316 DOI: 10.1038/sj.onc.1209706] [Citation(s) in RCA: 259] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
This study is to investigate the molecular mechanism of radiation-enhanced cell invasiveness of hepatocellular carcinoma (HCC) correlating with clinical patients undergoing radiotherapy and subsequently developing metastasis. Three HCC cell lines (HepG2, Hep3B and Huh7) and normal hepatocyte cell line (CL-48) were irradiated with different doses. The effect of radiation on cell invasiveness was determined using the Boyden chamber assay. Radiation-enhanced invasion capability was evident in HCC cells but not in normal hepatocytes. Invasion was observed in gelatin-coated but not fibronectin-coated or type I collagen-coated membranes. Radiation upregulated matrix metalloproteinase-9 (MMP-9) mRNA level, MMP-9 protein level and MMP-9 activity. MMP-9 antisense oligonucleotides inhibited radiation-induced MMP-9 expression and thereby significantly inhibited radiation-induced HCC invasion. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt chemical inhibitors LY294002 and wortmannin suppressed radiation-induced MMP-9 mRNA expression. Transient transfection with dominant-negative Akt plasmid also showed that the PI3K/Akt-signaling pathway was involved in this radiation-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed radiation enhanced MMP-9 promoter activity completely. PI3K/Akt chemical inhibitors inhibited radiation-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that sublethal dose of radiation could enhance HCC cell invasiveness by MMP-9 expression through the PI3K/Akt/NF-kappaB signal transduction pathway.
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Affiliation(s)
- J C-H Cheng
- Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
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Feo F, De Miglio MR, Simile MM, Muroni MR, Calvisi DF, Frau M, Pascale RM. Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim Biophys Acta Rev Cancer 2005; 1765:126-47. [PMID: 16216419 DOI: 10.1016/j.bbcan.2005.08.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2005] [Revised: 08/25/2005] [Accepted: 08/26/2005] [Indexed: 01/11/2023]
Abstract
The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepatocarcinogenesis susceptibility (Hcs) and 2 resistance (Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling (Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene-gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16(INK4A) upregulation occurs in susceptible and resistant rat lesions. p16(INK4A)-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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Affiliation(s)
- F Feo
- Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Via P. Manzella 4, 07100 Sasssari, Italy.
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Yau TO, Chan CY, Chan KL, Lee MF, Wong CM, Fan ST, Ng IOL. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 2005; 24:1607-14. [PMID: 15580286 DOI: 10.1038/sj.onc.1208340] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Oncogenic activation of the WNT/beta-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Dishevelled (Dvl), a key activator of the pathway, inhibits the adenomatous polyposis coli complex, and this leads to the accumulation of beta-catenin and promotes tumorigenesis. Recently, a novel inhibitor of Dishevelled, namely Dapper (Dpr), was isolated in Xenopus. To explore whether HDPR1, the human homologue of Dpr, has an anti-oncogenic role in hepatocarcinogenesis, we studied the expression of this gene in HCCs. We found that there were two alternatively spliced transcripts of HDPR1, designated as alpha and beta forms, in human liver. Downregulation of the gene expression was observed in 31 (43%) of the 72 human HCC samples using the primer pair that amplified both transcripts. Furthermore, the HDPR1alpha was downregulated in 42 (58%) of 72 human HCCs and the downregulation significantly correlated with accumulation of beta-catenin. Also, downregulation of HDPR1 by RNA interference in HLE cells led to cytoplasmic accumulation of beta-catenin. Furthermore, a CpG island located at the promoter region and exon 1 of the HDPR1 gene was methylated in 22 (51%) of human HCCs. We showed that downregulation of HDPR1, in hepatoma cell lines, was associated with methylation of this CpG island using bisulfite sequencing and 5-aza-2'-deoxycytidine demethylation experiment. In addition to methylation-mediated downregulation of HDPR1, allelic loss (13-28% of informative cases) was detected using microsatellite markers flanking the HDPR1 locus. To conclude, downregulation of HDPR1 is common in HCCs, frequently involves hypermethylation of the promoter region, and allelic loss of the HDPR1 locus may also play a role.
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Affiliation(s)
- Tai-On Yau
- Department of Pathology, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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