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Shatat AAS, Mahgoup EM, Rashed MH, Saleh IG, Akool ES. Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR. Purinergic Signal 2024; 20:669-680. [PMID: 38801618 PMCID: PMC11554961 DOI: 10.1007/s11302-024-10021-2] [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: 11/28/2023] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
One of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia-inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.
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Affiliation(s)
- Abdel-Aziz S Shatat
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Elsayed M Mahgoup
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohammed H Rashed
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Ibrahim G Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Sinai University, Kantra, Ismailia, Egypt
| | - El-Sayed Akool
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
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Yu H, Kohno S, Voon DC, Hussein NH, Zhang Y, Nakayama J, Takegami Y, Takahashi C. RECK/GPR124-driven WNT signaling in pancreatic and gastric cancer cells. Cancer Sci 2024; 115:3013-3025. [PMID: 38923741 PMCID: PMC11462976 DOI: 10.1111/cas.16258] [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: 04/23/2024] [Revised: 06/05/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024] Open
Abstract
RECK has been described to modulate extracellular matrix components through negative regulation of MMP activities. Recently, RECK was demonstrated to bind to an orphan G protein-coupled receptor GPR124 to mediate WNT7 signaling in nontumor contexts. Here, we attempted to clarify the role of RECK in driving WNT signaling in cancer cells. RECK and GPR124 formed a complex in 293T cells, and when both were expressed, WNT signaling was significantly enhanced in a WNT7-dependent manner. This cooperation was abolished when RECK mutants unable to bind to GPR124 were transduced. RECK stimulated the growth of KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) cells with increased sensitivity to WNT inhibitor in a GPR124-dependent manner. A gastric cancer cell line SH10TC endogenously expresses both RECK and GPR124 under regular culture conditions. In this cell line, inhibited cell growth and WNT signaling as well as increased apoptosis in the GPR124 depletion was dominantly found over those in the RECK deletion. These findings suggest that RECK promotes tumor cell growth by positively modulating WNT signaling through GPR124. This study proposes that the RECK/GPR124 complex might be a good therapeutic target in PDAC and gastric cancer.
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Affiliation(s)
- Hai Yu
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Susumu Kohno
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | | | - Nada Hamdy Hussein
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Yuanyuan Zhang
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Joji Nakayama
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | | | - Chiaki Takahashi
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
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Zhou X, Gao F, Xu G, Puyang Y, Rui H, Li J. SIAH1 facilitates the migration and invasion of gastric cancer cells through promoting the ubiquitination and degradation of RECK. Heliyon 2024; 10:e32676. [PMID: 38961977 PMCID: PMC11219971 DOI: 10.1016/j.heliyon.2024.e32676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 07/05/2024] Open
Abstract
Siah E3 ubiquitin protein ligase 1 (SIAH1) has been reported to participate in the development of several human cancers, including gastric cancer. However, the effect and mechanism of SIAH1 on the migration and invasion of gastric cancer cells need be further explored. Here, we first analyzed the clinical value of SIAH1 in gastric cancer, and found that SIAH1 was up-regulated in gastric cancer and associated with a poor prognosis. In addition, silencing of SIAH1 significantly inhibited the migration and invasion of gastric cancer cells through inhibiting the expression of matrix metalloproteinase-9 (MMP9), while overexpression of SIAH1 had the opposite effect. Molecularly, we provided the evidence that reversion-inducing cysteine-rich protein with Kazal motifs (RECK) was a potential substrate of SIAH1. We determined that SIAH1 could destabilize RECK through promoting its ubiquitination and degradation via proteasome pathway. We also found RECK was involved in SIAH1-regulated gastric cancer cell migration and invasion. In conclusion, SIAH1 is up-regulated in gastric cancer, which promotes the migration and invasion of gastric cancer cells through regulating RECK-MMP9 pathway.
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Affiliation(s)
- Xiaohua Zhou
- School of Medicine, Southeast University, China
- Department of General Surgery, Nanjing Gaochun People's Hospital, China
| | - Fuping Gao
- Department of Pathology, Nanjing Gaochun People's Hospital, China
| | - Guangqi Xu
- Department of General Surgery, Nanjing Gaochun People's Hospital, China
| | - Yongqiang Puyang
- Department of General Surgery, Nanjing Gaochun People's Hospital, China
| | - Hongqing Rui
- Department of General Surgery, Nanjing Gaochun People's Hospital, China
| | - Junsheng Li
- School of Medicine, Southeast University, China
- Department of General Surgery, Affiliated Zhongda Hospital of Southeast University, China
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Qi F, Wang Y, Yu B, Li F. Identification of RECK as a protective prognostic indicator and a tumor suppressor through regulation of the ERK/MAPK signaling pathway in gastric cancer. J Transl Med 2023; 21:766. [PMID: 37904179 PMCID: PMC10614389 DOI: 10.1186/s12967-023-04644-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 10/20/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) ranks as the fifth most common cancer worldwide and is characterized by its significant heterogeneity and unfavorable prognosis. Thus, identifying efficient prognostic factors and understanding the underlying molecular mechanisms in GC are essential for improving patient outcomes. In this study, we aimed to investigate the role of RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the prognostic significance and molecular mechanisms of its biological function in GC. METHODS Multiple bioinformatics strategies were performed to detect the potential functions and prognostic efficiency of RECK in GC. Rescue experiments revealed that the molecular mechanism by which RECK in inhibited tumor proliferation, migration, and invasion was mediated by ERK/MAPK signaling in AGS and HGC-27 cells. Using integrated bioinformatics analysis and western blot assay, we investigated the potential interaction between CALD1 and RECK. RESULTS Our findings revealed significantly decreased RECK expression in GC samples compared to normal samples and RECK was identified as a promising predictor for the prognosis of GC patients. Moreover, upregulation of RECK demonstrated a distinctly positive association with a high-immunity and low-metastasis microenvironment in GC. Mechanistically, the antitumour effects of RECK on hampering tumor cell growth, migration, and invasion were mediated by the ERK/MAPK signaling pathway. In addition, we also illustrated that RECK inhibited the phosphorylation of CALD1 mediated by decreased phosphorylation of ERK. CONCLUSIONS RECK is a promising prognostic biomarker and may shape a high-tumor-immunity and low-metastasis microenvironment in patients with GC. Moreover, RECK exerted its tumor-suppressive effects by the inactivation of ERK/MAPK signaling in GC cells.
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Affiliation(s)
- Fangyuan Qi
- The Key Laboratory of Zoonosis, Department of Pathogenobiology, Chinese Ministry of Education, College of Basic Medicine, Jilin University, No. 126 Xinmin Street, Changchun, 130021, Jilin, People's Republic of China
| | - Yaru Wang
- The Key Laboratory of Zoonosis, Department of Pathogenobiology, Chinese Ministry of Education, College of Basic Medicine, Jilin University, No. 126 Xinmin Street, Changchun, 130021, Jilin, People's Republic of China
| | - Bingxin Yu
- Department of Ultrasound, The Third Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Fan Li
- The Key Laboratory of Zoonosis, Department of Pathogenobiology, Chinese Ministry of Education, College of Basic Medicine, Jilin University, No. 126 Xinmin Street, Changchun, 130021, Jilin, People's Republic of China.
- The Key Laboratory for Bionics Engineering, Ministry of Education, Jilin University, Changchun, People's Republic of China.
- Engineering Research Center for Medical Biomaterials of Jilin Province, Jilin University, Changchun, People's Republic of China.
- Key Laboratory for Health Biomedical Materials of Jilin Province, Jilin University, Changchun, People's Republic of China.
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Urumqi, Xinjiang, People's Republic of China.
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Masuda T, Fukuda A, Yamakawa G, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Nagao M, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Masui T, Hatano E, Matsuzaki T, Noda M, Seno H. Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis. J Clin Invest 2023; 133:e161847. [PMID: 37712427 PMCID: PMC10503799 DOI: 10.1172/jci161847] [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: 05/12/2022] [Accepted: 07/27/2023] [Indexed: 09/16/2023] Open
Abstract
RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.
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Affiliation(s)
| | | | - Go Yamakawa
- Department of Gastroenterology and Hepatology
| | | | | | - Makoto Sono
- Department of Gastroenterology and Hepatology
| | - Yuichi Fukunaga
- Department of Gastroenterology and Hepatology
- Department of Drug Discovery Medicine, Medical Innovation Center
| | | | - Osamu Araki
- Department of Gastroenterology and Hepatology
| | | | | | - Kenji Masuo
- Department of Gastroenterology and Hepatology
| | | | | | - Yu Muta
- Department of Gastroenterology and Hepatology
| | | | | | | | - Toshihiko Masui
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, and
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, and
| | - Tomoko Matsuzaki
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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6
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Said EM, Salem AA, Shousha HI, Ahmad ES, Alazzouny MA, Ahmed IA, Elfeky HM, Abdelsalam FM. RECK gene polymorphisms in hepatitis B-related hepatocellular carcinoma: A case-control study. Arab J Gastroenterol 2022; 23:201-205. [PMID: 35941073 DOI: 10.1016/j.ajg.2022.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/31/2022] [Accepted: 05/10/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND STUDY AIMS Chronic hepatitis B (CHB) infection is a major risk factor for hepatocellular carcinoma (HCC). The RECK gene is a critical tumor suppressor gene. This study aimed to assess the association between RECK gene single nucleotide polymorphisms (SNPs) and the development of HCC in Egyptian patients with chronic hepatitis B. PATIENTS AND METHOD In this case-control study, we enrolled patients with CHB from the Gastroenterology Department, Benha University, from June 2016 to February 2018. The RECK gene SNP rs10814325 was identified using real-time PCR allelic discrimination via TaqMan SNP genotyping assays (Applied Biosystems, USA). RESULTS We enrolled 140 participants in this study. The participants were divided into Group I, which comprised 50 participants with CHB only, Group II, which comprised 50 participants with CHB and HCC, and Group III, which comprised 40 healthy participants. A significantly higher hepatitis B virus DNA viremia level was found in patients with HCC. The predominant RECK genotype was the T/T allele, followed by the T/C allele; however, no significant difference in the distribution of RECK gene SNPs was found between the study groups. No statistically significant difference in RECK gene SNPs was reported among patients with HCC of different Child classes or based on the number, site, size of HCC, and lymph node involvement. Receiver operating characteristic curves showed that a serum alpha-fetoprotein level of 92 ng/ml was 96 % sensitive and 100 % specific for the detection of HCC, with an area under the operating characteristic curve of 0.98. CONCLUSION RECK gene SNPs have no significant association with the development and characteristics of hepatitis B-related HCC in Egyptian patients.
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Affiliation(s)
- Ebada M Said
- Hepatology, Gastroenterology, and Infectious Diseases Department, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Hend I Shousha
- Endemic Medicine and Hepato-gastroenterology Department, Faculty of Medicine, Cairo University, Egypt.
| | - Enas S Ahmad
- Clinical and Chemical Pathology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Mahmoud A Alazzouny
- Clinical and Chemical Pathology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Inas A Ahmed
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Hala M Elfeky
- Hepatology, Gastroenterology, and Infectious Diseases Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Fatma M Abdelsalam
- Hepatology, Gastroenterology, and Infectious Diseases Department, Faculty of Medicine, Benha University, Benha, Egypt
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7
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Márquez-González RM, Saucedo-Sariñana AM, Barros-Núñez P, Gallegos-Arreola MP, Juárez-Vázquez CI, Pineda-Razo TD, Marin-Contreras ME, Flores-Martínez SE, Rosales-Reynoso MA. RECK Variants are Associated with Clinicopathological Features and Decreased Susceptibility in Mexican Patients with Colorectal Cancer. TOHOKU J EXP MED 2022; 257:163-169. [PMID: 35444107 DOI: 10.1620/tjem.2022.j032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Rosa María Márquez-González
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS)
| | | | - Patricio Barros-Núñez
- Research Unit of Metabolic Diseases, Pediatric UMAE, Instituto Mexicano del Seguro Social (IMSS).,Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara
| | | | - Clara Ibet Juárez-Vázquez
- Academic Direction of Devices and Systems I, Facultad de Medicina, Decanato Ciencias de la Salud, Universidad Autónoma de Guadalajara (UAG)
| | | | | | - Silvia Esperanza Flores-Martínez
- Molecular Medicine Division, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS).,Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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Low RECK Expression Is Part of the Cervical Carcinogenesis Mechanisms. Cancers (Basel) 2021; 13:cancers13092217. [PMID: 34066355 PMCID: PMC8124470 DOI: 10.3390/cancers13092217] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 12/15/2022] Open
Abstract
Human papillomavirus (HPV)-induced carcinogenesis comprises alterations in the expression and activity of matrix metalloproteinases (MMP) and their regulators. Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK) inhibits the activation of specific metalloproteinases and its expression is frequently lost in human cancers. Here we analyzed the role of RECK in cervical carcinogenesis. Cervical cancer derived cell lines over expressing RECK were used to determine tumor kinetics as well as, cellular, immune and molecular properties in vivo. Besides, we analyzed RECK expression in cervical cancer samples. RECK over expression (RECK+) delayed tumor growth and increased overall survival in vivo. RECK+ tumors displayed an increase in lymphoid-like inflammatory infiltrating cells, reduced number and viability of tumor and endothelial cells and lower collagenase activity. RECK+ tumors exhibited an enrichment of cell adhesion processes both in the mouse model and cervical cancer clinical samples. Finally, we found that lower RECK mRNA levels were associated with cervical lesions progression and worse response to chemotherapy in cervical cancer patients. Altogether, we show that increased RECK expression reduced the tumorigenic potential of HPV-transformed cells both in vitro and in vivo, and that RECK down regulation is a consistent and clinically relevant event in the natural history of cervical cancer.
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10
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Monteiro LN, Dos Reis DC, Salgado BS, Cassali GD. Clinical significance and prognostic role of tumor-associated macrophages infiltration according to histologic location in canine mammary carcinomas. Res Vet Sci 2020; 135:329-334. [PMID: 33097278 DOI: 10.1016/j.rvsc.2020.10.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/31/2020] [Accepted: 10/14/2020] [Indexed: 10/23/2022]
Abstract
Tumor-associated macrophages (TAMs) have been involved in growth and metastases of human and canine mammary tumors. However, the prognostic importance of TAM specific location in canine mammary tumors (CMT) was not evaluated. In this study, we evaluated the potential role of TAMs in specific histologic locations - intratumoral (iTAM) and stromal (sTAM), as well as total macrophage (tTAM) counts - as prognostic indicators in CMT. Clinicopathologic data from 66 animals with mammary carcinoma and their tumors were used in this study. Samples were stained with anti-macrophage antibody for subsequent TAM count. High levels of iTAM, sTAM, and tTAM were related with advanced clinical stage and vascular invasion. Additionally, tTAM revealed a relation with larger tumor size, while high levels of sTAM and tTAM were also correlated with node metastasis and a poor prognosis based on survival analysis. CMT with aggressive features can reveal higher TAM counts. TAMs are associated with vascular invasion and nodal metastasis, and sTAM and tTAM counts are correlated with overall survival, suggesting they could be used as prognostic indicators in canine mammary carcinomas.
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Affiliation(s)
- Lidianne Narducci Monteiro
- Laboratório de Patologia Comparada (LPC), Departamento de Patologia Geral, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais - UFMG, 31270-091 Belo Horizonte, Brazil
| | - Diego Carlos Dos Reis
- Laboratório de Patologia Comparada (LPC), Departamento de Patologia Geral, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais - UFMG, 31270-091 Belo Horizonte, Brazil
| | - Breno Souza Salgado
- Laboratório de Imunopatologia (LIFE), Departamento de Patologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo - UFES, 29043-900 Vitoria, Brazil.
| | - Geovanni Dantas Cassali
- Laboratório de Patologia Comparada (LPC), Departamento de Patologia Geral, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais - UFMG, 31270-091 Belo Horizonte, Brazil.
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11
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Saberinia A, Alinezhad A, Jafari F, Soltany S, Akhavan Sigari R. Oncogenic miRNAs and target therapies in colorectal cancer. Clin Chim Acta 2020; 508:77-91. [DOI: 10.1016/j.cca.2020.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/18/2022]
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12
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Chen HC, Tseng YK, Shu CW, Fu TY, Liou HH, Huang CH, Chen CC, Wang JS, Wu PC, Ger LP, Hung WC, Liu PF. Prognostic role of RECK in pathological outcome-dependent buccal mucosa squamous cell carcinoma. Oral Dis 2019; 26:62-71. [PMID: 31618798 DOI: 10.1111/odi.13214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/01/2019] [Accepted: 10/11/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features. MATERIALS AND METHODS The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models. RESULTS The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer. CONCLUSION The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.
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Affiliation(s)
- Hung-Chih Chen
- Department of Stomatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Department of Dental Technology, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Yu-Kai Tseng
- Department of Orthopedics, Show Chwan Memorial Hospital, Changhua, Taiwan.,Department of Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Chih-Wen Shu
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Ting-Ying Fu
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Huei-Han Liou
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Hui Huang
- Department of Otorhinolaryngology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Chou Chen
- Department of Family Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Jyh-Seng Wang
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Pi-Chuang Wu
- Department of Nutrition, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Luo-Ping Ger
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Feng Liu
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
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13
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Du Y, Chi X, An W. Downregulation of microRNA-200c-3p reduces damage of hippocampal neurons in epileptic rats by upregulating expression of RECK and inactivating the AKT signaling pathway. Chem Biol Interact 2019; 307:223-233. [PMID: 31018114 DOI: 10.1016/j.cbi.2019.04.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/21/2019] [Accepted: 04/17/2019] [Indexed: 01/02/2023]
Abstract
OBJECTIVE The aim of this study is to investigate the role of mircoRNA-200c-3p (miR-200c-3p) on hippocampal neuron injury in epileptic rats through the regulation of the AKT signaling pathway by targeting RECK. METHODS The epilepsy rat model was induced by intraperitoneal injection of lithium chloride-pilocarpine. Successful modeled rats were injected with miR-200c-3p inhibitors, inhibitors NC, siRNA-negative control (NC) and RECK-siRNA. The astrocyte activation, levels of oxidative stress indexes, contents of inflammatory factors and the AKT signaling pathway-related proteins in hippocampus tissues were evaluated. RESULTS High expression of miR-200c-3p and low expression of RECK were found in the hippocampus tissues of epileptic rats. Downregulation of miR-200c-3p or upregulation of RECK decreased apoptosis of hippocampal neurons, expression of GFAP, content of MDA and increased the activities of GSH-Px and SOD, decreased expression of TNF-α, IL-1β and IL-6 as well as expression of p-PI3K/t-PI3K and p-Akt/t-Akt in hippocampus tissues of epileptic rats. CONCLUSION Our study provides evidence that downregulation of miR-200c-3p reduces damage of hippocampal neurons in epileptic rats by upregulating RECK and inactivating the AKT signaling pathway.
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Affiliation(s)
- Yumin Du
- Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China.
| | - Xiaowen Chi
- Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China
| | - Wen An
- Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China
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14
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MMP-9 Overexpression Due to TIMP-1 and RECK Underexpression is Associated with Prognosis in Prostate Cancer. Int J Biol Markers 2018; 26:255-61. [DOI: 10.5301/jbm.2011.8831] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2011] [Indexed: 11/20/2022]
Abstract
Background Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9 and its specific inhibitors, TIMP-1 and RECK, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis and clinical outcome in prostate cancer (PC). Methods MMP-9, TIMP-1, and RECK expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue specimens collected from 79 patients with clinically localized PC submitted to radical prostatectomy (RP). Frozen benign prostatic tissue from another 10 men with prostate cancer, also submitted to RP, was analyzed to determine if the profile of gene expression was maintained. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). Results In the tumor samples, MMP-9 was overexpressed by 9.2 times, and TIMP-1 and RECK were underexpressed (0.75 and 0.80 times, respectively). Overexpression of MMP-9 was significantly related to PSA levels above 10 ng/mL (p=0.033). In addition, MMP-9 overexpression was related to biochemical recurrence, with a marginal statistical significance (p=0.089). MMP-9 was also overexpressed in benign tissues of patients with PC, as were TIMP-1 and RECK, in contrast to their underexpression in tumor samples. Conclusion Our results show that MMP-9 is overexpressed and its negative regulators are underexpressed in PC tissue, emphasizing a possible role of MMP-9 in the carcinogenesis process. Additionally, we noticed a relationship between MMP-9 overexpression and increased levels of PSA, an important prognostic factor. In benign tissue adjacent to tumors, the MMP-9 equilibrium is likely maintained because the expression of its negative regulators is preserved.
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Liu Y, Li L, Liu Y, Geng P, Li G, Yang Y, Song H. RECK inhibits cervical cancer cell migration and invasion by promoting p53 signaling pathway. J Cell Biochem 2018; 119:3058-3066. [PMID: 29064588 DOI: 10.1002/jcb.26441] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 10/18/2017] [Indexed: 12/15/2022]
Abstract
The present study was conducted to investigate the effects of RECK on cervical cancer cell migration and invasion to help understand relevant molecular mechanisms. QRT-PCR and western blot were respectively utilized to examine the transcriptional and translational levels of RECK in cervical cancer cell lines (HELA and C33A) and normal cell line (H8). After transfection with RECK overexpressing vectors, the expression of RECK mRNA, RECK and p53 signaling pathway-related proteins (p21, p53, bcl-2, and Bax) in cervical cancer cells were respectively examined using qRT-PCR and western blot. Cervical cancer cell migration after transfection was detected by wound healing assay and transwell assay. RECK expression was much lower in cervical cancer cell lines compared with normal cell line. Results of wound-healing assay results indicated that RECK could inhibit cervical cancer cell migration, and transwell assay results demonstrated that cell invasion was suppressed by RECK overexpression. Furthermore, western blot indicated that the overexpression of RECK could promote the activation of p53 signaling pathway by influencing related protein expression; whereas its inhibition by PFT-α could antagonize the effect of RECK on migrative and invasive abilities of cervical cancer cells. RECK could inhibit the migration and invasion of cervical cancer cells by activating p53 signaling pathway.
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Affiliation(s)
- Yuan Liu
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Lei Li
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Yang Liu
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Peng Geng
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Guilin Li
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Yanling Yang
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
| | - Hongjuan Song
- Department of Gynaecology, Xuzhou Maternal & Child Health Care Hospital, Xuzhou, Jiangsu, China
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Kowshik J, Mishra R, Sophia J, Rautray S, Anbarasu K, Reddy GD, Dixit M, Mahalingam S, Nagini S. Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model. Sci Rep 2017; 7:2045. [PMID: 28515436 PMCID: PMC5435722 DOI: 10.1038/s41598-017-01960-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 04/05/2017] [Indexed: 01/02/2023] Open
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis. We demonstrate that nimbolide upregulates RECK by targeting miR-21, and HIF-1α resulting in reduced MMP activity and blockade of VEGF and Notch signalling. Nimbolide reduced microvascular density, confirming its anti-angiogenic potential. Molecular docking analysis revealed interaction of nimbolide with HIF-1α. Additionally, we demonstrate that nimbolide upregulates RECK expression via downregulation of HIF-1α and miR-21 by overexpression and knockdown experiments in SCC4 and EAhy926 cell lines. Taken together, these findings provide compelling evidence that targeting RECK, a keystone protein that regulates mediators of invasion and angiogenesis with phytochemicals such as nimbolide may be a robust therapeutic approach to prevent oral cancer progression.
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Affiliation(s)
- Jaganathan Kowshik
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Rajakishore Mishra
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, 835205, Jharkhand, India
| | - Josephraj Sophia
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Satabdi Rautray
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
| | - Kumaraswamy Anbarasu
- Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - G Deepak Reddy
- Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India
| | - Madhulika Dixit
- Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Sundarasamy Mahalingam
- Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Siddavaram Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India.
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Bui TP, Hoang AN, Le PL, Pham BT, Nguyen LTT, Do HM, Ta TV, Trinh TH. Matrix metalloproteinases in Vietnamese patients with colorectal cancer. Oncol Lett 2017; 13:2097-2104. [PMID: 28454367 PMCID: PMC5403361 DOI: 10.3892/ol.2017.5680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/30/2016] [Indexed: 01/12/2023] Open
Abstract
Matrix metalloproteinases (MMPs), a family of endopeptidases also known as gelatinases, have been reported to affect the acquisition of the cell proliferative, cell invasive and metastatic phenotype of several types of cancer. In particular, the gelatinases MMP-2 and −9 have been revealed to facilitate tumor growth and invasion in patients with colorectal cancer (CRC). However, it is not known whether the gelatinase activity of MMP-2 and −9 is also elevated in Vietnamese patients with CRC. The activity of MMP-2 and −9 in the tissue samples of 103 patients with CRC was evaluated by gelatin zymography and quantified using ImageJ. The association between the level of activity of MMP-2 and −9 and various clinicopathological factors was analyzed, and Chisio BioPAX Editor software was used to visualize the biological pathways regulating the activity of the MMPs. The present study noticed significantly increased activity of active MMP-2 and MMP-9 in tumor tissues (P<0.01), and significantly decreased levels of pro-form MMP-2 and MMP-9 in tumor tissues (P<0.01), compared with that in adjacent tissues in patients with CRC. A correlation between the normalized different activity of MMP-2 and −9 and various clinicopathological features was observed. Furthermore, bioinformatics analysis indicated that the alteration in the activity of MMP-2 and MMP-9 may have been controlled by biological pathways involving the tissue inhibitors of metalloprotease-2 and −1. These findings indicate that the activity of the gelatinases MMP-2 and −9 affects the tumor progression and metastasis of patients with CRC, providing a potential novel approach for determining the prognosis of CRC.
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Affiliation(s)
- Thao Phuong Bui
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - Anh Ngoc Hoang
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - Phuong Lan Le
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - Bich Thi Pham
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - Linh Thi Tu Nguyen
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - Ha Minh Do
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
| | - To Van Ta
- Department of Anatomical Pathology-Cytopathology, Vietnam National Cancer Hospital, Hanoi 10000, Vietnam
| | - Thai Hong Trinh
- Department of Biology and Key Laboratory of Enzyme and Protein Technology, College of Science, Vietnam National University, Hanoi 10000, Vietnam
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18
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Nambiar J, Bose C, Venugopal M, Banerji A, Patel TB, Kumar GB, Nair BG. Anacardic acid inhibits gelatinases through the regulation of Spry2, MMP-14, EMMPRIN and RECK. Exp Cell Res 2016; 349:139-151. [PMID: 27737732 DOI: 10.1016/j.yexcr.2016.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 09/24/2016] [Accepted: 10/09/2016] [Indexed: 01/31/2023]
Abstract
Earlier studies from our laboratory have identified Anacardic acid (AA) as a potent inhibitor of gelatinases (MMP-2 and 9), which are over-expressed in a wide variety of cancers (Omanakuttan et al., 2012). Disruption of the finely tuned matrix metalloproteinase (MMP) activator/inhibitor balance plays a decisive role in determining the fate of the cell. The present study demonstrates for the first time, that in addition to regulating the expression as well as activity of gelatinases, AA also inhibits the expression of its endogenous activators like MMP-14 and Extracellular Matrix MetalloProteinase Inducer (EMMPRIN) and induces the expression of its endogenous inhibitor, REversion-inducing Cysteine-rich protein with Kazal motifs (RECK). In addition to modulating gelatinases, AA also inhibits the expression of various components of the Epidermal Growth Factor (EGF) pathway like EGF, Protein Kinase B (Akt) and Mitogen-activated protein kinases (MAPK). Furthermore, AA also activates the expression of Sprouty 2 (Spry2), a negative regulator of EGF pathway, and silencing Spry2 results in up-regulation of expression of gelatinases as well as MMP-14. The present study thus elucidates a novel mechanism of action of AA and provides a strong basis for utilizing this molecule as a template for cancer therapeutics.
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Affiliation(s)
- Jyotsna Nambiar
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Chinchu Bose
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Meera Venugopal
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Asoke Banerji
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Tarun B Patel
- Albany College of Pharmacy and Health Sciences, New York, USA
| | - Geetha B Kumar
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India
| | - Bipin G Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India.
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Guan Y, Guo L, Zukerberg L, Rueda BR, Styer AK. MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma. Reprod Biol Endocrinol 2016; 14:45. [PMID: 27530410 PMCID: PMC4988044 DOI: 10.1186/s12958-016-0180-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 08/04/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Human uterine leiomyoma (fibroids; LYO) are the most common benign neoplasms in reproductive-aged women. Dysregulated extracellular matrix and irregular LYO reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression are thought to be mediated by aberrant microRNA (miR) expression. The relationship of miR-15b and RECK expression in LYO has not been studied. METHODS The expression levels of miR-15b and RECK were determined by quantitative RT-PCR, Western blot, and immunohistochemistry in cultures derived from commercial primary leiomyoma (cpLYO) and myometrial (cpMYO) cell lines and leiomyoma (pLYO) and myometrium (pMYO) tissue from surgical samples respectively. The relationship between miR-15b and RECK expression in cpLYO and pLYO (compared to their respective myometrial controls) was evaluated following transfection of cell cultures with either miR-15b mimic or inhibitor. RESULTS Elevated levels of miR-15b were observed in cpLYO (2.82-fold; p = 0.04) and pLYO cell (1.30-fold; p = 0.0001) cultures respectively compared to corresponding MYO cell controls. Following transfection with miR-15b mimic, cpLYO cells (0.62-fold; p < 0.0001) and pLYO cells (0.68-fold; p < 0.0001) demonstrated reduced RECK protein expression. Following transfection with miR-15b inhibitor, cpLYO cells (1.20-fold; p < 0.0001) and pLYO cells (1.31-fold; p = 0.0007) demonstrated elevated RECK protein expression. RECK protein expression was reduced in pLYO tissues (0.73-fold; p < 0.0001) and pLYO (0.47-fold; p = 0.047) cells when compared to the corresponding MYO tissue controls. CONCLUSION Our findings suggest that miR-15b negatively regulates RECK expression in LYO, and increased miR-15b and decreased RECK expression may contribute to the pathobiology of LYO. The functional significance of miR-15b and RECK expression warrants further investigation as potential therapeutic targets for the treatment of human LYO.
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Affiliation(s)
- Yichun Guan
- Center for Reproductive Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan Province China
- Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Their 9, 55 Fruit Street, Boston, MA 02114 USA
| | - Lankai Guo
- Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Their 9, 55 Fruit Street, Boston, MA 02114 USA
| | - Lawrence Zukerberg
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 USA
| | - Bo R. Rueda
- Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Their 9, 55 Fruit Street, Boston, MA 02114 USA
- Departments of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA 02115 USA
| | - Aaron K. Styer
- Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Their 9, 55 Fruit Street, Boston, MA 02114 USA
- Departments of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA 02115 USA
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Cheng Y, Zhang X, Li P, Yang C, Tang J, Deng X, Yang X, Tao J, Lu Q, Li P. MiR-200c promotes bladder cancer cell migration and invasion by directly targeting RECK. Onco Targets Ther 2016; 9:5091-9. [PMID: 27574450 PMCID: PMC4993393 DOI: 10.2147/ott.s101067] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Increasing evidence suggests that the dysregulation of certain microRNAs plays an important role in tumorigenesis and metastasis. MiR-200c exhibits a disordered expression in many tumors and presents dual roles in bladder cancer (BC). Therefore, the definite role of miR-200c in BC needs to be investigated further. Materials and methods Quantitative reverse transcription polymerase chain reaction was used to assess miR-200c expression. Cell invasion and migration were evaluated using wound healing and transwell assays. The luciferase reporter assay was used to identify the direct target of miR-200c. The expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK) in BC tissues and adjacent nontumor tissues, as well as in BC cell lines, was detected through quantitative reverse transcription polymerase chain reaction, Western blot assay, and immunohistochemistry. Results The miR-200c expression was significantly upregulated in the BC tissues compared with the adjacent nontumor tissues. The downregulation of miR-200c significantly inhibited cell migration and invasion in the BC cell lines. The luciferase reporter assay showed that RECK was a direct target of miR-200c. The knockdown of RECK in the BC cell lines treated with anti-miR-200c elevated the previously attenuated cell migration and invasion. Conclusion Our findings indicated that miR-200c functions as oncogenes in BC and may provide a novel therapeutic strategy for the treatment of BC.
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Affiliation(s)
- Yidong Cheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaolei Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Peng Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Chengdi Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Jinyuan Tang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaheng Deng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Qiang Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Pengchao Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
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Lian PL, Liu Z, Yang GY, Zhao R, Zhang ZY, Chen YG, Zhuang ZN, Xu KS. Integrin αvβ6 and matrix metalloproteinase 9 correlate with survival in gastric cancer. World J Gastroenterol 2016; 22:3852-3859. [PMID: 27076771 PMCID: PMC4814749 DOI: 10.3748/wjg.v22.i14.3852] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 01/22/2016] [Accepted: 02/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients.
METHODS: Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ2 test and Fisher’s exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis.
RESULTS: The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007).
CONCLUSION: The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.
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Gomes LR, Fujita A, Mott JD, Soares FA, Labriola L, Sogayar MC. RECK is not an independent prognostic marker for breast cancer. BMC Cancer 2015; 15:660. [PMID: 26449734 PMCID: PMC4599748 DOI: 10.1186/s12885-015-1666-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 09/30/2015] [Indexed: 12/13/2022] Open
Abstract
Background The REversion-inducing Cysteine-rich protein with Kazal motif (RECK) is a well-known inhibitor of matrix metalloproteinases (MMPs) and cellular invasion. Although high expression levels of RECK have already been correlated with a better clinical outcome for several tumor types, its main function, as well as its potential prognostic value for breast cancer patients, remain unclear. Methods The RECK expression profile was investigated in a panel of human breast cell lines with distinct aggressiveness potential. RECK functional analysis was undertaken using RNA interference methodology. RECK protein levels were also analyzed in 1040 cases of breast cancer using immunohistochemistry and tissue microarrays (TMAs). The association between RECK expression and different clinico-pathological parameters, as well as the overall (OS) and disease-free (DFS) survival rates, were evaluated. Results Higher RECK protein expression levels were detected in more aggressive breast cancer cell lines (T4-2, MDA-MB-231 and Hs578T) than in non-invasive (MCF-7 and T47D) and non-tumorigenic (S1) cell lines. Indeed, silencing RECK in MDA-MB-231 cells resulted in elevated levels of pro-MMP-9 and increased invasion compared with scrambled (control) cells, without any effect on cell proliferation. Surprisingly, by RECK immunoreactivity analysis on TMAs, we found no association between RECK positivity and survival (OS and DFS) in breast cancer patients. Even considering the different tumor subtypes (luminal A, luminal B, Her2 type and basal-like) or lymph node status, RECK remained ineffective for predicting the disease outcome. Moreover, by multivariate Cox regression analysis, we found that RECK has no prognostic impact for OS and DFS, relative to standard clinical variables. Conclusions Although it continues to serve as an invasion and MMP inhibitor in breast cancer, RECK expression analysis is not useful for prognosis of these patients.
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Affiliation(s)
- Luciana R Gomes
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
| | - André Fujita
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil.
| | - Joni D Mott
- Lawrence Berkeley National Laboratory, Life Science Division, Berkeley, CA, USA.
| | - Fernando A Soares
- Departamento de Anatomia Patológica, Hospital A. C. Camargo, Fundação Antônio Prudente, São Paulo, SP, Brazil.
| | - Leticia Labriola
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
| | - Mari C Sogayar
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
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Yu Y, Hu Y, Li K, Chen Z, Zhang H, Zhang L. RECK Gene Polymorphism is Associated with Susceptibility and Prognosis of Wilms' Tumor in Chinese Children. Med Sci Monit 2015; 21:1928-33. [PMID: 26141647 PMCID: PMC4496031 DOI: 10.12659/msm.893606] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Wilms’ tumor (WT) is the most common malignant renal tumor in children. Previous studies suggested the reversion-inducing, cysteine-rich protein with Kazal motifs (RECK) down-regulation might have a role in numerous human cancers. The current study was done to investigate the associations of RECK single-nucleotide polymorphisms (SNPs) with the WT susceptibility in Chinese children. Material/Methods We analyzed 2 SNPs (rs10972727and rs11788747) in a total of 97 WT children and 194 healthy matched controls (1:2 ratio) by real-time PCR and PCR-RFLP genotyping analysis. Results We found that the G allele of rs11788747 in the RECK gene was significantly associated with WT in Chinese children (OR=0.7, 95% CI: 0.45–0.99; P=0.042); as with another SNP rs10972727, however, no statistically significant difference was detected. Further analysis showed there was also a statistically significant difference in genotype frequencies between terminal tumor stage (P=0.026) and metastatic groups (P=0.002). Conclusions The present data indicate that there is a significant association between mutant G of rs11788747 in RECK and WT risk. G carriers with advanced tumor stage or with metastasis might have an increased risk of WT.
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Affiliation(s)
- Yang Yu
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
| | - Yuanjun Hu
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
| | - Kaisheng Li
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
| | - Zhihong Chen
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
| | - Hongmei Zhang
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
| | - Lei Zhang
- Department of Pediatric Surgery, Jinan Children's Hospital, Jinan, Shandong, China (mainland)
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Bahgat DMR, Shahin RMH, Makar NN, Aziz AOA, Hunter SS. Reversion-Inducing-Cysteine-Rich Protein With Kazal Motifs (RECK) Gene Single Nucleotide Polymorphism With Hepatocellular Carcinoma: A Case-Control Study. J Clin Lab Anal 2014; 30:36-40. [PMID: 25278269 DOI: 10.1002/jcla.21806] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 06/02/2014] [Accepted: 08/11/2014] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene is a transformation suppressor gene that can negatively regulate matrix metalloproteinases (MMPs) and inhibit tumor invasion, angiogenesis, and metastasis. So, the aim of this study was to analyze the effect of RECK gene rs 11788747 single nucleotide polymorphism (SNP) on hepatocellular carcinoma (HCC) susceptibility and its relation to various clinical and laboratory data of the patients. METHODS This is a case-control study including 200 HCC patients and 200 healthy controls. RECK rs 11788747 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS RECK rs 11788747 A/G and G/G genotypes frequencies were significantly higher in HCC patients compared to the healthy controls. The HCC patients possessing at least one polymorphic G allele were significantly at a higher risk of developing lymph nodes involvement and distant metastasis. CONCLUSION This study revealed the role of RECK rs 11788747 SNP in HCC in Egyptian patients, which consequently might be used as a prognostic tool and could be added to its therapeutic strategies.
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Affiliation(s)
- Dina M Rasheed Bahgat
- Department of Clinical Pathology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | | | - Nada Nasr Makar
- Department of Clinical Pathology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
| | - Ashraf Omar Abdel Aziz
- Department of Tropical Medicine and Hepatology, Kasr Al Ainy Hospital, Cairo University, Cairo, Egypt
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25
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MiR-25 promotes gastric cancer cells growth and motility by targeting RECK. Mol Cell Biochem 2014; 385:207-13. [PMID: 24078004 DOI: 10.1007/s11010-013-1829-x] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 09/14/2013] [Indexed: 12/21/2022]
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death worldwide. Recently, accumulating evidence suggests that microRNAs (miRNAs) play prominent roles in tumorigenesis and metastasis. Here, we confirmed that miR-25 was significantly increased in human GC tissues and cell lines. Forced expression of miR-25 remarkably enhanced cell proliferation, migration, and invasion in GC cells, whereas inhibition of miR-25 by inhibitor caused significant suppression of proliferation and significant increase of apoptosis. Moreover, inhibition of miR-25 significantly decreased migration and invasion of GC cells. Finally, reversion-inducing-cysteine-rich protein with kazal motifs (RECK) was found to be a target of miR-25. Overexpression of RECK could significantly reverse the oncogenic effect of miR-25. Taken together, miR-25 might promote GC cells growth and motility partially by targeting RECK.
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26
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Liang QX, Liang YC, Xu ZY, Chen WL, Xie HL, Zhang B. RECK overexpression reduces invasive ability in ameloblastoma cells. J Oral Pathol Med 2014; 43:613-8. [PMID: 24646032 DOI: 10.1111/jop.12179] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2014] [Indexed: 12/17/2022]
Affiliation(s)
- Qi-xiang Liang
- Department of Oral and Maxillofacial Surgery; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou Guangdong China
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangzhou Higher Education Institutes; Sun Yat-sen University; Guangzhou Guangdong China
| | - Yan-can Liang
- Department of Oral and Maxillofacial Surgery; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou Guangdong China
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangzhou Higher Education Institutes; Sun Yat-sen University; Guangzhou Guangdong China
| | - Zhi-ying Xu
- Department of Stomatology; Peking University Shenzhen Hospital; Shenzhen Guangdong China
| | - Wei-liang Chen
- Department of Oral and Maxillofacial Surgery; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou Guangdong China
| | - Hong-liang Xie
- Department of Stomatology; Shenzhen People's Hospital; Shenzhen Guangdong China
| | - Bin Zhang
- Department of Oral and Maxillofacial Surgery; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou Guangdong China
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangzhou Higher Education Institutes; Sun Yat-sen University; Guangzhou Guangdong China
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Bai T, Dong DS, Pei L. Synergistic antitumor activity of resveratrol and miR-200c in human lung cancer. Oncol Rep 2014; 31:2293-7. [PMID: 24647918 DOI: 10.3892/or.2014.3090] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 02/26/2014] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs have emerged as promising molecular factors with potential for clinical applications in cancer diagnosis and therapy. In the present study, we demonstrated that the level of miR-200c in lung cancer tissues was lower than that in normal tissues using real-time PCR. To further investigate the effects of miR-200c expression in lung cancer cells, we upregulated miR-200c levels in H460 cells using transfection. We found that the percentage of apoptotic cells was higher in the cells expressing miR-200c than that in the untransfected cells. Furthermore, the antitumor activities of miR-200c were demonstrated in vivo. Notably, we confirmed that reservatol (RESV) showed stronger antitumor activities in miR-200c-positive cells than in miR-200c-negative cells. Finally, we demonstrated that expression of miR-200c in H460 cells suppressed cell growth by targeting RECK, followed by activation of the JNK signaling pathway and ER stress. Collectively, these data show that miR-200c expression sensitizes H460 cells to RESV and this is likely due to RECK expression.
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Affiliation(s)
- Tao Bai
- Department of Anaesthesiology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
| | - Dao-Song Dong
- Department of Anaesthesiology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
| | - Ling Pei
- Department of Anaesthesiology, The First Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
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Zhou X, Huang S, Jiang L, Zhang S, Li W, Chen Z, Zhang D. Expression of RECK and MMP-2 in salivary adenoid cystic carcinoma: Correlation with tumor progression and patient prognosis. Oncol Lett 2014; 7:1549-1555. [PMID: 24765174 PMCID: PMC3997680 DOI: 10.3892/ol.2014.1906] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 01/15/2014] [Indexed: 11/25/2022] Open
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of certain matrix metalloproteinases (MMPs). RECK has been studied in numerous human tumors, but the expression of RECK in salivary adenoid cystic carcinoma (SACC), and its correlation with patient prognosis, has never been investigated thus far. In the present study, the expression of RECK and MMP-2 was evaluated in two ACC cell lines and in 83 patients with SACC. The results of quantitative polymerase chain reaction and western blot analysis revealed that the ACC-2 and ACC-M cell lines expressed RECK and MMP-2 mRNA and protein. The immunohistochemical staining in the patients demonstrated that positive expression of RECK and MMP-2 was observed in 21/83 (25.3%) and 69/83 (83.1%) cases, respectively, and that RECK expression was significantly associated with the tumor-node-metastasis stage, histological grade and perineural invasion of patients with SACC (P<0.05). Furthermore, there was a significant association between the positive expression of RECK and that of MMP-2 (P<0.0001). Univariate and multivariate analyses confirmed that a lack of RECK expression was an independent and significant factor for the prediction of a poor prognosis. In conclusion, RECK is a promising prognostic marker and potential therapeutic agent in SACC.
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Affiliation(s)
- Xiaoqing Zhou
- Department of Oral and Maxillofacial Surgery, First People's Hospital of Jining, Jining, Shandong 272111, P.R. China
| | - Shengyun Huang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Licheng Jiang
- Department of Oral and Maxillofacial Surgery, Liaocheng Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Shizhou Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Wengang Li
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhanwei Chen
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Dongsheng Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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29
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Lee YM, Lee SH, Lee KB, Nguyen MP, Lee MY, Park GH, Kwon MJ. Silencing of reversion-inducing cysteine-rich protein with Kazal motifs stimulates hyperplastic phenotypes through activation of epidermal growth factor receptor and hypoxia-inducible factor-2α. PLoS One 2013; 8:e84520. [PMID: 24376819 PMCID: PMC3869844 DOI: 10.1371/journal.pone.0084520] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 11/14/2013] [Indexed: 01/16/2023] Open
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a tumor suppressor) is down-regulated by the oncogenic signals and hypoxia, but the biological function of RECK in early tumorigenic hyperplastic phenotypes is largely unknown. Knockdown of RECK by small interfering RNA (siRECK) or hypoxia significantly promoted cell proliferation in various normal epithelial cells. Hypoxia as well as knockdown of RECK by siRNA increased the cell cycle progression, the levels of cyclin D1 and c-Myc, and the phosphorylation of Rb protein (p-pRb), but decreased the expression of p21cip1, p27kip1, and p16ink4A. HIF-2α was upregulated by knockdown of RECK, indicating HIF-2α is a downstream target of RECK. As knockdown of RECK induced the activation of epidermal growth factor receptor (EGFR) and treatment of an EGFR kinase inhibitor, gefitinib, suppressed HIF-2α expression induced by the silencing of RECK, we can suggest that the RECK silenicng-EGFR-HIF-2α axis might be a key molecular mechanism to induce hyperplastic phenotype of epithelial cells. It was also found that shRNA of RECK induced larger and more numerous colonies than control cells in an anchorage-independent colony formation assay. Using a xenograft assay, epithelial cells with stably transfected with shRNA of RECK formed a solid mass earlier and larger than those with control cells in nude mice. In conclusion, the suppression of RECK may promote the development of early tumorigenic hyperplastic characteristics in hypoxic stress.
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Affiliation(s)
- You Mie Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
- * E-mail:
| | - Sun-Hee Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Kheun Byeol Lee
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Minh Phuong Nguyen
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Min-Young Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Gyu Hwan Park
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Mi Jeong Kwon
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
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Abstract
Metastasis is a major cause of cancer mortality. Metastasis is a complex process that requires the regulation of both metastasis-promoting and metastasis suppressor genes. The discovery of metastasis suppressor genes contributes significantly to our understanding of metastasis mechanisms and provides prognostic markers and therapeutic targets in clinical cancer management. In this review, we summarize the methods that have been used to identify metastasis suppressors and the potential clinical impact of these genes.
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Affiliation(s)
- Jinchun Yan
- University of Washington Medical Center, Seattle, WA, USA.
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31
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Lin HY, Chiang CH, Hung WC. STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer 2013; 109:731-8. [PMID: 23820254 PMCID: PMC3738132 DOI: 10.1038/bjc.2013.349] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 06/10/2013] [Accepted: 06/13/2013] [Indexed: 12/19/2022] Open
Abstract
Background: Signal transducer and activator of transcription 3 (STAT3) activation is frequently found in human lung cancer and is associated with increased metastasis and reduced survival. How STAT3 enhances invasiveness is unclear. Methods: The expression of microRNAs and target genes was measured by real-time RT–PCR. Protein level was studied by western blotting. Luciferase reporter assay was used to confirm the direct targeting of microRNAs. Gelatin zymography was used to study matrix metalloproteinase (MMP) activity. Transwell assay was used to investigate cell migration and invasion. Results: Enforced expression of STAT3 decreases the endogenous MMP inhibitor RECK protein but not mRNA level in H460 cells. Conversely, STAT3 inhibitor S3I-201 increases RECK protein in STAT3-activating H1299 cells. We demonstrate that STAT3 upregulates miR-92a to repress RECK via post-transcriptional inhibition. The RECK 3′-untranslated region (3′UTR) reporter activity assay suggests that RECK is a direct repression target of miR-92a. Delivery of pre-miR-92a reduces RECK protein level whereas transfection of anti-miR-92a restores STAT3-induced downregulation of RECK. Anti-miR-92a attenuates MMP activity, migration and invasion of H1299 cells and STAT3-overexpressing H460 cells, suggesting miR-92a is critical for STAT3-induced invasiveness. Conclusion: The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment.
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Affiliation(s)
- H-Y Lin
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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32
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Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression. Cell Death Dis 2013; 4:e684. [PMID: 23788041 PMCID: PMC3702298 DOI: 10.1038/cddis.2013.213] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated α-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer.
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Mao X, Liu L, Zhang B, Zhang D. Reversion-inducing cysteine-rich protein with Kazal motifs gene expression and its clinical significance in peripheral T-cell lymphoma. Oncol Lett 2013; 5:1867-1871. [PMID: 23833658 PMCID: PMC3700891 DOI: 10.3892/ol.2013.1306] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/12/2013] [Indexed: 11/12/2022] Open
Abstract
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene was originally identified as a transformation suppressor gene that is widely expressed in normal tissues. In tumor tissues, RECK expression levels are significantly reduced, and the downregulation of RECK has been implicated in tumors that are more aggressive with a poor prognosis. In the present study, RECK expression in peripheral T-cell lymphoma (PTCL; n=82) was examined using immunohistochemistry, and its correlation with clinicopathological factors was analyzed. According to the proportion of positively-stained cells and the staining intensity (SI), the patients were categorized into RECK-negative or RECK-positive groups. RECK expression was observed in 30 of the 82 patients (36.6%). The 3-year survival rate of the patients with RECK-positive tumors (65.5%) was significantly high compared with that of the patients with RECK-negative tumors (20.3%; P=0.046). Reduced RECK expression was found to be significantly correlated with extranodal lymphomatous involvement (P=0.012). The survival analysis showed that RECK-negative expression was an independent and significant factor for predicting a poor prognosis. RECK status is a useful prognostic factor for assessing the biological behavior in PTCL.
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Affiliation(s)
- Xia Mao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Matse JH, Yoshizawa J, Wang X, Elashoff D, Bolscher JGM, Veerman ECI, Bloemena E, Wong DTW. Discovery and prevalidation of salivary extracellular microRNA biomarkers panel for the noninvasive detection of benign and malignant parotid gland tumors. Clin Cancer Res 2013; 19:3032-8. [PMID: 23575476 DOI: 10.1158/1078-0432.ccr-12-3505] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE This study was conducted to explore the differences in salivary microRNA (miRNA) profiles between patients with malignant or benign parotid gland tumors as a potential preoperative diagnostic tool of tumors in the salivary glands. EXPERIMENTAL DESIGN Whole saliva samples from patients with malignant (n = 38) or benign (n = 29) parotid gland tumors were obtained from the Salivary Gland Tumor Biorepository (SGTB). After total RNA isolation, human miRNA cards were used for miRNA profiling. The differential miRNA expression was analyzed using two-sided Wilcoxon test. Quantitative real-time PCR (qRT-PCR) was used to validate selected miRNAs in an independent sample set. Receiver-operating characteristics curve and probability of malignancy was exploited to evaluate the diagnostic power of the validated miRNAs. RESULTS With miRNA profiling, 57 of 750 investigated miRNAs were differently expressed, of which 54 showed higher miRNA expression in samples from patients with malignant tumors than those from patients with benign tumors. Validating the expression in an independent sample set of 9 miRNAs revealed indeed higher expression of miRNAs in malignant samples compared with benign samples. The expression of 6 validated miRNAs was statistically significantly different between the two groups (P < 0.05). A four miRNA combination was able to discriminate between saliva samples from patients with malignant tumors from those of patients with benign parotid gland tumors (sensitivity 69%, specificity 95%). CONCLUSIONS Salivary miRNA profiles differ in saliva from patients with malignant from saliva from patients with a benign parotid gland tumor. These preliminary results are promising to develop a noninvasive diagnostic tool for diagnosing tumors in the salivary glands.
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Affiliation(s)
- Johannes H Matse
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Academic Centre for Dentistry Amsterdam/VU University Medical Center, Amsterdam, The Netherlands
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Xin C, Buhe B, Hongting L, Chuanmin Y, Xiwei H, Hong Z, Lulu H, Qian D, Renjie W. MicroRNA-15a promotes neuroblastoma migration by targeting reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and regulating matrix metalloproteinase-9 expression. FEBS J 2013; 280:855-866. [PMID: 23176145 DOI: 10.1111/febs.12074] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 09/20/2012] [Accepted: 11/21/2012] [Indexed: 12/19/2022]
Abstract
In this study, we found that the expression of miR-15a was positively correlated with neuroblastoma (NB) clinical pathological stage and was negatively correlated with reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression. Using the enhanced green fluorescent protein (EGFP) reporter construct carrying the 3'-UTR of RECK, we identified RECK as a direct target of miR-15a. Suppression of miR-15a significantly decreased the migration ability of GI-LA-N and SK-N-SH cell lines, whereas overexpression of miR-15a increased the migration ability; these effects could be partly reversed by RECK inhibition or ectopic expression. Moreover, inhibition of miR-15a significantly increased secreted matrix metalloproteinase-9 expression in culture medium through regulating the expression of RECK. These findings provide new insights into the characteristics of the miR-15a-RECK-matrix metalloproteinase-9 axis in NB progression, especially in NB migration and invasion.
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Affiliation(s)
- Chen Xin
- Department of Pediatric Surgery, The Affiliated Hospital of Medical College Qingdao University, Qingdao, China
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Matrix metalloproteinase 9 expression and prognosis in colorectal cancer: a meta-analysis. Tumour Biol 2012; 34:735-41. [PMID: 23269605 DOI: 10.1007/s13277-012-0601-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 11/19/2012] [Indexed: 01/29/2023] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is an important member of the matrix metalloproteinase family and is considered to be involved in the invasion and metastasis of cancer cells. Many studies were published to assess the prognostic role of MMP-9 overexpression in patients with colorectal cancer, but the findings from those studies were inconsistent. We searched eligible studies in Pubmed, Embase, and Web of Science databases. Thirteen studies with a total of 2, 390 CRC patients were finally included into the meta-analysis. The pooled hazard ratios (HRs) with the corresponding 95 % confidence interval (95 % CIs) for overall and progression-free survival were calculated by using meta-analysis. There were nine studies with a total of 1,674 colorectal cancer patients relating the progression-free survival, and eight studies with a total of 1,379 colorectal cancer patients relating the overall survival. Overall, MMP-9 overexpression was associated with poorer progression-free survival in patients with colorectal cancer (fixed-effects HR 1.81, 95 % CI 1.48-2.20, P < 0.001; random-effects HR 1.92, 95 % CI 1.46-2.53, P < 0.001). In addition, MMP-9 overexpression was also associated with poorer overall survival in patients with colorectal cancer (fixed-effects HR 1.74, 95 % CI 1.39-2.19, P < 0.001; random-effects HR 1.78, 95 % CI 1.31-2.41, P < 0.001). MMP-9 expression is associated with the prognosis of patients with colorectal cancer, and patients with higher MMP-9 expression have poorer survival.
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Herszényi L, Hritz I, Lakatos G, Varga MZ, Tulassay Z. The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer. Int J Mol Sci 2012; 13:13240-13263. [PMID: 23202950 PMCID: PMC3497324 DOI: 10.3390/ijms131013240] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/08/2012] [Accepted: 10/10/2012] [Indexed: 02/06/2023] Open
Abstract
Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future.
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Affiliation(s)
- László Herszényi
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - István Hritz
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- First Department of Medicine, Fejér County Szent György Hospital, Székesfehérvár, H-8000, Hungary
| | - Gábor Lakatos
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- Department of Oncology, Szent László Hospital, Budapest, H-1097, Hungary
| | - Mária Zsófia Varga
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - Zsolt Tulassay
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
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Zhang X, Healy C, Nothnick WB. Estrogen suppresses expression of the matrix metalloproteinase inhibitor reversion-inducing cysteine-rich protein with Kazal motifs (RECK) within the mouse uterus. Endocrine 2012; 42:97-106. [PMID: 22302680 DOI: 10.1007/s12020-012-9614-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/19/2012] [Indexed: 12/19/2022]
Abstract
RECK (reversion-inducing cysteine-rich protein with Kazal motifs) is a membrane-anchored glycoprotein which regulates MMP2 and MMP9 activity and has been proposed to play a role in embryo implantation while misexpression of RECK has been associated with a variety of carcinomas. Unfortunately, understanding on the steroidal regulation of uterine RECK is lacking. To address this gap in our knowledge, we examined steroidal regulation and cellular expression of Reck mRNA and protein within the mouse uterus in vivo. Uterine Reck mRNA and protein were decreased by estrogen, while progesterone alone had no effect. The estrogen-induced down regulation could be partially blocked by progesterone. RECK was localized primarily to luminal and glandular epithelial cells and the level of expression was regulated in a similar fashion as in whole tissue by the steroids. Knock-down of endogenous RECK in human endometrial epithelial and stromal cells resulted in a significant increase in active MMP9 expression but not that of pro-MMP9 or MMP2. These studies demonstrate that RECK expression in the mouse uterus is steroidally regulated and that within endometrial epithelial and stromal cells, RECK regulates MMP9, but not MMP2 activity.
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Affiliation(s)
- Xuan Zhang
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
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Jung HM, Phillips BL, Patel RS, Cohen DM, Jakymiw A, Kong WW, Cheng JQ, Chan EKL. Keratinization-associated miR-7 and miR-21 regulate tumor suppressor reversion-inducing cysteine-rich protein with kazal motifs (RECK) in oral cancer. J Biol Chem 2012; 287:29261-72. [PMID: 22761427 DOI: 10.1074/jbc.m112.366518] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that posttranscriptionally regulate gene expression during many biological processes. Recently, the aberrant expressions of miRNAs have become a major focus in cancer research. The purpose of this study was to identify deregulated miRNAs in oral cancer and further focus on specific miRNAs that were related to patient survival. Here, we report that miRNA expression profiling provided more precise information when oral squamous cell carcinomas were subcategorized on the basis of clinicopathological parameters (tumor primary site, histological subtype, tumor stage, and HPV16 status). An innovative radar chart analysis method was developed to depict subcategories of cancers taking into consideration the expression patterns of multiple miRNAs combined with the clinicopathological parameters. Keratinization of tumors and the high expression of miR-21 were the major factors related to the poor prognosis of patients. Interestingly, a majority of the keratinized tumors expressed high levels of miR-21. Further investigations demonstrated the regulation of the tumor suppressor gene reversion-inducing cysteine-rich protein with kazal motifs (RECK) by two keratinization-associated miRNAs, miR-7 and miR-21. Transfection of miR-7 and miR-21-mimics reduced the expression of RECK through direct miRNA-mediated regulation, and these miRNAs were inversely correlated with RECK in CAL 27 orthotopic xenograft tumors. Furthermore, a similar inverse correlation was demonstrated in CAL 27 cells treated in vitro by different external stimuli such as trypsinization, cell density, and serum concentration. Taken together, our data show that keratinization is associated with poor prognosis of oral cancer patients and keratinization-associated miRNAs mediate deregulation of RECK which may contribute to the aggressiveness of tumors.
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Affiliation(s)
- Hyun Min Jung
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL 32610, USA
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Reis ST, Leite KRM, Piovesan LF, Pontes-Junior J, Viana NI, Abe DK, Crippa A, Moura CM, Adonias SP, Srougi M, Dall'Oglio MF. Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer. BMC Urol 2012; 12:18. [PMID: 22695075 PMCID: PMC3424138 DOI: 10.1186/1471-2490-12-18] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 06/13/2012] [Indexed: 12/22/2022] Open
Abstract
Background Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9, MMP-2 and its specific inhibitors, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis in Bladder Cancer (BC). Methods MMP-9, MMP-2 and its specific inhibitors expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue collected from 40 patients with BC submitted to transurethral resection of bladder. The control group consisted of normal bladder tissue from five patients who had undergone retropubic prostatectomy to treat benign prostatic hyperplasia. Results MMP-9 was overexpressed in 59.0 % of patients, and MMP-2, TIMP-1, TIMP-2, MMP-14, RECK and IL-8 was underexpressed in most of the patients. Regarding prognostic parameters we observed that high-grade tumors exhibited significantly higher levels of MMP-9 and IL-8 (p = 0.012, p = 0.003). Invasive tumors (pT1-pT2) had higher expression levels of MMP-9 than superficial tumors (pTa) (p = 0.026). The same was noted for IL-8 that was more expressed by invasive tumors (p = 0.015, p = 0.048). Most importantly tumor recurrence was related with higher levels of both MMP-9 (p = 0.003) and IL-8 (p = 0.005). Conclusion We have demonstrated that the overexpression of MMP-9 and higher expression of IL-8 are related to unfavorable prognostic factors of urothelial bladder cancer and tumor recurrence and may be useful in the follow up of the patients.
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Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res 2012; 351:255-68. [DOI: 10.1007/s00441-012-1410-z] [Citation(s) in RCA: 162] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 03/06/2012] [Indexed: 12/17/2022]
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Cardeal LBDS, Boccardo E, Termini L, Rabachini T, Andreoli MA, di Loreto C, Filho AL, Villa LL, Maria-Engler SS. HPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratinocytes: possible implications in cervical carcinogenesis. PLoS One 2012; 7:e33585. [PMID: 22438955 PMCID: PMC3306414 DOI: 10.1371/journal.pone.0033585] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 02/16/2012] [Indexed: 12/28/2022] Open
Abstract
Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.
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Affiliation(s)
- Laura Beatriz da Silva Cardeal
- Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
- * E-mail:
| | - Enrique Boccardo
- Ludwig Institute for Cancer Research, Virology Group, São Paulo, Brazil
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Lara Termini
- Ludwig Institute for Cancer Research, Virology Group, São Paulo, Brazil
- HPV Institute – INCT-HPV, Santa Casa de Misericórdia, São Paulo, Brazil
| | - Tatiana Rabachini
- Ludwig Institute for Cancer Research, Virology Group, São Paulo, Brazil
| | | | - Celso di Loreto
- Nucleo de Patologia do Instituto Adolfo Lutz, São Paulo, Brazil
| | - Adhemar Longatto Filho
- Laboratory of Medical Investigation (LIM) 14, School of Medicine, University of São Paulo, São Paulo, Brazil
- PIO XII Foundation, Barretos Cancer Hospital, Barretos, Brazil
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Luisa Lina Villa
- Ludwig Institute for Cancer Research, Virology Group, São Paulo, Brazil
- HPV Institute – INCT-HPV, Santa Casa de Misericórdia, São Paulo, Brazil
| | - Silvya Stuchi Maria-Engler
- Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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Chung TT, Yeh CB, Li YC, Su SC, Chien MH, Yang SF, Hsieh YH. Effect of RECK gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features. PLoS One 2012; 7:e33517. [PMID: 22428065 PMCID: PMC3299798 DOI: 10.1371/journal.pone.0033517] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/10/2012] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03-3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. CONCLUSIONS RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan.
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Affiliation(s)
- Tsung-Te Chung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otolaryngology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Chao-Bin Yeh
- Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Ching Li
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Chi Su
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ming-Hsien Chien
- Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Department of Biochemistry, School of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
- * E-mail:
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Reversion-inducing cysteine-rich protein with Kazal motif (RECK) expression: an independent prognostic marker of survival in colorectal cancer. Hum Pathol 2012; 43:1314-21. [PMID: 22397871 DOI: 10.1016/j.humpath.2011.10.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 10/14/2011] [Accepted: 10/15/2011] [Indexed: 12/27/2022]
Abstract
Patient prognosis in colorectal cancer is determined as in most solid cancers by the extent of local invasion and the presence of lymph node and distant metastases. The invasive potential of a tumor depends on the ability to degrade extracellular matrix proteins, for example, by matrix metalloproteinases. An important inhibitor of matrix metalloproteinases is reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein. This study investigated the prognostic relevance of RECK expression in colorectal cancer in a cohort of 283 patients. Analysis of immunohistochemical tissue microarray data showed that RECK protein levels did not seem to correlate with clinicopathologic parameters (Spearman rank correlation coefficients between -0.14 and -0.18) and that decreased RECK expression was an independent prognostic factor of poor survival, with a mean survival of 70 months in RECK-negative (146 cases) versus 97 months in RECK-positive patients (137 cases) (log-rank test, P = .002).
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Prendergast A, Linbo TH, Swarts T, Ungos JM, McGraw HF, Krispin S, Weinstein BM, Raible DW. The metalloproteinase inhibitor Reck is essential for zebrafish DRG development. Development 2012; 139:1141-52. [PMID: 22296847 DOI: 10.1242/dev.072439] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The neural crest is a migratory, multipotent cell lineage that contributes to myriad tissues, including sensory neurons and glia of the dorsal root ganglia (DRG). To identify genes affecting cell fate specification in neural crest, we performed a forward genetic screen for mutations causing DRG deficiencies in zebrafish. This screen yielded a mutant lacking all DRG, which we named sensory deprived (sdp). We identified a total of four alleles of sdp, all of which possess lesions in the gene coding for reversion-inducing cysteine-rich protein containing Kazal motifs (Reck). Reck is an inhibitor of metalloproteinases previously shown to regulate cell motility. We found reck function to be both necessary for DRG formation and sufficient to rescue the sdp phenotype. reck is expressed in neural crest cells and is required in a cell-autonomous fashion for appropriate sensory neuron formation. In the absence of reck function, sensory neuron precursors fail to migrate to the position of the DRG, suggesting that this molecule is crucial for proper migration and differentiation.
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Affiliation(s)
- Andrew Prendergast
- Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195-7420, USA
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Wittschieber D, Stenzinger A, Klauschen F, Stephan C, Jung K, Erbersdobler A, Rabien A. Decreased RECK and Increased EMMPRIN expression in urothelial carcinoma of the bladder are associated with tumor aggressiveness. Pathobiology 2011; 78:123-31. [PMID: 21613799 DOI: 10.1159/000323563] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 12/10/2010] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Urothelial bladder carcinomas show a divergent biological behavior, which significantly complicates risk stratification and clinical management. The MMP repressor RECK and the MMP activator EMMPRIN regulate the invasive potential by metalloproteinase-induced stromal degradation. Data on RECK in urothelial bladder cancer are lacking and information on EMMPRIN is sparse. This study aims to investigate the expression of RECK and EMMPRIN in urothelial carcinoma of the bladder and to correlate these findings with clinicopathological parameters. METHODS Our study included 127 specimens of urothelial carcinomas derived from 103 patients who underwent either TUR-B or cystectomy. Immunohistochemical expression analysis was performed for RECK, EMMPRIN, MMP-2, MMP-9 and MMP-14. Expression levels were graded for staining intensity and correlated with pT stage and WHO tumor grade. RESULTS Invasive (≥pT1) as well as WHO high-grade urothelial carcinomas showed a statistically significant and stepwise downregulation of RECK (p < 0.001) and concomitant upregulation of EMMPRIN (p < 0.001) compared to non-invasive and WHO low-grade tumors. No correlation was observed for the MMPs investigated. CONCLUSION Decreased RECK and increased EMMPRIN expression are associated with increasing stage and grade. Both proteins may serve as molecular marker for the distinction between potentially invasive (≥pT1) and non-invasive tumors (≤pTa).
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Affiliation(s)
- Daniel Wittschieber
- Institute of Pathology, Charité University Hospital, Berlin, Germany. d.wittschieber @ gmx.de
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Chung TT, Pan MS, Kuo CL, Wong RH, Lin CW, Chen MK, Yang SF. Impact of RECK gene polymorphisms and environmental factors on oral cancer susceptibility and clinicopathologic characteristics in Taiwan. Carcinogenesis 2011; 32:1063-8. [PMID: 21565829 DOI: 10.1093/carcin/bgr083] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oral cancer is the fourth common male cancer and causally associated with environmental carcinogens in Taiwan. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumors through the extracellular matrix. RECK downregulation has been confirmed in many human cancers and associated with lymph node metastasis clinically. In the present hospital-based case-controlled study, the demographic, RECK genotype and clinicopathologic data from 341 male oral cancer patients and 415 cancer-free controls were investigated. We found that RECK rs10814325, rs16932912, rs11788747 or rs10972727 polymorphisms were not associated with oral cancer susceptibility. Among 488 smokers, RECK polymorphisms carriers with betel quid chewing have a 7.62-fold [95% confidence interval (CI), 2.96-19.64] to 25.33-fold (95% CI, 9.57-67.02) risk to have oral cancer compared with RECK wild-type carrier without betel quid chewing. Among 352 betel quid chewers, RECK polymorphisms carriers with smoking have a 6.68-fold (95% CI, 1.21-36.93) to 18.57-fold (95% CI, 3.80-90.80) risk to have oral cancer compared with those who carried wild-type without smoking. In 263 betel quid chewing oral cancer patients, RECK rs10814325 polymorphism have a 2.26-fold (95% CI, 1.19-4.29) risk to have neck lymph node metastasis compared with RECK wild-type carrier. These results support that gene-environment interactions between the RECK polymorphisms, smoking and betel quid may alter oral cancer susceptibility and metastasis.
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Affiliation(s)
- Tsung-Te Chung
- Institute of Medicine, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo North Road, Taichung 402, Taiwan
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Jensen SA, Vainer B, Bartels A, Brünner N, Sørensen JB. Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells--associations with histopathology and patients outcome. Eur J Cancer 2011; 46:3233-42. [PMID: 20801641 DOI: 10.1016/j.ejca.2010.07.046] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Revised: 07/26/2010] [Accepted: 07/29/2010] [Indexed: 12/20/2022]
Abstract
AIM To elucidate cellular features accountable for colorectal cancers' (CRC) capability to invade normal tissue and to metastasize, we investigated the level of the collagenase matrix metalloproteinase 9 (MMP-9) and its physiological inhibitor tissue inhibitor of metalloproteinases 1 (TIMP-1) in cancer cells and supporting stroma cells of CRC. METHODS Immunoreactivity of MMP-9 and TIMP-1 by carcinoma cells, lymphocytes and fibroblasts in archival specimens of paraffin-embedded primary tumours were retrospectively associated with outcome in 340 consecutive patients completely resected for CRC stages II-IV and subsequently treated with adjuvant 5-fluorouracil. RESULTS Expression of MMP-9 by carcinoma cells was demonstrated in 9% of specimens without association to recurrence free survival (RFS) (HR = 1.0; 95% CI: 0.6-1.8; P = 0.9) or overall survival (OS) (HR = 0.9; 95% CI: 0.5-1.6; P = 0.6). TIMP-1 expression by carcinoma cells, which appeared in 64% of the specimens, was inversely related with RFS (HR = 1.3; 95% CI: 0.9-1.8; P = 0.08) and OS (HR = 1.5; 95% CI: 1.1-2.1; P = 0.02). Expression of TIMP-1 by fibroblasts at the invasive border was directly related to RFS (HR = 0.7; 95% CI: 0.6-0.9; P = 0.02) and OS (HR = 0.7; 95% CI: 0.6-1.0; P = 0.05). Expression of MMP-9 by lymphocytes correlated significantly with the degree of peritumoural inflammation (P = 0.02) but not with RFS (HR = .9; 95% CI: 0.7-1.1; P = 0.2) or OS (HR = 0.8; 95% CI: 0.7-1.0; P = 0.07). CONCLUSION TIMP-1 in cancer cells is associated with poor prognosis independent of its function as inhibitor of MMP-9. MMP-9 and TIMP-1 are important mediators of the host-cancer cell interaction in the tumour microenvironment with significant influence on the histopathology and on prognosis of CRC.
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Affiliation(s)
- Søren Astrup Jensen
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Abstract
Over the past 25 years, an expanding set of metastasis-suppressor genes (MSGs) has been identified that specifically regulate metastasis formation without affecting primary growth. MSGs are involved in diverse molecular processes in multiple tumor types. Given the wealth of metastasis biology that underlies their functions, treatment strategies based on MSGs have an unparalleled potential to improve patient care. Using NM23 as a prime example, we discuss how specific MSGs have been used as prognostic markers, tools for predicting response to treatment, and targets for the development of novel therapies. Barriers specific to the translation of MSG biology into clinical practice are reviewed and future research directions necessary for clinical advances are delineated. Although to date the impact of MSGs on patient care is limited, it is an expanding field with vast potential to help develop new treatments and identify patients who will most benefit from them.
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Attenuated expression and function of the RECK tumor suppressor under hypoxic conditions is mediated by the MAPK signaling pathways. Arch Pharm Res 2011; 34:137-45. [DOI: 10.1007/s12272-011-0116-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 10/12/2010] [Accepted: 10/13/2010] [Indexed: 10/18/2022]
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