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Wang Y, Liu J, Yao Q, Wang Y, Liu Z, Zhang L. LncRNA SNHG6 Promotes Wilms' Tumor Progression Through Regulating miR-429/FRS2 Axis. Cancer Biother Radiopharm 2024; 39:264-275. [PMID: 33481659 DOI: 10.1089/cbr.2020.3705] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG6) has been reported to be an oncogene in a variety of cancers. However, the role of SNHG6 and its associated mechanisms in Wilms' tumor progression remain largely unknown. Methods: The expression of SNHG6, microRNA-429 (miR-429), and FGF receptor substrates 2 (FRS2) messenger RNA (mRNA) was detected by quantitative real-time polymerase chain reaction. Cell proliferation was analyzed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and plate colony assay. The apoptosis was assessed by flow cytometry. Cell glycolytic metabolism was analyzed through detecting the lactate dehydrogenase activity, glucose uptake, lactate production, and ATP level. The target relationship between miR-429 and SNHG6 or FRS2 was predicted by miRcode or Starbase and then validated by dual-luciferase reporter assay and RNA pull-down assay. Murine xenograft model was established to validate the function of SNHG6 in vivo. Results: The level of SNHG6 was elevated in Wilms' tumor tissues and cells, and SNHG6 played an oncogenic role to promote the proliferation and glycolysis and restrain the apoptosis of Wilms' tumor cells. MiR-429 was identified as a target of SNHG6, and miR-429 interference partly reversed the inhibitory effects induced by SNHG6 silencing on the malignant behaviors of Wilms' tumor cells. FRS2 mRNA bound to miR-429 in Wilms' tumor cells. SNHG6 upregulated the expression of FRS2 through acting as a sponge of miR-429. MiR-429-induced influences in Wilms' tumor cells were largely counteracted by the overexpression of FRS2. SNHG6 silencing suppressed the Wilms' tumor growth through miR-429/FRS2 axis in vivo. Conclusion: SNHG6 accelerated Wilms' tumor progression through regulating miR-429/FRS2 signaling in vitro and in vivo.
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Affiliation(s)
- Yingjie Wang
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Junli Liu
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Qiying Yao
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yuchuan Wang
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Zhengjuan Liu
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Li Zhang
- Department of Pediatrics, The Second Hospital of Dalian Medical University, Dalian, China
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Syllaios A, Gazouli M, Vailas M, Mylonas KS, Sakellariou S, Sougioultzis S, Karavokyros I, Liakakos T, Schizas D. The Expression Patterns and Implications of MALAT1, MANCR, PSMA3-AS1 and miR-101 in Esophageal Adenocarcinoma. Int J Mol Sci 2023; 25:98. [PMID: 38203269 PMCID: PMC10778904 DOI: 10.3390/ijms25010098] [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: 10/18/2023] [Revised: 12/09/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Esophageal adenocarcinoma (EAC) is a malignant tumor with poorly understood molecular mechanisms. This study endeavors to elucidate how the long non-coding RNAs (lncRNAs) MALAT1, MANCR and PSMA3-AS1, as well as the microRNA miR-101, exhibit specific expression patterns in the pathogenesis and prognosis of EAC. A total of 50 EAC tissue samples (tumors and lymph nodes) and a control group comprising 26 healthy individuals were recruited. The samples underwent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The relative expression levels of MALAT1, MANCR, PSMA3-AS1, and miR-101 were ascertained and correlated with various clinicopathological parameters including TNM staging, tumor characteristics (size and grade of the tumor) lymphatic invasion, disease-free (DFS) and overall survival (OS) of EAC patients. Quantitative analyses revealed that MALAT1 and MANCR were significantly upregulated in EAC tumors and positive lymph nodes when compared to control tissues (p < 0.05). Such dysregulations correlated positively with advanced lymphatic metastases and a higher N stage. DFS in the subgroup of patients with negative lymph nodes was higher in the setting of low-MANCR-expression patients compared to patients with high MANCR expression (p = 0.02). Conversely, miR-101 displayed a significant downregulation in EAC tumors and positive lymph nodes (p < 0.05), and correlated negatively with advanced tumor stage, lymphatic invasion and the grade of the tumor (p = 0.006). Also, patients with low miR-101 expression showed a tendency towards inferior overall survival. PSMA3-AS1 did not demonstrate statistically significant alterations (p > 0.05). This study reveals MALAT1, MANCR, and miR-101 as putative molecular markers for prognostic evaluation in EAC and suggests their involvement in EAC progression.
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Affiliation(s)
- Athanasios Syllaios
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (M.V.); (I.K.); (T.L.); (D.S.)
| | - Maria Gazouli
- Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Michail Vailas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (M.V.); (I.K.); (T.L.); (D.S.)
| | | | - Stratigoula Sakellariou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Stavros Sougioultzis
- Gastroenterology Unit, Department of Pathophysiology, School of Medicine, National and Kapodistrian University Athens, 115 27 Athens, Greece;
| | - Ioannis Karavokyros
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (M.V.); (I.K.); (T.L.); (D.S.)
| | - Theodoros Liakakos
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (M.V.); (I.K.); (T.L.); (D.S.)
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (M.V.); (I.K.); (T.L.); (D.S.)
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Al-Sisan SM, Zihlif MA, Hammad HM. Differential miRNA expression of hypoxic MCF7 and PANC-1 cells. Front Endocrinol (Lausanne) 2023; 14:1110743. [PMID: 37583428 PMCID: PMC10424510 DOI: 10.3389/fendo.2023.1110743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 06/21/2023] [Indexed: 08/17/2023] Open
Abstract
Background Hypoxia plays a critical role in the tumor microenvironment by affecting cellular proliferation, metabolism, apoptosis, DNA repair, and chemoresistance. Since hypoxia provokes a distinct shift of microRNA, it is important to illustrate the relative contribution of each hypoxamiR to cancer progression. Aims The present study aims to shed light on the hypoxamiRs that are involved in pancreatic and breast cancer progression to highlight novel targets for the development of new therapies. Methods For 20 cycles, MCF7 breast cancer cells and PANC-1 pancreatic cancer cells were subjected to chronic cyclic hypoxia, which consisted of 72 hours of hypoxia followed by 24 hours of reoxygenation. After 10 and 20 cycles of hypoxia, miRNA expression alterations were profiled using RT-PCR array and further analyzed using a visual analytics platform. The MTT cell proliferation assay was used to determine hypoxic cells' chemoresistance to doxorubicin. Results Under chronic cyclic hypoxia, hypoxic PANC-1 cells have a comparable doubling time with their normoxic counterparts, whereas hypoxic MCF7 cells show a massive increase in doubling time when compared to their normoxic counterparts. Both hypoxic cell lines developed EMT-like phenotypes as well as doxorubicin resistance. According to the findings of miRNet, 6 and 10 miRNAs were shown to play an important role in enriching six hallmarks of pancreatic cancer in the 10th and 20th cycles of hypoxia, respectively, while 7 and 11 miRNAs were shown to play an important role in enriching the four hallmarks of breast cancer in the 10th and 20th cycles of hypoxia, respectively. Conclusions miR-221, miR-21, miR-155, and miR-34 were found to be involved in the potentiation of hypoxic PANC-1 hallmarks at both the 10th and 20th cycles, while miR-93, miR-20a, miR-15, and miR-17 were found to be involved in the potentiation of hypoxic MCF7 hallmarks at both the 10th and 20th cycles. This variation in miRNA expression was also connected to the emergence of an EMT-like phenotype, alterations in proliferation rates, and doxorubicin resistance. The chemosensitivity results revealed that chronic cyclic hypoxia is critical in the formation of chemoresistant phenotypes in pancreatic and breast cancer cells. miR-181a and let-7e expression disparities in PANC1, as well as miR-93, miR-34, and miR-27 expression disparities in MCF7, may be associated with the formation of chemoresistant MCF7 and PANC-1 cells following 20 cycles of chronic cyclic hypoxia. Indeed, further research is needed since the particular mechanisms that govern these processes are unknown.
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Affiliation(s)
- Sandy M. Al-Sisan
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Malek A. Zihlif
- Department of Pharmacology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Hana M. Hammad
- Department of Biological Sciences, School of Science, The University of Jordan, Amman, Jordan
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Syllaios A, Sakellariou S, Garmpis N, Sarlani E, Damaskos C, Apostolou K, Kykalos S, Gazouli M, Karavokyros I, Schizas D. The role of miR-101 in esophageal and gastric cancer. Per Med 2021; 18:491-499. [PMID: 34402321 DOI: 10.2217/pme-2021-0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/02/2021] [Indexed: 12/22/2022]
Abstract
miR-101 is downregulated in various types of cancer, leading to the notion that miR-101 acts as a suppressor in cancer cell progression. The comprehensive mechanisms underlying the effects of miR-101 and the exact role of miR-101 dysregulations in esophagogastric tumors have not been fully elucidated. This review aims to summarize all current knowledge on the association between miR-101 expression and esophagogastric malignancies and to clarify the pathogenetic pathways and the possible prognostic and therapeutic role of miR-101 in those cancer types. miR-101 seems to play crucial role in esophageal and gastric cancer biology and tumorigenesis. It could also be a promising novel diagnostic and therapeutic target, as well as it may serve as a significant predictive biomarker in esophagogastric cancer.
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Affiliation(s)
- Athanasios Syllaios
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
| | - Stratigoula Sakellariou
- First Department of Pathology, Medical School, National & Kapodistrian University of Athens, Athens, 11527, Greece
| | - Nikolaos Garmpis
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
| | - Eleni Sarlani
- First Department of Pathology, Medical School, National & Kapodistrian University of Athens, Athens, 11527, Greece
| | - Christos Damaskos
- N.S. Christeas Laboratory of Experimental Surgery & Surgical Research, Medical School, National & Kapodistrian University of Athens, Athens, 11527, Greece
| | - Konstantinos Apostolou
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National & Kapodistrian University of Athens, Athens, 11527, Greece
| | - Ioannis Karavokyros
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 11527, Greece
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Wang X, Sun H, Zhu S. Long non-coding RNA PTAR inhibits apoptosis but promotes proliferation, invasion and migration of cervical cancer cells by binding miR-101. Bioengineered 2021; 12:4536-4545. [PMID: 34323178 PMCID: PMC8806890 DOI: 10.1080/21655979.2021.1946634] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
In this study, the expression of PTAR in cervical cancer tissues and cells was quantified by real-time PCR. Then, the roles of PTAR in HeLa cell proliferation and cell cycle were analyzed by a CCK-8 assay and flow cytometry, respectively.The effects of PTAR on cell migration and invasion were checked by Transwell and wound healing assays.The effect of PTAR on HeLa cell apoptosis was analyzed using annexin V/FITC staining. Finally, the interaction between PTAR and miR-101 in uterine cancer was verified through a dual-luciferase reporter assay and correlation analysis. The results showed that PTAR expression was aberrantly ascended in cervical cancer tissues and cell lines (Caski, SW756, SiHa, C33A and HeLa cells). Overexpressed PTAR could promote cell proliferation, migration and invasion in HeLa cells, which were suppressed by PTAR knockdown. Moreover, cell cycle progression stalled at the G1-G0 phase could be released with PTAR overexpression. The transfection of a PTAR vector inhibited apoptosis, while si-PTAR transfection increased apoptosis. Furthermore, PTAR could act as an endogenous sponge by directly binding to miR-101 and downregulating miR-101 expression. In conclusion, lncRNAPTAR plays a vital role and may be an effective target for the diagnosis and therapy of cervical cancer.
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Affiliation(s)
- Xuehe Wang
- Department of Gynaecology, Songshan Hospital of Qingdao University Medical College, QingdaoShandong, China
| | - Huaqin Sun
- Department of Gynaecology, The Affiliated Hospital of Qingdao University, Qingdao China
| | - Simin Zhu
- Department of Gynaecology, The Affiliated Hospital of Qingdao University, Qingdao China
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LncRNA TUG1 Contributes to Hypoxia-Induced Myocardial Cell Injury Through Downregulating miR-29a-3p in AC16 Cells. J Cardiovasc Pharmacol 2021; 76:533-539. [PMID: 33165134 DOI: 10.1097/fjc.0000000000000906] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Myocardial ischemia is a common reason that causes human death globally. Long noncoding RNA taurine upregulated 1 (TUG1) serves as an oncogene in a variety of cancers. In this article, we aimed to investigate the role of TUG1 and its underlying signal pathway in hypoxia-induced myocardial cell injury. Cell viability, apoptosis, and lactate dehydrogenase (LDH) release were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, western blot assay, and LDH cytotoxicity assay. Quantitative real-time polymerase chain reaction was applied to measure the enrichment of TUG1 and miR-29a-3p. MiR-29a-3p was predicted as a target of TUG1 by StarBase bioinformatic software, and the target relationship between TUG1 and miR-29a-3p was verified by dual-luciferase reporter assay. Hypoxia treatment induced the apoptosis and LDH release while inhibited the viability of AC16 cells. TUG1 was markedly upregulated while the level of miR-29a-3p was notably decreased in hypoxia-stimulated AC16 cells. TUG1 contributed to hypoxia-induced AC16 injury. MiR-29a-3p depletion intensified hypoxia-induced AC16 damage. TUG1 negatively regulated the expression of miR-29a-3p through their direct interaction in AC16 cells. TUG1 silencing-mediated influences in hypoxia-induced AC16 cells were partly reversed by the interference of miR-29a-3p. In conclusion, TUG1 accelerated hypoxia-induced AC16 injury through inversely modulating the level of miR-29a-3p. TUG1/miR-29a-3p axis might be an underlying therapeutic target for myocardial ischemia.
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Gong Z, Huang W, Wang B, Liang N, Long S, Li W, Zhou Q. Interplay between cyclooxygenase‑2 and microRNAs in cancer (Review). Mol Med Rep 2021; 23:347. [PMID: 33760116 PMCID: PMC7974460 DOI: 10.3892/mmr.2021.11986] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor‑associated inflammation and aberrantly expressed biomarkers have been demonstrated to play crucial roles in the cancer microenvironment. Cyclooxygenase‑2 (COX‑2), a prominent inflammatory factor, is highly expressed in tumor cells and contributes to tumor growth, recurrence and metastasis. Overexpression of COX‑2 may occur at both transcriptional and post‑transcriptional levels. Thus, an improved understanding of the regulatory mechanisms of COX‑2 can facilitate the development of novel antitumor therapies. MicroRNAs (miRNAs) are a group of small non‑coding RNAs that act as translation repressors of target mRNAs, and play vital roles in regulating cancer development and progression. The present review discusses the association between miRNAs and COX‑2 expression in different types of cancer. Understanding the regulatory role of miRNAs in COX‑2 post‑transcription can provide novel insight for suppressing COX‑2 expression via gene silencing mechanisms, which offer new perspectives and future directions for the development of novel COX‑2 selective inhibitors based on miRNAs.
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Affiliation(s)
- Zexiong Gong
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
| | - Weiguo Huang
- Cancer Research Institute, Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Baiyun Wang
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
| | - Na Liang
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
| | - Songkai Long
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
| | - Wanjun Li
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
| | - Qier Zhou
- Department of Anesthesiology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, P.R. China
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Non coding RNAs as the critical factors in chemo resistance of bladder tumor cells. Diagn Pathol 2020; 15:136. [PMID: 33183321 PMCID: PMC7659041 DOI: 10.1186/s13000-020-01054-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 11/05/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Bladder cancer (BCa) is the ninth frequent and 13th leading cause of cancer related deaths in the world which is mainly observed among men. There is a declining mortality rates in developed countries. Although, the majority of BCa patients present Non-Muscle-Invasive Bladder Cancer (NMIBC) tumors, only 30% of patients suffer from muscle invasion and distant metastases. Radical cystoprostatectomy, radiation, and chemotherapy have proven to be efficient in metastatic tumors. However, tumor relapse is observed in a noticeable ratio of patients following the chemotherapeutic treatment. Non-coding RNAs (ncRNAs) are important factors during tumor progression and chemo resistance which can be used as diagnostic and prognostic biomarkers of BCa. MAIN BODY In present review we summarized all of the lncRNAs and miRNAs associated with chemotherapeutic resistance in bladder tumor cells. CONCLUSIONS This review paves the way of introducing a prognostic panel of ncRNAs for the BCa patients which can be useful to select a proper drug based on the lncRNA profiles of patients to reduce the cytotoxic effects of chemotherapy in such patients.
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Yan Z, Yin H, Lin G. CircDDX42 Accelerates the Development of Pancreatic Cancer via miR-613/ID4/PI3K/AKT Axis. Onco Targets Ther 2020; 13:10945-10957. [PMID: 33149610 PMCID: PMC7604853 DOI: 10.2147/ott.s233000] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 01/15/2020] [Indexed: 01/01/2023] Open
Abstract
Background Pancreatic cancer (PC) is one of the fatal cancers globally. CircDEAD-box helicase 42 (circDDX42) has been reported to play an oncogenic role in many cancers. The purpose of our study was to explore the relationship between circDDX42 and PC development and the potential mechanism by which circDDX42 modulating the progression of PC. Methods The enrichment of circDDX42, miR-613 and inhibitor of DNA binding 4 (ID4) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) in PC tissues and cells. The proliferation, apoptosis and metastasis of PC cells were examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Western blot, flow cytometry and transwell migration and invasion assays, respectively. The binding sites between miR-613 and circDDX42 or ID4 were predicted by Starbase bioinformatic software, and dual-luciferase reporter assay was conducted to verify the combination between miR-613 and circDDX42 or ID4. Western blot was carried out to detect the abundance of ID4, p-phosphatidylinositol 3-kinase (p-PI3K), PI3K, p-AKT serine/threonine kinase (p-AKT) and AKT in PC cells. The in vivo role of circDDX42 was verified through using murine xenograft model. Results The level of circDDX42 was enhanced in PC tissues and cells compared with that in matching normal tissues and HPDE cells. CircDDX42 promoted the proliferation and metastasis and suppressed the apoptosis of PC cells. CircDDX42 could sponge miR-613, and miR-613 was negatively regulated by circDDX42 in PC cells. MiR-613 suppressed the progression of PC. ID4 was a direct target of miR-613. ID4 was inversely modulated by miR-613 and positively regulated by circDDX42 in PC cells. ID4 played an oncogenic role in the tumorigenesis of PC. CircDDX42/miR-613/ID4 axis regulated the activation of PI3K/AKT pathway in PC cells. ID4 facilitated the progression of PC via activating PI3K/AKT signal pathway. CircDDX42 promoted the tumor growth of PC in vivo. Conclusion CircDDX42 accelerated the proliferation and metastasis while impeded the apoptosis of PC cells via circDDX42/miR-613/ID4/PI3K/AKT axis. This axis might be a promising target for PC therapy.
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Affiliation(s)
- Zhen Yan
- Department of General Surgery, The First Hospital of Qiqihar, Qiqihar 161005, People's Republic of China.,Department of General Surgery, Qiqihar Hospital Affiliated to Southern Medical University, Qiqihar 161005, People's Republic of China
| | - Heliang Yin
- Department of General Surgery, The First Hospital of Qiqihar, Qiqihar 161005, People's Republic of China.,Department of General Surgery, Qiqihar Hospital Affiliated to Southern Medical University, Qiqihar 161005, People's Republic of China
| | - Guoying Lin
- Department of General Surgery, The First Hospital of Qiqihar, Qiqihar 161005, People's Republic of China.,Department of General Surgery, Qiqihar Hospital Affiliated to Southern Medical University, Qiqihar 161005, People's Republic of China
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Che L, Wu ZL, Huang LY, Wu JS, Du ZB, Lin JX, Su YH, Chen XX, Lin ZN, Lin YC. MicroRNA-101 inhibits cadmium-induced angiogenesis by targeting cyclooxygenase-2 in primary human umbilical vein endothelial cells. Biochem Pharmacol 2020; 189:114192. [PMID: 32783891 DOI: 10.1016/j.bcp.2020.114192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022]
Abstract
Exposure to toxic metal contaminants, such as cadmium compounds (Cd2+), has been shown to induce adverse effects on various organs and tissues. In particular, blood vessels are severely impacted by Cd2+ exposure, which may lead to cardiovascular diseases (CVDs). According to previous studies, CVDs are associated with increased cyclooxygenase 2 (COX-2) levels. However, the mechanisms by which CdCl2-induced COX-2 overexpression leads to cardiovascular dysfunction remain unclear. Herein, we show that the relative gene expressions of VEGF and PTGS2 (COX-2 encoding gene) are positively correlated in CVDs patients. Moreover, we demonstrate that the in vitro administration of CdCl2 induces cytotoxicity and endoplasmic reticulum (ER) stress in primary human umbilical vein endothelial cells (HUVECs). The induction of ER stress and the overexpression of COX-2 in CdCl2-treated cells alters the protein level of vascular endothelial growth factor (VEGF), resulting in abnormal angiogenesis and increased cytotoxicity. At the pre-transcription level, the inhibition of ER stress by siGRP78 (a key mediator of ER stress) can restore normal angiogenesis in the CdCl2-exposed cells. Meanwhile, at the transcription level, the adverse effects of CdCl2 exposure may be reversed via genetic modification with siRNA (siPTGS2) or by using phytochemical inhibitors (parthenolide, PN) of COX-2. Finally, at the post-transcription level, COX-2 expression may be restricted by the binding of microRNA-101 (miR-101) to the 3'-UTR of PTGS2 mRNA. The use of mimic miR-101 (mi101) to induce the expression of miR-101 eventually leads to reduced COX-2 protein levels, relieved ER stress, and less abnormal angiogenesis and cytotoxicity of CdCl2-exposed primary HUVECs. Overall, our results suggest that CdCl2-induced abnormal angiogenesis is mediated by miR-101/COX-2/VEGF-axis-dependent ER stress, and that cardiovascular dysfunction may be controlled by manipulating COX-2 at the pre-transcription, transcription, and post-transcription levels.
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Affiliation(s)
- Lin Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zi-Li Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Lian-Yun Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jia-Shen Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ze-Bang Du
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jin-Xian Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yan-Hua Su
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xiao-Xuan Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zhong-Ning Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yu-Chun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
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Harati R, Mohammad MG, Tlili A, El-Awady RA, Hamoudi R. Loss of miR-101-3p Promotes Transmigration of Metastatic Breast Cancer Cells through the Brain Endothelium by Inducing COX-2/MMP1 Signaling. Pharmaceuticals (Basel) 2020; 13:144. [PMID: 32645833 PMCID: PMC7407639 DOI: 10.3390/ph13070144] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
Brain metastases represent one of the incurable end stages in breast cancer (BC). Developing effective or preventive treatments is hampered by a lack of knowledge on the molecular mechanisms driving brain metastasis. Transmigration of BC cells through the brain endothelium is a key event in the pathogenesis of brain metastasis. In this study, we identified miR-101-3p as a critical micro-RNA able to reduce transmigration of BC cells through the brain endothelium. Our results revealed that miR-101-3p expression is downregulated in brain metastatic BC cells compared to less invasive variants, and varies inversely compared to the brain metastatic propensity of BC cells. Using a loss-and-gain of function approach, we found that miR-101-3p downregulation increased transmigration of BC cells through the brain endothelium in vitro by inducing COX-2 expression in cancer cells, whereas ectopic restoration of miR-101-3p exerted a metastasis-reducing effect. In regulatory experiments, we found that miR-101-3p mediated its effect by modulating COX-2-MMP1 signaling capable of degrading the inter-endothelial junctions (claudin-5 and VE-cadherin), key components of the brain endothelium. These findings suggest that miR-101-3p plays a critical role in the transmigration of breast cancer cells through the brain endothelium by modulating the COX-2-MMP1 signaling and thus may serve as a therapeutic target that can be exploited to prevent or suppress brain metastasis in human breast cancer.
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Affiliation(s)
- Rania Harati
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, UAE;
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, UAE; (M.G.M.); (R.H.)
| | - Mohammad G. Mohammad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, UAE; (M.G.M.); (R.H.)
- Department of Medical Laboratories, College of Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, UAE
| | - Abdelaziz Tlili
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah P.O. Box 27272, UAE;
| | - Raafat A. El-Awady
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, UAE;
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, UAE; (M.G.M.); (R.H.)
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, UAE; (M.G.M.); (R.H.)
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, UAE
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12
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Zimta AA, Tigu AB, Braicu C, Stefan C, Ionescu C, Berindan-Neagoe I. An Emerging Class of Long Non-coding RNA With Oncogenic Role Arises From the snoRNA Host Genes. Front Oncol 2020; 10:389. [PMID: 32318335 PMCID: PMC7154078 DOI: 10.3389/fonc.2020.00389] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/04/2020] [Indexed: 12/24/2022] Open
Abstract
The small nucleolar RNA host genes (SNHGs) are a group of long non-coding RNAs, which are reported in many studies as being overexpressed in various cancers. With very few exceptions, the SNHGs (SNHG1, SNHG3, SNHG5, SNHG6, SNHG7, SNHG12, SNHG15, SNHG16, SNHG20) are recognized as inducing increased proliferation, cell cycle progression, invasion, and metastasis of cancer cells, which makes this class of transcripts a viable biomarker for cancer development and aggressiveness. Through our literature research, we also found that silencing of SNHGs through small interfering RNAs or short hairpin RNAs is very effective in both in vitro and in vivo experiments by lowering the aggressiveness of solid cancers. The knockdown of SNHG as a new cancer therapeutic option should be investigated more in the future.
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Affiliation(s)
- Alina-Andreea Zimta
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Adrian Bogdan Tigu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina Stefan
- African Organisation for Research and Training in Cancer, Cape Town, South Africa
| | - Calin Ionescu
- Surgical Department, Municipal Hospital, Cluj-Napoca, Romania
- Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. I. Chiricuta”, Cluj-Napoca, Romania
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13
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Yang W, Gong P, Yang Y, Yang C, Yang B, Ren L. Circ-ABCB10 Contributes to Paclitaxel Resistance in Breast Cancer Through Let-7a-5p/DUSP7 Axis. Cancer Manag Res 2020; 12:2327-2337. [PMID: 32273769 PMCID: PMC7108723 DOI: 10.2147/cmar.s238513] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/14/2020] [Indexed: 12/20/2022] Open
Abstract
Background Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy. Methods The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo. Results Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo. Conclusion Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.
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Affiliation(s)
- Weiping Yang
- Department of Thyroid Breast Surgery, Qingdao Chengyang People's Hospital, Qingdao 266109, Shandong, People's Republic of China
| | - Piguo Gong
- Department of Thyroid Breast Surgery, Qingdao Chengyang People's Hospital, Qingdao 266109, Shandong, People's Republic of China
| | - Yifeng Yang
- Department of Thyroid Breast Surgery, Qingdao Chengyang People's Hospital, Qingdao 266109, Shandong, People's Republic of China
| | - Chunyan Yang
- Obstetric Breast Health Clinic, Qingdao Haici Medical Center, Qingdao 266033, Shandong, People's Republic of China
| | - Baohui Yang
- Department of Internal Medicine, Qingdao Chengyang Second People's Hospital, Qingdao 266109, Shandong, People's Republic of China
| | - Lijun Ren
- Department of Thyroid Breast Surgery, Qingdao Chengyang People's Hospital, Qingdao 266109, Shandong, People's Republic of China
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14
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Velmurugan BK, Hua CH, Tsai MH, Lee CP, Chung CM, Ko YC. Combination of celecoxib and calyculin-A inhibits epithelial-mesenchymal transition in human oral cancer cells. Biotech Histochem 2020; 95:341-348. [PMID: 31937145 DOI: 10.1080/10520295.2019.1700429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Expression of cyclo-oxygenase-2 (COX-2) and protein phosphatase 2A (PP2A) deactivation occurs frequently in oral squamous cell carcinoma (OSCC). We initially assessed COX-2 and PP2A protein expression in OSCC specimens using immunohistochemical (IHC) staining and western blot analysis. We found strong COX-2 and phosphorylated PP2A (p-PP2A) expression in OSCC samples. No significant difference in total PP2A expression was observed between cancer and nontumor tissues. The effect of combining COX-2 inhibitor and celecoxib (CXB) with the PP2A inhibitor, calyculin-A (CLA) on the OSCC cell line, HSC3, was evaluated in vitro. We found that a combination of 1 nM CLA and 50 µM CXB significantly inhibited cell viability, and migration and invasion of HSC3 cells. Western blots for AKT, p-AKT, ERK, p-ERK, E-cadherin, vimentin and β-catenin were conducted after treatment with CXB and/or CLA. Increased E-cadherin and decreased β-catenin expression were found in CXB or CLA treated hsc-3 cells, whereas the combined CXB and CLA treatment showed no difference in E-cadherin or β-catenin expression. Our findings suggest that CLA alone was more effective than CXB alone, but not in the combined drug treatment.
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Affiliation(s)
- Bharath Kumar Velmurugan
- Toxicology and Biomedicine Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Chun-Hung Hua
- Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Hsui Tsai
- Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Chi-Pin Lee
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Min Chung
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan
| | - Ying-Chin Ko
- Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan
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15
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Saul MJ, Emmerich AC, Steinhilber D, Suess B. Regulation of Eicosanoid Pathways by MicroRNAs. Front Pharmacol 2019; 10:824. [PMID: 31379585 PMCID: PMC6659501 DOI: 10.3389/fphar.2019.00824] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/26/2019] [Indexed: 01/07/2023] Open
Abstract
Over the last years, many microRNAs (miRNAs) have been identified that regulate the formation of bioactive lipid mediators such as prostanoids and leukotrienes. Many of these miRNAs are involved in complex regulatory circuits necessary for the fine-tuning of biological functions including inflammatory processes or cell growth. A better understanding of these networks will contribute to the development of novel therapeutic strategies for the treatment of inflammatory diseases and cancer. In this review, we provide an overview of the current knowledge of miRNA regulation in eicosanoid pathways with special focus on novel miRNA functions and regulatory circuits of leukotriene and prostaglandin biosynthesis.
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Affiliation(s)
- Meike J Saul
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Anne C Emmerich
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.,Institute of Pharmaceutical Chemistry, Goethe Universität Frankfurt, Frankfurt, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe Universität Frankfurt, Frankfurt, Germany
| | - Beatrix Suess
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
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16
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Xu XC, Zhang WB, Li CX, Gao H, Pei Q, Cao BW, He TH. Up-Regulation of MiR-1915 Inhibits Proliferation, Invasion, and Migration of Helicobacter pylori-Infected Gastric Cancer Cells via Targeting RAGE. Yonsei Med J 2019; 60:38-47. [PMID: 30554489 PMCID: PMC6298885 DOI: 10.3349/ymj.2019.60.1.38] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Helicobacter pylori (HP)-infected gastric cancer (GC) is known to be a fatal malignant tumor, but the molecular mechanisms underlying its proliferation, invasion, and migration remain far from being completely understood. Our aim in this study was to explore miR-1915 expression and its molecular mechanisms in regulating proliferation, invasion, and migration of HP-infected GC cells. MATERIALS AND METHODS Quantitative real-time PCR and western blot analysis were performed to determine miR-1915 and receptor for advanced glycation end product (RAGE) expression in HP-infected GC tissues and gastritis tissues, as well as human gastric mucosal cell line GES-1 and human GC cell lines SGC-7901 and MKN45. CCK8 assay and transwell assay were performed to detect the proliferation, invasion, and migration capabilities. MiR-1915 mimics and miR-1915 inhibitor were transfected into GC cells to determine the target relationship between miR-1915 and RAGE. RESULTS MiR-1915 was under-expressed, while RAGE was over-expressed in HP-infected GC tissues and GC cells. Over-expressed miR-1915 could attenuate cellular proliferation, invasion, and migration capacities. RAGE was confirmed to be the target gene of miR-1915 by bioinformatics analysis and luciferase reporter assay. Moreover, HP-infected GC cellular proliferation, invasion, and migration were inhibited after treatment with pcDNA-RAGE. CONCLUSION MiR-1915 exerted tumor-suppressive effects on cellular proliferation, invasion, and migration of HP-infected GC cells via targeting RAGE, which provided an innovative target candidate for treatment of HP-infected GC.
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Affiliation(s)
- Xin Cai Xu
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wen Bin Zhang
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
| | - Chun Xing Li
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua Gao
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Qi Pei
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Bo Wei Cao
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tie Han He
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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17
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Wang Y, Zhang S. Berberine suppresses growth and metastasis of endometrial cancer cells via miR-101/COX-2. Biomed Pharmacother 2018; 103:1287-1293. [DOI: 10.1016/j.biopha.2018.04.161] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 04/23/2018] [Accepted: 04/23/2018] [Indexed: 12/27/2022] Open
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19
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Development of a novel cationic liposome: Evaluation of liposome mediated transfection and anti-proliferative effects of miR-101 in acute myeloid leukemia. J Drug Deliv Sci Technol 2018. [DOI: 10.1016/j.jddst.2018.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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20
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miR-101-3p induces autophagy in endometrial carcinoma cells by targeting EZH2. Arch Gynecol Obstet 2018; 297:1539-1548. [PMID: 29691644 DOI: 10.1007/s00404-018-4768-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 01/24/2018] [Indexed: 10/17/2022]
Abstract
OBJECTIVE This study aimed to investigate the effect of miR-101-3p on autophagy in endometrial carcinoma (EC) cells and the connection between miR-101-3p and EZH2. METHODS The expression levels of miRNAs were analyzed by microarray. The expression level of autophagy related proteins was measured by western blot. The mRNA expression level of beclin-1 was determined by qRT-PCR. Autophagy in EC cells was traced by GFP-LC3 fusion protein and observed by fluorescence microscopy. The number of autophagic vacuoles was determined by transmission electron microscopy (TEM). A luciferase reporter assay was utilized to assess the target relationship between miR-101-3p and EZH2. RESULTS The expression level of miR-101-3p in EC tissues was lower than in normal tissues. miR-101-3p upregulated the expression levels of the autophagy-related proteins LC3-II and beclin-1 in EC cells in a time- and dose-dependent manner. Overexpression of miR-101-3p and silencing of EZH2 both promoted autophagy in EC cells. Luciferase reporter assays verified that miR-101-3p inhibited EZH2 expression by binding to its 3'-UTR region. CONCLUSION miR-101-3p promoted autophagy in EC cells by downregulating the expression of EZH2, and it induced autophagy in EC cells by suppressing EZH2 expression. Inhibition of miR-101-3p could reduce its autophagy induction effect on EC cells.
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21
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Wen Y, Cai J, Hou Y, Huang Z, Wang Z. Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target. Oncotarget 2018; 8:37974-37990. [PMID: 28415635 PMCID: PMC5514966 DOI: 10.18632/oncotarget.16467] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Epigenetic modifications in cancer stem cells largely result in phenotypic and functional heterogeneity in many solid tumors. Increasing evidence indicates that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb repressor complex 2, is highly expressed in cancer stem cells of numerous malignant tumors and has a critical function in cancer stem cell expansion and maintenance. Here, we review up-to-date information regarding EZH2 expression patterns, functions, and molecular mechanisms in cancer stem cells in various malignant tumors and discuss the therapeutic potential of targeting EZH2 in tumors.
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Affiliation(s)
- Yiping Wen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaya Hou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zaiju Huang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zehua Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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22
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Liu Y, Li H, Zhao C, Jia H. MicroRNA-101 inhibits angiogenesis via COX-2 in endometrial carcinoma. Mol Cell Biochem 2018; 448:61-69. [PMID: 29404887 DOI: 10.1007/s11010-018-3313-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/27/2018] [Indexed: 12/22/2022]
Abstract
Abnormal angiogenesis is critically involved in tumor progression and metastasis including endometrial cancer and is regulated by microRNAs such as microRNA-101 (miR-101). We hypothesize that miR-101 expression is disrupted in endometrial cancer and modulation of miR-101 levels is sufficient to regulate tumor growth through angiogenesis. We examined the expression levels of miR-101 and factors involved in angiogenesis in the patients with endometrial cancer. We also overexpressed or inhibited miR-101 in RL-95-2 cells and examined their effects on cell toxicity and tumor growth. Finally, we determined if miR-101 regulated tumorigenesis through cyclooxygenase-2 (COX-2). We found that miR-101 levels were significantly reduced. Factors involved in angiogenesis included vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and aromatase (P450arom), which were increased in endometrial carcinoma. Modulation of miR-101 level was sufficient to affect tumor growth. Finally, we found that the effects of miR-101 inhibition on tumor growth were suppressed by COX-2 inhibition. Our results suggest that modulating miR-101 and COX-2 levels or their activity may be a potential therapeutic strategy for endometrial cancer.
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Affiliation(s)
- Ying Liu
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Haiyan Li
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
| | - Congying Zhao
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Hanbing Jia
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
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23
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Yao ZS, Li C, Liang D, Jiang XB, Tang JJ, Ye LQ, Yuan K, Ren H, Yang ZD, Jin DX, Zhang SC, Ding JY, Tang YC, Xu JX, Chen K, Xie WX, Guo DQ, Cui JC. Diagnostic and prognostic implications of serum miR-101 in osteosarcoma. Cancer Biomark 2018; 22:127-133. [PMID: 29630525 PMCID: PMC6004928 DOI: 10.3233/cbm-171103] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Blood-circulating microRNAs (miRNAs) have been reported to be used as potential biomarkers in various cancers. MiR-101 has been found to act as a tumor suppressor in many tumor types, but little is known for osteosarcoma. The purpose of this study was to investigate miR-101 expression in osteosarcoma patients and assess its correlation with clinical features and prognosis. Serum samples from 152 osteosarcoma patients and 70 healthy controls were detected using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The data showed that miR-101 expression levels were remarkably underexpressed in serum samples from osteosarcoma patients compared to controls, and the post-treatment serum miR-101 expression was significantly higher than that in the pre-treatment expression. Low serum miR-101 expression was positively associated with advanced clinical stage and distant metastasis. Receiver operating characteristic (ROC) curve analysis showed that serum miR-101 could serve as a useful marker for osteosarcoma diagnosis, with a high sensitivity and specificity. Moreover, patients with high miR-101 expression had longer overall survival and recurrence free survival than those with low miR-101 expression. In addition, both univariate and multivariate analyses showed that serum miR-101 downregulation was associated with shorter overall survival and recurrence free survival. Our present results implicated serum miR-101 might be a useful biomarker for the clinical diagnosis and prognosis of osteosarcoma.
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Affiliation(s)
- Z.-S. Yao
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - C. Li
- Departments of Clinical Laboratory, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D. Liang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - X.-B. Jiang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J.-J. Tang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - L.-Q. Ye
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - K. Yuan
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - H. Ren
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Z.-D. Yang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D.-X. Jin
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - S.-C. Zhang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J.-Y. Ding
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Y.-C. Tang
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J.-X. Xu
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - K. Chen
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - W.-X. Xie
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - D.-Q. Guo
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - J.-C. Cui
- Departments of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
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Abbas M, Habib M, Naveed M, Karthik K, Dhama K, Shi M, Dingding C. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice. Biomed Pharmacother 2017; 95:1082-1090. [PMID: 28922727 DOI: 10.1016/j.biopha.2017.09.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 09/07/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023] Open
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Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma. Oncotarget 2017; 8:92770-92777. [PMID: 29190954 PMCID: PMC5696220 DOI: 10.18632/oncotarget.21576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 09/03/2017] [Indexed: 12/11/2022] Open
Abstract
Ursolic acid (UA) induces apoptosis in gastric cancer cells by inhibiting cyclooxygenase-2 (COX-2). Paclitaxel (PTX) is an important chemotherapy agent used to treat solid tumors. We evaluated the in vitro antitumor activity of UA in combination with PTX against gastric cancer cells and investigated the mechanisms underlying the combined effects. A cytotoxicity test and flow cytometry were utilized to study the effects of UA and PTX on proliferation and apoptosis, respectively. To further elucidate the mechanism, Western blot analysis was used to assess changes in the expression of a series of related proteins, including COX-2, proliferating cell nuclear antigen (PCNA), Bcl-2, and Bax. UA and PTX dose- and time-dependently inhibited BGC-823 and SGC-7901 gastric cancer cell proliferation. Combined delivery of UA and PTX synergistically reduced cell proliferation and induced apoptosis in these cells by lowering COX-2, PCNA, and Bcl-2 expression and by increasing Bax expression. These results indicate that the synergistic inhibition of proliferation and induction of apoptosis by UA and PTX may be induced by reducing COX-2 expression in gastric cancer cells.
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Low plasma levels of miR-101 are associated with tumor progression in gastric cancer. Oncotarget 2017; 8:106538-106550. [PMID: 29290969 PMCID: PMC5739754 DOI: 10.18632/oncotarget.20860] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 08/15/2017] [Indexed: 12/16/2022] Open
Abstract
Background Several studies have identified the decreased expression of the tumor suppressor miR-101 in various cancers. In this study, we tested miR-101 as a potential therapeutic target and novel plasma biomarker for gastric cancer (GC). Results The miR-101 expression level was significantly lower in GC tissues (P = 0.0038) and GC cell lines (P = 0.0238) than in normal gastric mucosa. Both exosomal and plasma miR-101 were significantly downregulated in GC patients compared with healthy volunteers (P = 0.0281 and P < 0.0001, respectively). Low miR-101 plasma level was significantly associated with advanced T factor, advanced disease stage, and peritoneal metastasis and predicted poor prognosis in GC patients (P = 0.0368; hazard ratio, 3.079; 95% confidence interval: 1.06–11.08). Overexpression of miR-101 in GC cells induced apoptosis by inhibiting MCL1 and suppressed cell migration and invasion by regulating ZEB1. Conclusions Depletion of the tumor suppressor miRNA-101 in plasma is related to tumor progression and poor outcomes. Low plasma miR-101 may be a biomarker for GC, and its restoration might be a novel anticancer treatment strategy.
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Zhang S, Wang W, Liu G, Xie S, Li Q, Li Y, Lin Z. Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis. Biomed Pharmacother 2017; 95:711-720. [PMID: 28886531 DOI: 10.1016/j.biopha.2017.08.133] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/21/2017] [Accepted: 08/29/2017] [Indexed: 01/19/2023] Open
Abstract
Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) are known to regulate carcinogenesis and metastasis of various cancers. The aim of this study was to identify the function role of lncRNAs in the hypoxia-induced EMT of malignant glioma. We used U87 and U251 cell lines were treated under hypoxia to induce EMT, then lncRNA microarray analyse was performed between U87-hypoxia and parental cell line. The relative expression of lncRNA and HIF-1α were detected by qRT-PCR between glioma tissues without metastasis and that with metastasis. Hypoxia could induce EMT and increase HOTTIP expression in glioma cells. Among the different expressions of lncRNAs, HOTTIP was the most upregulated lncRNA in glioma cells treated by hypoxia. High levels of HOTTIP and HIF-1α were correlated with glioma metastasis and poor patient prognosis. Knockdown of HIF-1α and HOTTIP blocked hypoxia-induced EMT, and suppressed invasion and migration of glioma cells. Finally, HOTTIP sponged endogenous miR-101 and inhibited its activity, which resulted in increased ZEB1 expression and promoted process of EMT. HIF-1α/HOTTIP/miR-101/ZEB1 axis plays essential role in hypoxia-induced EMT and metastasis of glioma, and HOTTIP may serve as a therapeutic target to reverse EMT and prevent glioma progression.
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Affiliation(s)
- Shanyi Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | | | | | - Shule Xie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qunxing Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yingru Li
- Department of Gastroenterology, Hernia and Abdominal Wall Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Zhaoyu Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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Bao J, Xu Y, Wang Q, Zhang J, Li Z, Li D, Li J. miR-101 alleviates chemoresistance of gastric cancer cells by targeting ANXA2. Biomed Pharmacother 2017; 92:1030-1037. [PMID: 28609840 DOI: 10.1016/j.biopha.2017.06.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/05/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chemoresistance remains a main clinical obstacle in the treatment of gastric cancer (GC). microRNAs have been revealed to participate in the regulation of drug resistance in a variety of cancers. However, little is known about the function and detailed molecular mechanism of miR-101 in GC chemoresistance. METHODS The expressions of miR-101 and Annexin A2 (ANXA2) in GC tissues and cells were detected by qRT-PCR and western blot. The effects of miR-101 overexpression on P-glycoprotein (P-gp) at mRNA and protein levels, cell viability, and apoptosis in drug-resistant GC cells were examined by qRT-PCR, western blot, MTT and flow cytometry analysis, respectively. Luciferase reporter assay, RNA immunoprecipitation (RIP) and qRT-PCR were applied to confirm whether miR-101 could target ANXA2 and regulate its expression. Rescue experiment was performed to verify the mechanism by which miR-101 involved in chemoresistance. RESULTS miR-101 was downregulated in GC tissues and drug-resistant GC cells. A negative correlation between miR-101 and ANXA2 expression was observed in GC tissues. Forced expression of miR-101 significantly reduced P-gp expression at mRNA and protein levels in drug-resistant GC cells. Overexpression of miR-101 enhanced sensitivity to cisplatin (DDP) or vincristine (VCR) via viability inhibition and apoptosis promotion. ANXA2 was identified as a direct target of miR-101 and miR-101 negatively regulated ANXA2 expression. Moreover, ectopic expression of ANXA2 reversed the effect of miR-101 on P-gp expression, cell viability and apoptosis. CONCLUSION miR-101 alleviated chemoresistance of gastric cancer cells by targeting ANXA2. Therefore, targeting miR-101 may be a potential therapeutic approach for drug-resistant GC.
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Affiliation(s)
- Jie Bao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Yun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Qunying Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Jinping Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Zhenjie Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Dongying Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Jiansheng Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
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Deng M, Qin Y, Chen X, Li D, Wang Q, Zheng H, Gu L, Deng C, Xue Y, Zhu D, Wang Q, Wang J. Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation. Oncol Lett 2017; 13:3850-3858. [PMID: 28521485 PMCID: PMC5431146 DOI: 10.3892/ol.2017.5914] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 10/24/2016] [Indexed: 12/16/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinase 1/2 (ERK1/2) may serve as potential targets in various types of cancer; however, the roles of these proteins in gallbladder carcinoma (GBC) have not been reported previously. In the present study, the expression levels of COX-2 and phospho (p)-ERK1/2 in GBC were examined and the biological activities of celecoxib and PD184161 (specific inhibitors of COX-2 and p-ERK1/2, respectively) on the proliferation, cell cycle and apoptosis of the GBC-SD and NOZ human GBC cell lines were evaluated by a series of in vitro and in vivo studies. COX-2 and p-ERK1/2 protein expression levels were found to be significantly elevated in GBC tissues as well as in GBC-SD and NOZ cells. Treatments with celecoxib and PD184161 significantly inhibited GBC-SD and NOZ cell growth in a concentration-dependent manner, and their combination produced a synergistic inhibitory effect. In addition, celecoxib and PD184161 significantly inhibited tumor growth in xenograft nude mice. Celecoxib treatment led to G1 arrest via the upregulation of p21 and p27 expression in GBC-SD and NOZ cells, whereas PD184161 did not affect cell cycle distribution. The combination of celecoxib and PD184161 was able to promote cell apoptosis by triggering a collapse of mitochondrial membrane potential and activating caspase-3-mediated apoptosis. In conclusion, COX-2 and p-ERK1/2 protein may serve as potential targets for GBC chemotherapy, and the combination of celecoxib and PD184161 could significantly inhibit GBC cell growth, induce cell G1 arrest and trigger cell apoptosis of GBC cells.
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Affiliation(s)
- Min Deng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Yiyu Qin
- Clinical Medical College, Research Centre of Biomedical Technology, Yancheng Institute of Health Sciences, Yancheng, Jiangsu 224005, P.R. China
| | - Xiaodong Chen
- Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Dapeng Li
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Qiangwu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Hailun Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Lin Gu
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Chaojing Deng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Yongju Xue
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Danyu Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
| | - Qizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
- Correspondence to: Dr Qizhi Wang or Dr Jianchao Wang, Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui 233004, P.R. China, E-mail: , E-mail:
| | - Jianchao Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
- Correspondence to: Dr Qizhi Wang or Dr Jianchao Wang, Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui 233004, P.R. China, E-mail: , E-mail:
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Anauate AC, Leal MF, Wisnieski F, Santos LC, Gigek CO, Chen ES, Geraldis JC, Calcagno DQ, Assumpção PP, Demachki S, Arasaki CH, Lourenço LG, Artigiani R, Burbano RR, Smith MAC. Identification of suitable reference genes for miRNA expression normalization in gastric cancer. Gene 2017; 621:59-68. [PMID: 28411081 DOI: 10.1016/j.gene.2017.04.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 03/28/2017] [Accepted: 04/10/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Ana Carolina Anauate
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil; Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, Brazil; Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Fernanda Wisnieski
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Leonardo Caires Santos
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil; Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Elizabeth Suchi Chen
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Jaqueline Cruz Geraldis
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Paulo Pimentel Assumpção
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Samia Demachki
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil
| | - Carlos Haruo Arasaki
- Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Laércio Gomes Lourenço
- Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Ricardo Artigiani
- Departamento de Patologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Rommel Rodríguez Burbano
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, Brazil; Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil; Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém, Brazil
| | - Marília Arruda Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil.
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Wu X, Zhou J, Wu Z, Chen C, Liu J, Wu G, Zhai J, Liu F, Li G. miR-101-3p Suppresses HOX Transcript Antisense RNA (HOTAIR)-Induced Proliferation and Invasion Through Directly Targeting SRF in Gastric Carcinoma Cells. Oncol Res 2017; 25:1383-1390. [PMID: 28251884 PMCID: PMC7841108 DOI: 10.3727/096504017x14879366402279] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
miR-101-3p has been identified as a tumor suppressor in several cancers, but its exact role in gastric adenocarcinoma is still largely unknown. In this study, we found that, compared with the RGM-1 human normal gastric epithelial cells, miR-101-3p was significantly downregulated in all six human gastric adenocarcinoma cell lines, including BGC-823, MNK-45, MGC-803, SGC-7901, AGS, and HGC-27. Overexpression of miR-101-3p suppressed both the proliferation and invasion of AGS gastric adenocarcinoma cells, and knockdown of miR-101-3p displayed the opposite effect. In addition, miR-101-3p could directly target and suppress the expression of the serum response factor (SRF) gene, which is a transcription factor of HOTAIR, a well-characterized tumor promoter lncRNA. miR-101-3p negatively regulated SRF-mediated transcription of HOTAIR. Moreover, silencing of either SRF or HOTAIR could counteract the promotion of gastric adenocarcinoma cell proliferation and invasion by miR-101-3p inhibition. Our findings indicate that miR-101-3p suppresses HOTAIR-induced proliferation and invasion through directly targeting SRF in gastric carcinoma cells.
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32
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Lin F, Li Y, Yan S, Liu S, Qian W, Shen D, Lin Q, Mao W. MicroRNA-181a inhibits tumor proliferation, invasiveness, and metastasis and is downregulated in gastric cancer. Oncol Res 2017; 22:75-84. [PMID: 25706394 PMCID: PMC7838452 DOI: 10.3727/096504014x14024160459203] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer. The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of gastric cancer. Here we show that miR-181a levels were significantly downregulated in gastric cancer tissues compared with the adjacent normal regions in 80 paired samples. Moreover, the lower levels of miR-181a were associated with the pM or pTNM stage in clinical gastric cancer patients. In addition, the ectopic expression of miR-181a in the gastric cancer cell line HGC-27 inhibited cell proliferation, cell migration, and invasion by directly interacting with the mRNA encoding the oncogenic factor Prox1. Taken together, our results indicate that miR-181a might act as a tumor suppressor in gastric cancer, which may provide a novel diagnostic and therapeutic option for human gastric cancer in the near future.
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Affiliation(s)
- Feng Lin
- Department of Oncology, the Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu, PR China
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Liu C, Yang C, Lu L, Wang W, Tan W, Leung CH, Ma DL. Luminescent iridium( iii) complexes as COX-2-specific imaging agents in cancer cells. Chem Commun (Camb) 2017; 53:2822-2825. [DOI: 10.1039/c6cc08109f] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
This is the first application of iridium(iii) complexes as imaging agents for COX-2.
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Affiliation(s)
- Chenfu Liu
- Department of Chemistry
- Hong Kong Baptist University
- Kowloon Tong
- China
| | - Chao Yang
- State Key Laboratory of Quality Research in Chinese Medicine
- Institute of Chinese Medical Sciences
- University of Macau
- Macao
- China
| | - Lihua Lu
- Department of Chemistry
- Hong Kong Baptist University
- Kowloon Tong
- China
- College of Chemistry and Pharmaceutical Sciences
| | - Wanhe Wang
- Department of Chemistry
- Hong Kong Baptist University
- Kowloon Tong
- China
| | - Weihong Tan
- Department of Chemistry and Department of Physiology and Functional Genomics
- Center for Research at the Bio/Nano Interface
- Shands Cancer Center
- UF Genetics Institute
- McKnight Brain Institute
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine
- Institute of Chinese Medical Sciences
- University of Macau
- Macao
- China
| | - Dik-Lung Ma
- Department of Chemistry
- Hong Kong Baptist University
- Kowloon Tong
- China
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35
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Tie J, Zhang X, Fan D. Epigenetic roles in the malignant transformation of gastric mucosal cells. Cell Mol Life Sci 2016; 73:4599-4610. [PMID: 27464701 PMCID: PMC5097112 DOI: 10.1007/s00018-016-2308-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/10/2016] [Accepted: 07/08/2016] [Indexed: 12/14/2022]
Abstract
Gastric carcinogenesis occurs when gastric epithelial cells transition through the initial, immortal, premalignant, and malignant stages of transformation. Epigenetic regulations contribute to this multistep process. Due to the critical role of epigenetic modifications , these changes are highly likely to be of clinical use in the future as new biomarkers and therapeutic targets for the early detection and treatment of cancers. Here, we summarize the recent findings on how epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, regulate gastric carcinogenesis, and we discuss potential new strategies for the diagnosis and treatments of gastric cancer. The strategies may be helpful in the further understanding of epigenetic regulation in human diseases.
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Affiliation(s)
- Jun Tie
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Xiangyuan Zhang
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China.
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36
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Moazeni-Roodi A, Allameh A, Harirchi I, Motiee-Langroudi M, Garajei A. Studies on the Contribution of Cox-2 Expression in the Progression of Oral Squamous Cell Carcinoma and H-Ras Activation. Pathol Oncol Res 2016; 23:355-360. [PMID: 27628320 DOI: 10.1007/s12253-016-0114-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/07/2016] [Indexed: 02/07/2023]
Abstract
The aim of this study was to investigate the relationship between the H-ras and Cox-2 gene expression in tumors from Iranian Oral Squamous Cell Carcinoma (OSCC) patients. Fresh tumor biopsies removed from oral cavity were collected from 67 new cases. Total RNA was extracted from biopsies and processed for quantification of H-ras and Cox-2 specific RNA expression using real-time PCR (QPCR). In addition, 59 gingival biopsies from apparently normal individuals were processed for QPCR assays. The results showed that Cox-2 expression at mRNA levels was at minimal levels in normal gingival biopsies. However, there was a surge in Cox-2 expression in tumor tissues (11.5 fold, p < 0.0001). Cox-2 expression was elevated depending on the tumor grade and there was a 1.7 fold increase (p = 0.003) in tumors diagnosed as MD/PD compared to that pathologically diagnosed as WD. This inflammatory marker was increased more significantly in smoker patients compared to non-smoker matching group. The H-ras expression at mRNA levels was significantly higher in OSCC samples compared to normal gingival (3 fold; p = 0.044). This expression was significantly higher in tumors diagnosed as MD/PD compared to WD (1.59 fold, p = 0.033). In conclusion, we found a correlation between H-ras expression and Cox-2 induction in OSCC tissue, suggesting that together these genes are contributing to cancer progression. Cox-2 is an early event in cancers of mucosal epithelial cells and a surge in Cox-2 expression in OSCC could be partly due to pro-inflammatory factors such as smoking.
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Affiliation(s)
- Abdolkarim Moazeni-Roodi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, I.R., Iran
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, I.R., Iran.
| | - Iraj Harirchi
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, I.R., Iran
| | - Maziar Motiee-Langroudi
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, I.R., Iran
| | - Ata Garajei
- Department of Oral and Maxillofacial Surgery, School of Dentistry and Department of Head and Neck Surgical Oncology and Reconstructive Surgery, The Cancer Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes. Tumour Biol 2016; 37:14117-14128. [DOI: 10.1007/s13277-016-5205-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 07/13/2016] [Indexed: 12/22/2022] Open
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38
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Yu XJ, Sun K, Tang XH, Zhou CJ, Sun H, Yan Z, Fang L, Wu HW, Xie YK, Gu B. Harmine combined with paclitaxel inhibits tumor proliferation and induces apoptosis through down-regulation of cyclooxygenase-2 expression in gastric cancer. Oncol Lett 2016; 12:983-988. [PMID: 27446381 DOI: 10.3892/ol.2016.4696] [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: 02/26/2015] [Accepted: 03/10/2016] [Indexed: 12/16/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) serves an important role in the carcinogenesis and progression of gastric cancer. Harmine (HM) and paclitaxel (PTX) are reported as promising drug candidates for cancer therapy, but whether a synergistic anti-tumor effect of HM combined with PTX exists in human gastric cancer remains unknown. The present study evaluated the effects of HM and/or PTX on cell proliferation and apoptosis in a gastric cancer cell line, SGC-7901. HM and PTX inhibited cell proliferation in a dose-dependent manner. Both HM and PTX alone induced apoptosis in gastric cancer cells. The combination of HM and PTX exerted synergistic effects on proliferation inhibition and apoptosis induction in SGC-7901 cells, with down-regulation of COX-2, PCNA and Bcl-2 and up-regulation of Bax expression. The results indicated that combination chemotherapy using HM with PTX exerts an anti-tumor effect for treating gastric cancer. The combination of the two drugs inhibits gastric cancer development more effectively than each drug alone through down-regulation of COX-2 expression.
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Affiliation(s)
- Xiao-Juan Yu
- Department of Emergency, People's Hospital of Taizhou, Jiangsu 225300, P.R. China
| | - Kun Sun
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Xiao-He Tang
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Cun-Jin Zhou
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Hui Sun
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Zhe Yan
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Ling Fang
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Hong-Wen Wu
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Yi-Kui Xie
- Department of Gastroenterology, First Hospital of Zibo, Shandong 255200, P.R. China
| | - Bin Gu
- Department of Emergency, People's Hospital of Taizhou, Jiangsu 225300, P.R. China
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Codocedo JF, Inestrosa NC. Wnt-5a-regulated miR-101b controls COX2 expression in hippocampal neurons. Biol Res 2016; 49:9. [PMID: 26895946 PMCID: PMC4759731 DOI: 10.1186/s40659-016-0071-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 02/12/2016] [Indexed: 02/07/2023] Open
Abstract
Background Wnt-5a is a member of the WNT family of secreted lipoglycoproteins, whose expression increases during development; moreover, Wnt-5a plays a key role in synaptic structure and function in the adult nervous system. However, the mechanism underlying these effects is still elusive. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the gene expression of their targets through hybridization with complementary sequences in the 3′ UTR, thereby inhibiting the translation of the target proteins. Several evidences indicate that the miRNAs are actively involved in the regulation of neuronal function. Results In the present study, we examined whether Wnt-5a modulates the levels of miRNAs in hippocampal neurons. Using PCR arrays, we identified a set of miRNAs that respond to Wnt-5a treatment. One of the most affected miRNAs was miR-101b, which targets cyclooxygenase-2 (COX2), an inducible enzyme that converts arachidonic acid to prostanoids, and has been involved in the injury/inflammatory response, and more recently in neuronal plasticity. Consistent with the Wnt-5a regulation of miR-101b, this Wnt ligand regulates COX2 expression in a time-dependent manner in cultured hippocampal neurons. Conclusion The biological processes induced by Wnt-5a in hippocampal neurons, involve the regulation of several miRNAs including miR-101b, which has the capacity to regulate several targets, including COX-2 in the central nervous system.
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Affiliation(s)
- Juan Francisco Codocedo
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile. .,CARE, Biomedical Research Center, Pontificia Universidad Católica de Chile, Av. Alameda 340, 8331150, Santiago, Chile.
| | - Nibaldo C Inestrosa
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile. .,Faculty of Medicine, Center for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia. .,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. .,CARE, Biomedical Research Center, Pontificia Universidad Católica de Chile, Av. Alameda 340, 8331150, Santiago, Chile.
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Wang Z, He R, Xia H, Wei YU, Wu S. MicroRNA-101 has a suppressive role in osteosarcoma cells through the targeting of c-FOS. Exp Ther Med 2016; 11:1293-1299. [PMID: 27073439 PMCID: PMC4812594 DOI: 10.3892/etm.2016.3085] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 01/15/2016] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRs) have been implicated in the development and progression of osteosarcoma (OS). However, the underlying mechanism of miR-101 in regulating of the proliferation, migration and invasion of OS cells remains to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction data revealed that miR-101 was frequently downregulated in the tissue samples of 12 patients with OS compared with their matched adjacent non-tumor tissues. Furthermore, miR-101 was significantly downregulated in three common OS cell lines, Saos-2, MG63 and U2OS, compared with the human osteoblast cell line, hFOB1.19 (P<0.01). A luciferase reporter assay was also performed and identified c-FOS as a novel target of miR-101 in U2OS cells; overexpression of miR-101 significantly suppressed the protein expression levels of c-FOS, while knockdown of miR-101 significantly enhanced the formers' expression levels in U2OS cells (P<0.01). Independent inhibition of c-FOS and overexpression of miR-101 expression levels significantly suppressed U2OS cell proliferation, migration and invasion (P<0.01). However, overexpression of c-FOS reversed the inhibitory effect of miR-101 upregulation on proliferation, migration and invasion of U2OS cells, suggesting that miR-101 acts as a tumor suppressor in OS cells via targeting of c-FOS. Thus, we propose that the miR-101/c-FOS axis may be a potential therapeutic target for OS.
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Affiliation(s)
- Zili Wang
- Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Rongzhen He
- Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hansong Xia
- Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Y U Wei
- Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Song Wu
- Department of Orthopaedic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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Ahn HJ, Lee DS. Helicobacter pylori in gastric carcinogenesis. World J Gastrointest Oncol 2015; 7:455-65. [PMID: 26690981 PMCID: PMC4678392 DOI: 10.4251/wjgo.v7.i12.455] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 10/10/2015] [Accepted: 11/03/2015] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to the occurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cagA and vacA are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis.
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Shih JW, Wang LY, Hung CL, Kung HJ, Hsieh CL. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism. Int J Mol Sci 2015; 16:28943-78. [PMID: 26690121 PMCID: PMC4691085 DOI: 10.3390/ijms161226138] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/17/2015] [Accepted: 11/26/2015] [Indexed: 12/19/2022] Open
Abstract
Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.
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Affiliation(s)
- Jing-Wen Shih
- Integrated Translational Lab, The Center of Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
| | - Ling-Yu Wang
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817, USA.
| | - Chiu-Lien Hung
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817, USA.
| | - Hsing-Jien Kung
- Integrated Translational Lab, The Center of Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817, USA.
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
| | - Chia-Ling Hsieh
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
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Xue M, Zhao L, Yang F, Li Z, Li G. MicroRNA‑145 inhibits the malignant phenotypes of gastric carcinoma cells via downregulation of fascin 1 expression. Mol Med Rep 2015; 13:1033-9. [PMID: 26647829 DOI: 10.3892/mmr.2015.4609] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 11/05/2015] [Indexed: 11/06/2022] Open
Abstract
MicroRNA (miR)‑145 has been demonstrated to act as a tumor suppressor, and deregulation of fascin 1 (FSCN1) has been observed in several types of human malignancy, including gastric carcinoma. However, the molecular mechanism underlying the function of miR‑145, specifically its targets in gastric carcinoma have yet to be fully elucidated. In the present study, downregulation of miR‑145 and upregulation of FSCN1 was identified in gastric carcinoma cell lines, compared with normal gastric mucosal epithelial cells. A luciferase reporter assay demonstrated that miR‑145 was able to bind to the 3'‑untranslated region of FSCN1 mRNA. Overexpression of miR‑145 led to a significant decrease in FSCN1 expression levels, whereas knockdown of miR‑145 resulted in increased FSCN1 expression levels in gastric carcinoma cells. Furthermore, overexpression of miR‑145 inhibited proliferation, migration and invasion in gastric carcinoma cells. Similar effects were also observed in gastric carcinoma cells transfected with FSCN1 small interfering RNA. In addition, overexpression of FSCN1 reversed the suppressive effects of miR‑145 upregulation on proliferation, migration and invasion in gastric carcinoma cells, suggesting that FSCN1 is indeed involved in the miR‑145‑mediated malignant phenotype of gastric carcinoma cells. The present study revealed an anti‑oncogenic role of miR‑145 in gastric carcinoma via inhibition of FSCN1, and suggested that miR‑145 may be used for the treatment of gastric carcinoma.
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Affiliation(s)
- Minghui Xue
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Lunde Zhao
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Fang Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Zhenjuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Guangyan Li
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Konno Y, Dong P, Xiong Y, Suzuki F, Lu J, Cai M, Watari H, Mitamura T, Hosaka M, Hanley SJB, Kudo M, Sakuragi N. MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells. Oncotarget 2015; 5:6049-62. [PMID: 25153722 PMCID: PMC4171612 DOI: 10.18632/oncotarget.2157] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.
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Affiliation(s)
- Yosuke Konno
- Department of Gynecology, Hokkaido University, Sapporo, Japan; These authors contributed equally to this work
| | - Peixin Dong
- Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan; These authors contributed equally to this work
| | - Ying Xiong
- Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China; These authors contributed equally to this work
| | - Fumihiko Suzuki
- Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan; These authors contributed equally to this work
| | - Jiabin Lu
- Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Muyan Cai
- Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | | | | | | | - Sharon J B Hanley
- Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan
| | - Masataka Kudo
- Department of Gynecology, Hokkaido University, Sapporo, Japan
| | - Noriaki Sakuragi
- Department of Gynecology, Hokkaido University, Sapporo, Japan; Department of Women's Health Educational System, Hokkaido University, Sapporo, Japan
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Li G, Yang F, Gu S, Li Z, Xue M. MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C. Mol Med Rep 2015; 13:572-8. [PMID: 26573417 DOI: 10.3892/mmr.2015.4560] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 10/22/2015] [Indexed: 12/11/2022] Open
Abstract
Deregulation of microRNAs (miRNAs) is known to be associated with drug resistance in human cancers. However, the precise role of miR‑101 in the cisplatin (DPP) resistance of human gastric cancer cells has not been elucidated, yet. The present study revealed that miR‑101 was markedly downregulated in gastric cancer cell lines compared to that in the normal gastric mucosa epithelial cell line GES1. Furthermore, a significant decrease in miR‑101 levels, accompanied with an increased expression of vascular endothelial growth factor (VEGF)‑C in DDP‑resistant SGC7901 gastric cancer cells (SGC7901/DDP) compared with those in native SGC7901 cells was observed. In addition, forced overexpression of miR‑101 significantly inhibited cell proliferation, while enhancing cisplatin‑induced apoptosis of SGC7901/DDP cells. A luciferase reporter assay confirmed that VEGF‑C was a direct target of miR‑101 in SGC7901/DDP cells. Forced overexpression of miR‑101 in SGC7901/DDP cells reduced the expression of VEGF‑C, while knockdown of miR‑101 expression significantly enhanced VEGF‑C expression in SGC7901/DDP cells. Finally, overexpression of VEGF‑C inhibited DDP‑induced apoptosis in SGC7901 cells. In conclusion, the results of the present study suggested that miR‑101 inhibited the proliferation and promoted DDP‑induced apoptosis of DDP‑resistant gastric cancer cells, at least in part via targeting VEGF-C.
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Affiliation(s)
- Guangyan Li
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Fang Yang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Shiyu Gu
- Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Zhenjuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Minghui Xue
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Shao Y, Li P, Zhu ST, Yue JP, Ji XJ, He Z, Ma D, Wang L, Wang YJ, Zong Y, Wu YD, Zhang ST. Cyclooxygenase-2, a Potential Therapeutic Target, Is Regulated by miR-101 in Esophageal Squamous Cell Carcinoma. PLoS One 2015; 10:e0140642. [PMID: 26556718 PMCID: PMC4640815 DOI: 10.1371/journal.pone.0140642] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 09/29/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND & AIMS Cyclooxygenase-2 (COX-2) is known to promote the carcinogenesis of esophageal squamous cell carcinoma (ESCC). There are no reports on whether microRNAs (miRNAs) regulate COX-2 expression in ESCC. This study investigated the effect of miR-101 on ESCC through modulating COX-2 expression in ESCC. METHODS Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify miR-101 expression in ESCC clinical tissues and cell lines. The effects of miR-101 on ESCC progression were evaluated by cell counting kit-8 (CCK8), transwell migration and invasion assays, as well as by flow cytometry. The COX-2 and PEG2 levels were determined by western blot and enzyme-linked immunosorbent assays (ELISA). The luciferase reporter assay was used to verify COX-2 as a direct target of miR-101. The anti-tumor activity of miR-101 in vivo was investigated in a xenograft nude mouse model of ESCC. RESULTS Downregulation of miR-101 was confirmed through comparison of 30 pairs of ESCC tumor and adjacent normal tissues (P < 0.001), as well as in 11 ESCC cell lines and a human immortalized esophageal cell line (P < 0.001). Transfection of miR-101 in ESCC cell lines significantly suppressed cell proliferation, migration, and invasion (all P < 0.001). The antitumor effect of miR-101 was verified in a xenograft model. Furthermore, COX-2 was shown to be a target of miR-101. CONCLUSIONS Overexpression of miR-101 in ESCC inhibits proliferation and metastasis. Therefore, the miR-101/COX-2 pathway might be a therapeutic target in ESCC.
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MESH Headings
- Animals
- Carcinoma, Squamous Cell/enzymology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/therapy
- Cell Line, Tumor
- Cell Movement
- Cyclooxygenase 2/biosynthesis
- Cyclooxygenase 2/genetics
- Down-Regulation
- Enzyme Induction/genetics
- Esophageal Neoplasms/enzymology
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/therapy
- Esophagus/chemistry
- Gene Expression Regulation, Neoplastic/genetics
- Genes, Reporter
- Genetic Therapy
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/biosynthesis
- MicroRNAs/genetics
- Molecular Targeted Therapy
- Neoplasm Invasiveness
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- Real-Time Polymerase Chain Reaction
- Transfection
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ying Shao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Sheng-tao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Ji-ping Yue
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Xiao-jun Ji
- Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhen He
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Dan Ma
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Li Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Yong-jun Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Ye Zong
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Yong-dong Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Shu-tian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
- * E-mail:
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Wang P, Guo X, Zong W, Song B, Liu G, He S. MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer. Biochem Biophys Res Commun 2015; 467:798-804. [PMID: 26478435 DOI: 10.1016/j.bbrc.2015.10.062] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 10/11/2015] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future.
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Affiliation(s)
- Ping Wang
- Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710068, China
| | - Xueyan Guo
- Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710068, China
| | - Wei Zong
- Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710068, China
| | - Bin Song
- Department of General Surgery, The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710068, China
| | - Guisheng Liu
- Department of Gastroenterology, The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710068, China
| | - Shuixiang He
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
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Deng G, Teng Y, Huang F, Nie W, Zhu L, Huang W, Xu H. MicroRNA-101 inhibits the migration and invasion of intrahepatic cholangiocarcinoma cells via direct suppression of vascular endothelial growth factor-C. Mol Med Rep 2015; 12:7079-85. [PMID: 26299768 DOI: 10.3892/mmr.2015.4239] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 07/02/2015] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRs) have important roles in the pathogenesis of human malignancy. It has previously been suggested that deregulation of miR‑101 is associated with the progression of intrahepatic cholangiocarcinoma (ICC); however, the exact role of miR‑101 in the regulation of ICC metastasis remains largely unknown. The present study demonstrated that the expression levels of miR‑101 were significantly decreased in ICC tissue, as compared with matched adjacent normal tissue. Furthermore, miR‑101 was downregulated in the ICC‑9810 human ICC cell line, as compared with in the normal human intrahepatic biliary epithelial cell (HIBEC) line. Vascular endothelial growth factor (VEGF)‑C was identified as a target gene of miR‑101 in ICC‑9810 cells. The expression of VEGF‑C was negatively regulated by miR‑101 at the post‑transcriptional level in ICC‑9810 cells. Further investigation demonstrated that overexpression of miR‑101 markedly suppressed the migration and invasion of ICC‑9810 cells, and these effects were similar to those observed following VEGF‑C knockdown. Conversely, restoration of VEGF‑C reversed the inhibitory effects of miR‑101 overexpression on ICC‑9810 cell migration and invasion, thus suggesting that miR‑101 may suppress ICC‑9810 cell migration and invasion, at least partly via inhibition of VEGF‑C. It was also demonstrated that the mRNA and protein expression levels of VEGF‑C were frequently upregulated in ICC tissue and cells, and its expression level was inversely correlated with that of miR‑101 in ICC tissue. In conclusion, the present study identified important roles for miR‑101 and VEGF‑C in ICC, suggesting that miR‑101/VEGF‑C signaling may be a promising diagnostic and/or therapeutic target for ICC.
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Affiliation(s)
- Gang Deng
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yinglu Teng
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Feizhou Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Wanpin Nie
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Lei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Wei Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hongbo Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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Zheng Z, Yan D, Chen X, Huang H, Chen K, Li G, Zhou L, Zheng D, Tu L, Dong XD. MicroRNA-206: Effective Inhibition of Gastric Cancer Progression through the c-Met Pathway. PLoS One 2015; 10:e0128751. [PMID: 26186594 PMCID: PMC4505964 DOI: 10.1371/journal.pone.0128751] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 05/01/2015] [Indexed: 01/24/2023] Open
Abstract
MicroRNAs are endogenous short chain nucleotide RNAs that regulate gene function by direct binding of target mRNAs. In this study, we investigated the effects of microRNA-206 (miR-206) on the development of gastric cancer. miR-206 was first confirmed to be downregulated in gastric cancer specimens. Conversely, upregulation of c-Met was confirmed in tissue samples of human gastric cancer, with its level inversely correlated with miR-206 expression. Introduction of miR-206 inhibited cellular proliferation by inducing G1 cell cycle arrest, as well as migration and invasion. Moreover, important proliferation and/or migration related molecules such as c-Met, CDK4, p-Rb, p-Akt and p-ERK were confirmed to be downregulated by Western blot analysis. Targeting of c-Met also directly affected AGS cell proliferation, migration and invasion. In vivo, miR-206 expressing tumor cells also displayed growth delay in comparison to unaffected tumor cells. Our results demonstrated that miR-206 suppressed c-Met expression in gastric cancer and could function as a potent tumor suppressor in c-Met overexpressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation and migration, leading to gastric cancer development.
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Affiliation(s)
- Zhiqiang Zheng
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dongsheng Yan
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Xiaoyan Chen
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - He Huang
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ke Chen
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guangjing Li
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Linglin Zhou
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - Dandan Zheng
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
| | - LiLi Tu
- Wenzhou Medical University, Wenzhou, Zhejiang, China
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health of P. R. China, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China
- * E-mail: (XD); (LT)
| | - Xiang Da Dong
- Department of Surgery, Stamford Hospital—Affiliate of Columbia University, Stamford, Connecticut, United States of America
- * E-mail: (XD); (LT)
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Sun K, Tang XH, Xie YK. Paclitaxel combined with harmine inhibits the migration and invasion of gastric cancer cells through downregulation of cyclooxygenase-2 expression. Oncol Lett 2015; 10:1649-1654. [PMID: 26622726 DOI: 10.3892/ol.2015.3425] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 05/20/2015] [Indexed: 01/13/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM. The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression.
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Affiliation(s)
- Kun Sun
- Department of Gastroenterology, The First Hospital of Zibo, Zibo, Shandong 255200, P.R. China
| | - Xiao-He Tang
- Department of Gastroenterology, The First Hospital of Zibo, Zibo, Shandong 255200, P.R. China
| | - Yi-Kui Xie
- Department of Gastroenterology, The First Hospital of Zibo, Zibo, Shandong 255200, P.R. China
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