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Yu Y, Chen Y, Wang L, Cheng J, Du M, Pan S. Rno-miR-130b Attenuates Lipid Accumulation Through Promoting Apoptosis and Inhibiting Differentiation in Rat Intramuscular Adipocytes. Int J Mol Sci 2025; 26:1399. [PMID: 40003868 PMCID: PMC11855280 DOI: 10.3390/ijms26041399] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 02/27/2025] Open
Abstract
Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Ccnd1 tended to decrease, while the BCL2 protein level was significantly decreased at 48 h. In contrast, miR-130b inhibition significantly increased the BCL2 protein level. At 7 d, the miR-130b mimic significantly decreased intracellular TG content and tended to decrease Hsd11b1 mRNA expression while significantly promoting Lpl mRNA expression. Additionally, the miR-130b mimic significantly increased the CASP3 protein level and tended to decrease the BCL2 protein level. In conclusion, our data indicated for the first time that miR-130b could reduce lipid deposition in rat IMAs through different mechanisms: at the early stage of differentiation by inhibiting proliferation and promoting apoptosis and at the late stage by inhibiting adipogenic differentiation, promoting lipid hydrolysis, and promoting apoptosis.
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Affiliation(s)
- Yichen Yu
- Guangling College, Yangzhou University, Yangzhou 225009, China;
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (Y.C.); (L.W.); (J.C.)
| | - Yongfang Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (Y.C.); (L.W.); (J.C.)
| | - Lijun Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (Y.C.); (L.W.); (J.C.)
| | - Ji Cheng
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (Y.C.); (L.W.); (J.C.)
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA 99163, USA;
| | - Shifeng Pan
- Guangling College, Yangzhou University, Yangzhou 225009, China;
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (Y.C.); (L.W.); (J.C.)
- Department of Animal Sciences, Washington State University, Pullman, WA 99163, USA;
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
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Diagnostic Value of Prostate-Specific Antigen Combined with Plasma miRNA-149 Expression in Patients with Prostate Cancer Based on Experimental Data and Bioinformatics. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:6094409. [PMID: 35935308 PMCID: PMC9337946 DOI: 10.1155/2022/6094409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/12/2022] [Accepted: 06/23/2022] [Indexed: 11/17/2022]
Abstract
Purpose The aim of this study is to explore the diagnostic value of prostate-specific antigen (PSA) combined with serum miRNA-149 expression in prostate cancer (PCa) by conducting experiments and bioinformatics analysis. Patients and Methods. 50 PCa patients were enrolled on the experimental group from January 2020 to December 2021. 56 patients with benign prostatic hyperplasia (BPH) were selected as the control group at the same time. Real-time fluorescent quantitative PCR was applied to investigate the miRNA-149 expression. PSA was detected by using a chemiluminescence meter using Abbott i4000. Applying bioinformatics analysis, we explored the expression of hsa-miR-149 in PCa in The Cancer Genome Atlas (TCGA) database. Kaplan–Meier analyses were used to evaluate the prognostic value, and the ROC curve was applied. Results The expression level of miRNA-149 in the PCa group was significantly higher than that in the BPH group (P < 0.05). The PSA level in the PCa group was also significantly higher than that in the BPH group (P < 0.05). TCGA data analysis revealed that PCa tissues had significantly increased hsa-miR-149 expression. The results of survival analysis showed that patients with high expression of hsa-miR-149 had better prognosis. Additionally, the pathological N stage of PCa correlates with the hsa-miR-149 expression level (P = 0.002). According to ROC curve analysis, the region under the curve was 0.653, 95% CI: 0.576–0.730. Conclusion High expression of serum miRNA-149 is associated with PCa patients. Although combined PSA did not improve the diagnostic efficacy, miRNA-149 has high specificity in the diagnosis of PCa. miRNA-149 might be a novel marker for early diagnosis and prognosis assessment for PCa.
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Tian W, Pang X, Luan F. Diagnosis value of miR-181, miR-652, and CA72-4 for gastric cancer. J Clin Lab Anal 2022; 36:e24411. [PMID: 35446997 PMCID: PMC9169223 DOI: 10.1002/jcla.24411] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/01/2022] Open
Abstract
PURPOSE To find a useful disease marker for early diagnosis of gastric cancer, we tried to explore the expression of serum miR-181, miR-652, and carbohydrate antigen 72-4 (CA72-4). PATIENTS AND METHODS According to clinical pathologic stages, 112 patients with gastric cancer were divided into early gastric cancer group (n = 60) and advanced gastric cancer group (n = 52), stage I-II (n = 65), and stage III-IV (n = 47). Another 50 cases of gastric benign lesions and 40 healthy controls were also selected. Real-time quantitative PCR together with chemiluminescence were applied to detect expression levels. ROC curve was applied to judge their diagnostic efficiency. Pearson's correlation analysis was put into use to investigate the relevance of three indicators. RESULTS Compared with benign lesions group and control group, significantly higher expression levels were found in patients of gastric cancer (all p < 0.001). Similarly, compared with early gastric cancer group, significantly higher expression levels were found in advanced gastric cancer group (all p < 0.001). The same result was also found in stage III-IV (all p < 0.001). The best cutoff values were 0.93, 2.38, and 16.94 U/ml, respectively. The area under the curve (0.917, 95%CI: 0.856-0.975) of the three combined diagnosis of early gastric cancer was the largest, and its sensitivity and specificity were 92.5% and 86.8%. And miR-181 and miR-652 were positively correlated with CA72-4 (r = 0.772, p < 0.001, r = 0.853, p < 0.001). CONCLUSION Serum miR-181, miR-652, and CA72-4 are closely linked to the occurrence and development of gastric cancer. Combination of three indicators has diagnostic value for early gastric cancer.
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Affiliation(s)
- Wenyan Tian
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Xueqin Pang
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Fujuan Luan
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
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4
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Mi C, Zhang D, Li Y, Ren M, Ma W, Lu G, He S. miR-4677-3p participates proliferation and metastases of gastric cancer cell via CEMIP-PI3K/AKT signaling pathway. Cell Cycle 2021; 20:1978-1987. [PMID: 34437815 DOI: 10.1080/15384101.2021.1971375] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Gastric cancer is one of the top three leading causes of cancer-related death in the world. Evidence indicated that miR-4677-3p was dysregulated and involved in modulating invasion and migration in multiple types of cancer cells. The aim of this research is to explore the function and mechanism of miR-4677-3p in the development of gastric cancer. In this study, we discovered that miR-4677-3p was down-regulated in gastric cancer tissues and cells. Over-expression of miR-4677-3p suppressed the proliferation, migration and invasion of gastric cancer cells. Furthermore, miR-4677-3p directly bond to CEMIP 3'UTR region and inhibited CEMIP expression. CEMIP promoted cell proliferation, migration and invasion of gastric cancer cells via accelerating PI3K/AKT signaling pathway. siCEMIP or PI3K/AKT signaling inhibitor (Akti-1/2 and LY294002) partly reversed the effects of miR-4677-3p on the cellular growth and metastasis of gastric cancer. In general, miR-4677-3p regulated the development of gastric cancer through CEMIP-PI3K/AKT signaling pathway axis. This study verified the function and molecular mechanism of miR-4677-3p in gastric cancer cells, and may provide a potential diagnosis/prognosis target for patients with gastric cancer.
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Affiliation(s)
- Chen Mi
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Dan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Yarui Li
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Mudan Ren
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Wenhui Ma
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Guifang Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
| | - Shuixiang He
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi 'An City, Shaanxi Province, China
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Chen J, Liu Z, Gao G, Mo Y, Zhou H, Huang W, Wu L, He X, Ding J, Luo C, Long H, Feng J, Sun Y, Guan X. Efficacy of circulating microRNA-130b and blood routine parameters in the early diagnosis of gastric cancer. Oncol Lett 2021; 22:725. [PMID: 34429765 PMCID: PMC8371962 DOI: 10.3892/ol.2021.12986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/16/2021] [Indexed: 12/26/2022] Open
Abstract
Patients with gastric cancer (GC) have a poor prognosis, which is mainly due to the low rate of early diagnosis. The present study aimed to evaluate whether circulating microRNA-130b (miR-130b) and blood routine parameters [neutrophil count (N#), lymphocyte count (L#), monocyte count (M#), neutrophil percentage (N%), lymphocyte percentage (L%), monocyte percentage (M%), hemoglobin (Hb) level, hematocrit (Hct), red blood cell distribution width (RDW), platelet count, platelet distribution width (PDW), mean platelet volume (MPV), MPV to platelet count ratio (MPV/PC), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR)] are useful biomarkers for GC, early stage GC (EGC) and precancerous lesion (Pre) detection, and to identify more effective diagnostic models by combining circulating blood markers. Circulating levels of M#, M%, RDW-coefficient of variation (RDW-CV), MPV, PDW, MLR and NLR were significantly higher, and the levels of Hb and L% were significantly lower in patients with GC and Pre compared with those in healthy controls (NCs) (all P<0.05). The N#, N% and PLR in patients with GC were significantly higher and the Hct was significantly lower than those in the NCs (all P<0.05). The values of MPV/PC were significantly higher in the Pre cohort compared with those in the NCs. The area under the curve (AUC) of the receiver operating characteristic curve of potential biomarkers for GC was 0.634-0.887 individually, and this increased to 0.978 in the combination model of miR-130b-PDW-MLR-Hb. Additionally, the values for RDW-CV, PLR, NLR, N# and N% were positively correlated with cancer stage, while the values for MPV, L#, L%, Hb and Hct were negatively correlated with cancer stage. Furthermore, the circulating levels of miRNA-130b, and the values for NLR, RDW-CV, PDW, M%, red blood cell count, Hct, Hb and MLR differed between the EGC and NC groups. The AUC values of these biomarkers were 0.6491-0.911 individually in the diagnosis of EGC, and these increased to 0.960 in combination. In addition, the AUC values for miR-130b, RDW-CV, MPV/PC ratio, MLR, NLR, PDW, L%, M%, M# and Hb in the diagnosis of Pre were 0.638-0.811 individually. The dual-model of miR-130b-PDW manifested the largest AUC of 0.896 in the diagnosis of Pre, and the sensitivity and accuracy were increased when miR-130b and PDW were combined. All these results suggested that circulating miR-130b and blood routine parameters might be potential biomarkers, and combinations of measurements of these biomarkers may improve the GC, EGC and Pre diagnostic accuracy.
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Affiliation(s)
- Jianlin Chen
- Department of Clinical Laboratory, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Zhaohui Liu
- Department of Anesthesia, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Gan Gao
- Department of Clinical Laboratory, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545001, P.R. China
| | - Yuandong Mo
- Department of General Surgery, People's Hospital Rong'an County, Liuzhou, Guangxi Zhuang Autonomous Region 545400, P.R. China
| | - Hongling Zhou
- Department of Nursing, People's Hospital Rong'an County, Liuzhou, Guangxi Zhuang Autonomous Region 545400, P.R. China
| | - Wenjie Huang
- Department of Clinical Laboratory, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Lihua Wu
- Department of Digestive Internal Medicine, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Xiaoling He
- Department of Clinical Laboratory, People's Hospital Rong'an County, Liuzhou, Guangxi Zhuang Autonomous Region 545400, P.R. China
| | - Junping Ding
- Department of General Surgery, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Changjun Luo
- Department of Internal Medicine-Cardiovascular, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Haihua Long
- Department of Digestive Internal Medicine, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Jingrong Feng
- Department of General Surgery, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Yifan Sun
- Department of Clinical Laboratory, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545007, P.R. China
| | - Xiaoyong Guan
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi University of Science and Technology, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
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Lei Y, Yang M, Li H, Xu R, Liu J. miR‑130b regulates PTEN to activate the PI3K/Akt signaling pathway and attenuate oxidative stress‑induced injury in diabetic encephalopathy. Int J Mol Med 2021; 48:141. [PMID: 34080640 PMCID: PMC8175068 DOI: 10.3892/ijmm.2021.4974] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
Diabetic encephalopathy (DE) is one of the main chronic complications of diabetes, and is characterized by cognitive defects. MicroRNAs (miRNAs/miRs) are widely involved in the development of diabetes-related complications. The present study evaluated the role of miR-130b in DE and investigated its mechanisms of action. PC12 cells and hippocampal cells were exposed to a high glucose environment to induce cell injuries to mimic the in vitro model of DE. Cells were transfected with miR-130b mimic, miR-130b inhibitor and small interfering RNA (si)-phosphatase and tensin homolog (PTEN) to evaluate the protective effect of the miR-130b/PTEN axis against oxidative stress in high glucose-stimulated cells involving Akt activity. Furthermore, the effect of agomir-130b was also assessed on rats with DE. The expression of miR-130b was reduced in the DE models in vivo and in vitro. The administration of miR-130b mimic increased the viability of high glucose-stimulated cells, prevented apoptosis, increased the activity of superoxide dismutase (SOD), decreased the malondialdehyde (MDA) content, activated Akt protein levels and inhibited the mitochondria-mediated apoptotic pathway. The administration of miR-130b inhibitor exerted opposite effects, while si-PTEN reversed the effects of miR-130b inhibitor. In vivo, the administration of agomir-130b attenuated cognitive disorders and neuronal damage, increased SOD activity, reduced the MDA content, activated Akt protein levels and inhibited the mitochondria-mediated apoptosis pathway in rats with DE. On the whole, these results suggest that miR-130b activates the PI3K/Akt signaling pathway to exert protective effects against oxidative stress injury via the regulation of PTEN in rats with DE.
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Affiliation(s)
- Yonghua Lei
- Department of Traditional Chinese Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Ming Yang
- Department of Traditional Chinese Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
| | - Hong Li
- Department of Endocrinology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Rongjuan Xu
- Department of Endocrinology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
| | - Junbao Liu
- Department of Traditional Chinese Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, P.R. China
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Inoue H, Hirasaki M, Kogashiwa Y, Kuba K, Ebihara Y, Nakahira M, Sakai A, Okuda A, Sugasawa M. Predicting the radiosensitivity of HPV-negative oropharyngeal squamous cell carcinoma using miR-130b. Acta Otolaryngol 2021; 141:640-645. [PMID: 33794725 DOI: 10.1080/00016489.2021.1897160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma shows a higher rate of radiation resistance than HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Radioresistant HPV-negative OPSCC is associated with unfavourable outcomes, but validated prognostic biomarkers remain lacking. AIMS/OBJECTIVES This study investigated biomarkers for radioresistant HPV-negative OPSCC. MATERIAL AND METHODS The Cancer Genome Atlas included miRNA sequence and mRNA sequence data from 528 HNSCC tumours. Of these, we used gene expression data for HPV-negative head and neck squamous cell carcinoma for which data were available on the effects of radiation, and compared miRNA sequence and mRNA sequence data between radioresistant and radiosensitive groups. We subsequently estimated downstream miRNA from the results. Finally, we validated miRNAs related to the outcomes of radiotherapy in our clinical cases. RESULTS Investigation of miRNA sequence revealed expression of miR-130b as the greatest difference between radiosensitive and radioresistant groups. We subsequently evaluated miR-130b expression in our clinical OPSCC cases. Values of miR-130b >5.372 (low expression), determined from receiver operating characteristic curve analyses, were associated with significantly longer progression-free survival and overall survival (p = .006, p = .04, respectively). CONCLUSIONS AND SIGNIFICANCE Our results suggest that miR-130b has potential as a biomarker for the radiosensitivity of HPV-negative OPSCC.
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Affiliation(s)
- Hitoshi Inoue
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Masataka Hirasaki
- Department of Clinical Cancer Genomics, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Yasunao Kogashiwa
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Kiyomi Kuba
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Yasuhiro Ebihara
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Mitsuhiko Nakahira
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Akihiro Sakai
- Department Otolaryngology, Tokai University, Kanagawa, Japan
| | - Akihiko Okuda
- Division of Biomedical Sciences, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan
| | - Masashi Sugasawa
- Department of Head and Neck Surgery, Division of Otolaryngology, Saitama Medical University International Medical Center, Hidaka, Japan
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Chu H, Han N, Xu J. CMPK1 Regulated by miR-130b Attenuates Response to 5-FU Treatment in Gastric Cancer. Front Oncol 2021; 11:637470. [PMID: 33816278 PMCID: PMC8013733 DOI: 10.3389/fonc.2021.637470] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) remains a major world-wide challenge, especially in Asian countries. Chemotherapy with 5-fluorouracil (5-FU) and cisplatin is used as the first-line treatment and development of chemoresistance is a major cause of progression. UMP/CMP kinase is responsible for the phosphorylation of the ribonucleotide metabolite 5-fluoro-5′-monophosphate (FUMP) in 5-FU metabolic process, and recognized as a key step in the conversion of 5-FU to cytotoxic metabolites. Our bioinformatics analysis and molecular experiments demonstrated that high expression of CMPK1 was associated with prolonged survival and response to 5-FU treatment in GC samples. Further analysis demonstrated that miR-130b as a key epigenetic regulator of CMPK1, and miR-130b-mediated attenuation of CMPK1 resulted in resistance of gastric cancer cells to DNA damage and cell death after treatment with 5-FU. Rescue experiments with augmented CMPK1 expression abolished the effect of miR-130b demonstrating the key function of this miRNA in this pathway. Thus, this newly identified miR-130b-CMPK1 axis suggests a potentially new chemotherapeutic strategy for improved response to 5-FU therapy.
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Affiliation(s)
- Huaizhu Chu
- Department of Oncological Surgery, Qinghai Provincial People's Hospital, Xining, China
| | - Nahui Han
- Department of Pain Medicine, Qinghai Provincial People's Hospital, Xining, China
| | - Jianguo Xu
- Department of Oncological Surgery, Qinghai Provincial People's Hospital, Xining, China
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Kim Y, Kim H, Bang S, Jee S, Jang K. MicroRNA-130b functions as an oncogene and is a predictive marker of poor prognosis in lung adenocarcinoma. J Transl Med 2021; 101:155-164. [PMID: 32999430 DOI: 10.1038/s41374-020-00496-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is an aggressive disease and the leading cause of cancer-related deaths worldwide. In the past several decades, the incidence of adenocarcinoma has significantly increased, and accounts for ~40% of all lung cancer cases. In the present study, we investigated the clinicopathologic significance of microRNA-130b (miR-130b) in lung adenocarcinoma and analyzed its cancer-specific functions. RNA was extracted from formalin-fixed paraffin-embedded specimens of 146 lung adenocarcinoma cases, and miR-130b expression was analyzed using quantitative real-time polymerase chain reaction. NCI-H1650 cells were transfected with miR-130b mimic and inhibitor to determine its effects on tumor cell proliferation, migration, and invasion. The expression of miR-130b in lung adenocarcinoma tissues was classified into two groups according to the median value. High expression of miR-130b was associated with higher histological grade, advanced pathologic T stage, lymph node metastasis, and lymphovascular invasion. Moreover, survival analysis showed that high miR-130b expression was significantly associated with unfavorable prognosis. In addition, miR-130b upregulation promoted cell migration and invasion, while its downregulation resulted in decreased cell proliferation, migration, and wound healing in in vitro experiments. In conclusion, these findings suggest that miR-130b promotes tumor progression and serves as a biomarker of poor prognosis for patients with lung adenocarcinoma. Hence, targeting miR-130b may serve as a potential therapeutic strategy for lung cancer.
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Affiliation(s)
- Yeseul Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Hyunsung Kim
- Department of Pathology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Seongsik Bang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Seungyun Jee
- Department of Pathology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Republic of Korea.
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10
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Ding L, Li Q, Chakrabarti J, Munoz A, Faure-Kumar E, Ocadiz-Ruiz R, Razumilava N, Zhang G, Hayes MH, Sontz RA, Mendoza ZE, Mahurkar S, Greenson JK, Perez-Perez G, Hanh NTH, Zavros Y, Samuelson LC, Iliopoulos D, Merchant JL. MiR130b from Schlafen4 + MDSCs stimulates epithelial proliferation and correlates with preneoplastic changes prior to gastric cancer. Gut 2020; 69:1750-1761. [PMID: 31980446 PMCID: PMC7377952 DOI: 10.1136/gutjnl-2019-318817] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 12/26/2019] [Accepted: 01/09/2020] [Indexed: 12/26/2022]
Abstract
UNLABELLED The myeloid differentiation factor Schlafen4 (Slfn4) marks a subset of myeloid-derived suppressor cells (MDSCs) in the stomach during Helicobacter-induced spasmolytic polypeptide-expressing metaplasia (SPEM). OBJECTIVE To identify the gene products expressed by Slfn4+-MDSCs and to determine how they promote SPEM. DESIGN We performed transcriptome analyses for both coding genes (mRNA by RNA-Seq) and non-coding genes (microRNAs using NanoString nCounter) using flow-sorted SLFN4+ and SLFN4- cells from Helicobacter-infected mice exhibiting metaplasia at 6 months postinfection. Thioglycollate-elicited myeloid cells from the peritoneum were cultured and treated with IFNα to induce the T cell suppressor phenotype, expression of MIR130b and SLFN4. MIR130b expression in human gastric tissue including gastric cancer and patient sera was determined by qPCR and in situ hybridisation. Knockdown of MiR130b in vivo in Helicobacter-infected mice was performed using Invivofectamine. Organoids from primary gastric cancers were used to generate xenografts. ChIP assay and Western blots were performed to demonstrate NFκb p65 activation by MIR130b. RESULTS MicroRNA analysis identified an increase in MiR130b in gastric SLFN4+ cells. Moreover, MIR130b colocalised with SLFN12L, a human homologue of SLFN4, in gastric cancers. MiR130b was required for the T-cell suppressor phenotype exhibited by the SLFN4+ cells and promoted Helicobacter-induced metaplasia. Treating gastric organoids with the MIR130b mimic induced epithelial cell proliferation and promoted xenograft tumour growth. CONCLUSION Taken together, MiR130b plays an essential role in MDSC function and supports metaplastic transformation.
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Affiliation(s)
- Lin Ding
- Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA,Medicine, University of Arizona, Tucson, Arizona, USA
| | - Qian Li
- Department of Gastroenterology, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Jayati Chakrabarti
- Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Andres Munoz
- Medicine, University of Arizona, Tucson, Arizona, USA
| | | | - Ramon Ocadiz-Ruiz
- Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Nataliya Razumilava
- Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Guiying Zhang
- Department of Gastroenterology, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Michael H Hayes
- Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ricky A Sontz
- Medicine, University of Arizona, Tucson, Arizona, USA
| | | | - Swapna Mahurkar
- Medicine-Digestive Diseases, UCLA, Los Angeles, California, USA
| | | | | | | | - Yana Zavros
- Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Linda C Samuelson
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Juanita L Merchant
- Internal Medicine-Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA .,Medicine, University of Arizona, Tucson, Arizona, USA.,Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
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11
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Faridi A, Afgar A, Mousavi SM, Nasibi S, Mohammadi MA, Farajli Abbasi M, Fasihi Harandi M. Intestinal Expression of miR-130b, miR-410b, and miR-98a in Experimental Canine Echinococcosis by Stem-Loop RT-qPCR. Front Vet Sci 2020; 7:507. [PMID: 33005638 PMCID: PMC7480022 DOI: 10.3389/fvets.2020.00507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/03/2020] [Indexed: 12/19/2022] Open
Abstract
Echinococcus granulosus is a zoonotic cestode dwelling in the small intestine of canid definitive hosts. Intermediate hosts are a wide range of domestic and wild ungulates. Human infection with the larval stage causes cystic echinococcosis. Understanding the nature and extent of molecular mechanisms involved in host–parasite interactions helps to answer some very basic questions in the biology of cestode parasites with significant implications in the management and control of cystic echinococcosis. Little is known on the miRNAs expression in the intestinal tissues of dogs infected with E. granulosus. In the present study, expression of a selected profile of miRNAs was evaluated in experimental canine echinococcosis. MiRNAs were extracted from 20 different parts of small intestinal tract of two sibling 3-months-old mix-breed dogs. Complementary DNA was specifically synthesized using an optimized stem-loop system. Intestinal expression of four miRNAs (cfa-let7g, cfa-miR-98, cfamiR-410, cfa-miR-130b) was evaluated using RT-qPCR. The results of the study indicate a significant difference between test and control dogs in cfamiR-130b, cfa-miR-98, and cfa-miR-410 (P ≤ 0.05); however, there was no significant difference for cfa-let7g. The most upregulated miRNAs were cfamiR-130b and cfa-miR-98. An increasing trend for cfa-let7g and a declining trend for cfa-miR-98, cfa-miR-410, and cfamiR-130b were found toward the distal segments of the small intestine. Our study revealed that cfa-miR-98, cfa-miR-410, and cfamiR-130b are involved in the definitive host response in canine echinococcosis. The study provides new information on the molecular basis of interactions between E. granulosus and dogs in terms of miRNA expression and showed that E. granulosus infection could increase the expression of some pro-inflammatory miRNAs at the cellular level in the definitive host.
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Affiliation(s)
- Ashkan Faridi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.,Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Afgar
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Seyed Mohammad Mousavi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Saeid Nasibi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Ali Mohammadi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Farajli Abbasi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
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12
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M2 macrophage-derived extracellular vesicles promote gastric cancer progression via a microRNA-130b-3p/MLL3/GRHL2 signaling cascade. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:134. [PMID: 32660626 PMCID: PMC7359233 DOI: 10.1186/s13046-020-01626-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/21/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND Transfer of noncoding microRNAs (miRNAs) by extracellular vesicles (EVs) promotes the development of chemoresistance in many tumor types. Additionally, restoration or depletion of several miRNAs has been observed in multiple cancer types including gastric cancer (GC). In this present study, we aimed to investigate the mechanism of miR-130b-3p in M2 macrophage-derived EVs in the development of GC through regulation of mixed lineage leukemia 3 (MLL3) and grainyhead-like 2 (GRHL2). METHODS Expression of miR-130b-3p and GRHL2 was quantified in 63 pairs of cancerous and noncancerous gastric tissues. The predicted binding between miR-130b-3p and MLL3, together with the enrichment of MLL3, H3K4me1, and H3K27ac in gene enhancer region, was verified by luciferase activity assay and chromatin immunoprecipitation. Effects of miR-130b-3p on GC cell proliferation, apoptosis, migration and invasion, as well as tube formation of human umbilical endothelial vein cells (HUEVCs) were further determined by gain- and loss-of function assays in vitro. RESULTS miR-130b-3p was upregulated in GC tissues, and miR-130b-3p promoted survival, metastasis and angiogenesis of GC cells as well as enhanced tumor formation and angiogenesis in GC in vivo. Additionally, miR-130b-3p delivered in M2 macrophage-derived EVs promoted survival, migration, invasion, and angiogenesis of GC cells. Notably, MLL3 inhibited GC cell proliferation, migration, invasion, and vessel-like tube formation of HUEVCs by increasing GRHL2. Furthermore, downregulation of miR-130b-3p in M2 macrophage-derived EVs or upregulation of GRHL2 inhibited tumor formation and angiogenesis in GC. CONCLUSION This study highlights that EVs loaded with the specific miRNA cargo miR-130b-3p mediate communication between M2 macrophages and cancer cells in the tumor microenvironment through the modulation of MLL3 and GRHL2 in GC.
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13
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Peng Z, Duan F, Yin J, Feng Y, Yang Z, Shang J. Prognostic values of microRNA-130 family expression in patients with cancer: a meta-analysis and database test. J Transl Med 2019; 17:347. [PMID: 31640738 PMCID: PMC6805372 DOI: 10.1186/s12967-019-2093-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/11/2019] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND Emerging evidence shows that microRNA-130 (miRNA-130) family may be useful as prognostic biomarkers in cancer. However, there is no confirmation in an independent validation study. The aim of this study was to summarize the prognostic value of miRNA-130 family (miRNA-130a and miRNA-130b) for survival in patients with cancer. METHODS The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the association strength between miRNA-130 family expression and prognosis. Kaplan-Meier plotters were used to verify the miRNA-130b expression and overall survival (OS). RESULTS A total of 2141 patients with OS and 1159 patients with disease-free survival (DFS)/progression-free survival (PFS) were analyzed in evidence synthesis. For the miRNA-130a, the overall pooled effect size (HR) was HR 1.58 (95% CI: 1.21-2.06, P < 0.001). Tissue and serum expression of miRNA-130a was significantly associated with the OS (HR = 1.54, 95% CI: 1.11-2.14, P = 0.009; HR = 1.65, 95% CI: 1.14-2.38, P = 0.008), and in gastric cancer (HR = 1.81, 95% CI: 1.34-2.45, P < 0.001). For the miRNA-13b, a statistical correlation was observed between high miRNA-130b expression and poor OS in patients with cancer (HR = 1.95, 95% CI: 1.47-2.59, P < 0.001), especially in tissue sample (HR = 2.01, 95% CI: 1.39-2.91, P < 0.001), Asian (HR = 2.55, 95% Cl: 1.77-3.69, P < 0.001) and hepatocellular carcinoma (HR = 1.87, 95% CI: 1.23-2.85, P = 0.004). The expression of miRNA-130b was significantly correlated with DFS/PFS (HR = 1.53, 95% CI: 1.31-1.77, P < 0.001), in tissue (HR = 1.98, 95% CI: 1.50-2.62, P < 0.001) and serum (HR = 1.37, 95% CI: 1.15-1.64, P < 0.001), especially in HCC (HR = 1.98, 95% CI: 1.50, 2.62, P < 0.001). In database test, a significant correlation between high miRNA-130b expression and poor OS for HCC patients was observed (HR = 1.55, 95% CI: 1.01, 2.35, P = 0.0045). CONCLUSION The high expression of miRNA-130 family might predict poor prognosis in cancer patients. Prospectively, combining miRNA-130a and miRNA-130b may be considered as powerful prognostic predictor for clinical application.
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Affiliation(s)
- Zhen Peng
- Department of Infectious Disease, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.
| | - Fujiao Duan
- Medical Research Office, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
| | - Jingjing Yin
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yajing Feng
- Department of Nosocomial Infection Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhongyu Yang
- College of Art and Science, The Ohio State University, Columbus, OH, USA
| | - Jia Shang
- Department of Infectious Disease, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
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14
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Wang J, Yu XF, OUYang N, Luo Q, Tong J, Chen T, Li J. Role of DNA methylation regulation of miR-130b expression in human lung cancer using bioinformatics analysis. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2019; 82:935-943. [PMID: 31524549 DOI: 10.1080/15287394.2019.1667634] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
MicroRNAs (miRNAs) are involved in various crucial biological processes including regulation of cell differentiation, proliferation, and migration, and are closely associated with tumor development. This study aimed to investigate miR-130b expression levels in lung cancer patient tissues. Two Gene Expression Omnibus (GEO) databases, including GSE48414 and GSE74190, and two The Cancer Genome Atlas (TCGA) databases including TCGA LUAD and TCGA LUSC, were accessed to obtain information for differential expression analysis and clinical-pathological correlation analysis. The results showed that miR-130b expression levels were significantly increased in lung cancer compared to normal tissues. Data also demonstrated that confounding factors such as tumor clinical stages and tumor invasion depth markedly affected miR-130b expression levels in cancer patients. A total of 169 target genes modified by miR-130b expression were identified by using 4 online websites for target gene prediction. Further enrichment analysis indicated that these 169 target genes were significantly enriched in several cancer-related biological processes and signaling pathways, including wound healing, cell proliferation, Wnt signaling, Ras signaling, and mTOR signaling. It was also of interest to examine the seven sites on the promoter region of miR-130b encoding gene in lung cancer patients and then compare methylation at these loci with miR-130b expression. The correlation analysis between encoding gene methylation and miR-130b expression in TCGA datasets revealed that decreased methylation in the promoter region was significantly associated with elevated miR-130b expression. This phenomenon was markedly dependent upon smoking history and clinical-pathological features. In conclusion, data indicated alterations in the methylation of DNA promoter region of miR-130b encoding gene were associated with disturbances in miR-130b expression in lung cancer patients suggesting that the DNA methylation process and miR-130b expression may serve as biomarkers for detection of lung cancer.
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Affiliation(s)
- Jin Wang
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
| | - Xiao-Fan Yu
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
| | - Nan OUYang
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
| | - Qiulin Luo
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
| | - Jian Tong
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
| | - Tao Chen
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
| | - Jianxiang Li
- Department of Toxicology, School of Public Health, Medical College of Soochow University , Suzhou , China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases , Suzhou , Jiangsu , China
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15
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Affandi AJ, Carvalheiro T, Ottria A, Broen JC, Bossini-Castillo L, Tieland RG, Bon LV, Chouri E, Rossato M, Mertens JS, Garcia S, Pandit A, de Kroon LM, Christmann RB, Martin J, van Roon JA, Radstake TR, Marut W. Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis. Ann Rheum Dis 2019; 78:1249-1259. [PMID: 31126957 DOI: 10.1136/annrheumdis-2018-214991] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/15/2019] [Accepted: 04/22/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology. METHODS In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre:Runx3f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model. RESULTS Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis. CONCLUSIONS We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease.
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Affiliation(s)
- Alsya J Affandi
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Tiago Carvalheiro
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Andrea Ottria
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Jasper Ca Broen
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Lara Bossini-Castillo
- Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
- Department of Cellular Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
| | - Ralph G Tieland
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Lenny van Bon
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Eleni Chouri
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Marzia Rossato
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Biotechnology, University of Verona, Verona, Italy
| | - Jorre S Mertens
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Samuel Garcia
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Aridaman Pandit
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Laurie Mg de Kroon
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Romy B Christmann
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Javier Martin
- Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
| | - Joel Ag van Roon
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Timothy Rdj Radstake
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Rheumatology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Wioleta Marut
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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16
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Hashimoto Y, Shiina M, Dasgupta P, Kulkarni P, Kato T, Wong RK, Tanaka Y, Shahryari V, Maekawa S, Yamamura S, Saini S, Deng G, Tabatabai ZL, Majid S, Dahiya R. Upregulation of miR-130b Contributes to Risk of Poor Prognosis and Racial Disparity in African-American Prostate Cancer. Cancer Prev Res (Phila) 2019; 12:585-598. [PMID: 31266828 DOI: 10.1158/1940-6207.capr-18-0509] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 05/23/2019] [Accepted: 06/24/2019] [Indexed: 12/18/2022]
Abstract
Prostate cancer incidence and mortality rates are higher in African-American (AA) than in European-American (EA) men. The main objective of this study was to elucidate the role of miR-130b as a contributor to prostate cancer health disparity in AA patients. We also determined whether miR-130b is a prognostic biomarker and a new therapeutic candidate for AA prostate cancer. A comprehensive approach of using cell lines, tissue samples, and the TCGA database was employed. We performed a series of functional assays such as cell proliferation, migration, invasion, RT2-PCR array, qRT-PCR, cell cycle, luciferase reporter, immunoblot, and IHC. Various statistical approaches such as Kaplan-Meier, uni-, and multivariate analyses were utilized to determine the clinical significance of miR-130b. Our results showed that elevated levels of miR-130b correlated with race disparity and PSA levels/failure and acted as an independent prognostic biomarker for AA patients. Two tumor suppressor genes, CDKN1B and FHIT, were validated as direct functional targets of miR-130b. We also found race-specific cell-cycle pathway activation in AA patients with prostate cancer. Functionally, miR-130b inhibition reduced cell proliferation, colony formation, migration/invasion, and induced cell-cycle arrest. Inhibition of miR-130b modulated critical prostate cancer-related biological pathways in AA compared with EA prostate cancer patients. In conclusion, attenuation of miR-130b expression has tumor suppressor effects in AA prostate cancer. miR-130b is a significant contributor to prostate cancer racial disparity as its overexpression is a risk factor for poor prognosis in AA patients with prostate cancer. Thus, regulation of miR-130b may provide a novel therapeutic approach for the management of prostate cancer in AA patients.
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Affiliation(s)
- Yutaka Hashimoto
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Marisa Shiina
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Pritha Dasgupta
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Priyanka Kulkarni
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Taku Kato
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Ryan K Wong
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Yuichiro Tanaka
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Varahram Shahryari
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Shigekatsu Maekawa
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Soichiro Yamamura
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Sharanjot Saini
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Guoren Deng
- Department of Urology, San Francisco VA Medical Center, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Z Laura Tabatabai
- Department of Pathology, San Francisco VA Medical Center, California.,University of California San Francisco, San Francisco, California
| | - Shahana Majid
- Department of Urology, San Francisco VA Medical Center, San Francisco, California. .,University of California San Francisco, San Francisco, California
| | - Rajvir Dahiya
- Department of Urology, San Francisco VA Medical Center, San Francisco, California. .,University of California San Francisco, San Francisco, California
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17
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An X, Ge J, Guo H, Mi H, Zhou J, Liu Y, Weiyue, Wu Z. Retracted
: Overexpression of miR‐4286 is an unfavorable prognostic marker in individuals with non–small cell lung cancer. J Cell Biochem 2019; 120:17573-17583. [PMID: 31111550 DOI: 10.1002/jcb.29024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 04/20/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Xian An
- Health Care Unit Jining No.1 People's Hospital Jining China
| | - Jiwen Ge
- Department of Respiratory Medicine Affiliated Hospital of Jining Medical College Jining China
| | - Huihui Guo
- Department of Respiratory Medicine Jining No.1 People's Hospital Jining China
| | - Huaixue Mi
- Department of Cardiac Surgery Jining No.1 People's Hospital Jining China
| | - Jinhua Zhou
- Department of Respiratory Medicine Jining No.1 People's Hospital Jining China
| | - Yongrui Liu
- Department of Respiratory Medicine Jining No.1 People's Hospital Jining China
| | - Weiyue
- Department of Respiratory Medicine Jining No.1 People's Hospital Jining China
| | - Zhilian Wu
- Health Care Unit Jining No.1 People's Hospital Jining China
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18
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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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Zhu Y, Ma Y, Peng H, Gong L, Xiao M, Xiang L, He D, Cao K. MiR-130b promotes the progression of oesophageal squamous cell carcinoma by targeting SASH1. J Cell Mol Med 2018; 23:93-103. [PMID: 30443973 PMCID: PMC6307769 DOI: 10.1111/jcmm.13887] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/06/2018] [Accepted: 08/07/2018] [Indexed: 12/19/2022] Open
Abstract
MiR‐130b and SAM and SH3 domain containing 1 (SASH1) play an important role in many types of human cancers. The aim of our research was to study their interactions in the process of the proliferation and aggressiveness of oesophageal squamous cell carcinoma (ESCC) cells. Microarray analysis was done to screen the differentially expressed genes in the ESCC tissues. miR‐130b and SASH1 mRNA levels in the ESCC tissues and cells were detected by qRT‐PCR. Dual luciferase reporter system was used to verify the target relationship between miR‐130b and SASH1. The effects of miR‐130b on SASH1 expression were explored by western blot in KYSE30 and TE1 cell lines. CCK‐8 assay, flow cytometry, Transwell, and wound healing assays were conducted to explore the effects of miR‐130b and SASH1 in vitro. In addition, in vivo experiments were conducted to study the roles of miR‐130b and SASH1. miR‐130b was highly expressed, while SASH1 was the opposite in both the ESCC tissues and cells. The expression of SASH1 was inhibited by the direct binding of miR‐130b. The inhibition of miR‐130b reduced the proliferation and aggressiveness of ESCC cells, while it also induced apoptosis and cell cycle arrest in the ESCC cells by suppressing SASH1. The in vivo assay suggested that the overexpression of miR‐130b promoted the growth of ESCC tumours. MiR‐130b was up‐regulated in the ESCC tumour tissues and cells, acting as a tumour promoter. A stimulating effect was demonstrated on ESCC cell growth and aggressiveness by suppressing SASH1, which is an anti‐oncogene.
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Affiliation(s)
- Yuxing Zhu
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yanni Ma
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Honghua Peng
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Lian Gong
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Mengqin Xiao
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Liang Xiang
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Dong He
- Department of Respiration, The Second People's Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ke Cao
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
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Yan R, Li K, Yuan DW, Wang HN, Zhang Y, Dang CX, Zhu K. Downregulation of microRNA-4295 enhances cisplatin-induced gastric cancer cell apoptosis through the EGFR/PI3K/Akt signaling pathway by targeting LRIG1. Int J Oncol 2018; 53:2566-2578. [PMID: 30320337 PMCID: PMC6203147 DOI: 10.3892/ijo.2018.4595] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-associated mortality worldwide. The aim of the present study was to investigate the mechanism of microRNA-4295 (miR-4295), which regulates cisplatin (DDP)-induced apoptosis in GC cells through the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1)-mediated epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Two cell lines were selected, one with the highest expression of miR-4295 and one with the lowest expression of LRIG1, for the experiments. The half maximal inhibitory concentration of DDP in the human GC MKN-28 and MKN-45 cell lines was calculated, and mitochondrial membrane potentials of the GC cells were detected by tetramethylrhodamine, ethyl ester, perchlorate staining. The proliferation and apoptosis of GC cells with or without DDP treatment were assessed by MTT assay and plate colony formation, as well as flow cytometry and TUNEL staining. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were employed to determine the expression of EGFR/PI3K/Akt signaling pathway-related genes and apoptosis-related genes. LRIG1 was identified as a target gene of miR-4295. The expression of miR-4295 was upregulated, and the expression of LRIG1 was downregulated in GC cells. Furthermore, DDP enhanced the decrease in miR-4295 expression and the increase in LRIG1 expression in GC cells. miR-4295 promoted the proliferation and inhibited the DDP-induced apoptosis of GC cells without DDP treatment. In addition, miR-4295 increased the expression levels of EGFR, PI3K, Akt, p-PI3K and p-Akt, suggesting that miR-4295 promotes the activation of the EGFR/PI3K/Akt signaling pathway by targeting LRIG1. miR-4295 targeted and negatively regulated LRIG1 expression to activate the EGFR/PI3K/Akt signaling pathway, thereby promoting the proliferation of the GC cells and inhibiting the apoptosis of the GC cells induced by DDP. Therefore, miR-4295 may be a novel therapeutic target in patients with GC.
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Affiliation(s)
- Rong Yan
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kang Li
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Da-Wei Yuan
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Hao-Nan Wang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yong Zhang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Cheng-Xue Dang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kun Zhu
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Li CW, Jheng BR, Chen BS. Investigating genetic-and-epigenetic networks, and the cellular mechanisms occurring in Epstein-Barr virus-infected human B lymphocytes via big data mining and genome-wide two-sided NGS data identification. PLoS One 2018; 13:e0202537. [PMID: 30133498 PMCID: PMC6105016 DOI: 10.1371/journal.pone.0202537] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 08/03/2018] [Indexed: 12/17/2022] Open
Abstract
Epstein-Barr virus (EBV), also known as human herpesvirus 4, is prevalent in all human populations. EBV mainly infects human B lymphocytes and epithelial cells, and is therefore associated with their various malignancies. To unravel the cellular mechanisms during the infection, we constructed interspecies networks to investigate the molecular cross-talk mechanisms between human B cells and EBV at the first (0-24 hours) and second (8-72 hours) stages of EBV infection. We first constructed a candidate genome-wide interspecies genetic-and-epigenetic network (the candidate GIGEN) by big database mining. We then pruned false positives in the candidate GIGEN to obtain the real GIGENs at the first and second infection stages in the lytic phase by their corresponding next-generation sequencing data through dynamic interaction models, the system identification approach, and the system order detection method. The real GIGENs are very complex and comprise protein-protein interaction networks, gene/microRNA (miRNA)/long non-coding RNA regulation networks, and host-virus cross-talk networks. To understand the molecular cross-talk mechanisms underlying EBV infection, we extracted the core GIGENs including host-virus core networks and host-virus core pathways from the real GIGENs using the principal network projection method. According to the results, we found that the activities of epigenetics-associated human proteins or genes were initially inhibited by viral proteins and miRNAs, and human immune responses were then dysregulated by epigenetic modification. We suggested that EBV exploits viral proteins and miRNAs, such as EBNA1, BPLF1, BALF3, BVRF1 and miR-BART14, to develop its defensive mechanism to defeat multiple immune attacks by the human immune system, promotes virion production, and facilitates the transportation of viral particles by activating the human genes NRP1 and CLIC5. Ultimately, we propose a therapeutic intervention comprising thymoquinone, valpromide, and zebularine to act as inhibitors of EBV-associated malignancies.
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Affiliation(s)
- Cheng-Wei Li
- Laboratory of Control and Systems Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Bo-Ren Jheng
- Laboratory of Control and Systems Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Bor-Sen Chen
- Laboratory of Control and Systems Biology, National Tsing Hua University, Hsinchu, Taiwan
- * E-mail:
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Hu XY, Li L, Wu HT, Liu Y, Wang BD, Tang Y. Serum miR-130b level, an ideal marker for monitoring the recurrence and prognosis of primary hepatocellular carcinoma after radiofrequency ablation treatment. Pathol Res Pract 2018; 214:1655-1660. [PMID: 30153957 DOI: 10.1016/j.prp.2018.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 07/29/2018] [Accepted: 08/06/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE This study was aimed to explore the potential roles of miR-130b for the efficacy of radiofrequency ablation (RFA) in patients with primary hepatocellular carcinoma (PHC). METHODS The serum sample of 110 PHC patients, which underwent RFA treatment, was collected on 1d pre-operation (Pre 1), 7d (POD 7) and 14d post-operation (POD 14). qRT-PCR was used to detect miR-130b expression. The relationship between miR-130b expression and clinicopathological features, postoperative recurrence and survival rate were analyzed. RESULTS The liver function of PHC patients was improved after RFA treatment. The level of alpha fetoprotein (AFP) was gradually reduced on POD 7 and POD 14 (all P < 0.05). Before RFA, the expression of miR-130b in PHC patients was upregulated, while the expression of miR-130b decreased significantly with time after RFA treatment. And high expression of miR-130b was closely related to cirrhosis (P = 0.027) and tumor differentiation degree (P < 0.01). Serum miR-130b levels were significantly higher in patients with recurrence than in patients without recurrence (P < 0.05). Patients were divided into two groups according to miR-130b expression level (median ΔCt), compared with low ΔCt group, the incidence of recurrence in high ΔCt group was significantly higher after RFA (P = 0.020). Kaplan-Meier survival analysis showed that the survival rate of high ΔCt group was significantly shorter than that of low ΔCt group (P < 0.001). CONCLUSION Our study provided evidence that serum miR-130b level may be used as an ideal marker for monitoring the recurrence and prognosis of PHC after RFA treatment.
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Affiliation(s)
- Xiang-Yu Hu
- Department of Ultrasound, Tianjin First Center Hospital, 300300, Tianjin, China
| | - Li Li
- Department of Ultrasound, Tianjin First Center Hospital, 300300, Tianjin, China
| | - Hong-Tao Wu
- Department of Ultrasound, Tianjin First Center Hospital, 300300, Tianjin, China
| | - Ying Liu
- Department of Ultrasound, Tianjin First Center Hospital, 300300, Tianjin, China
| | - Bei-Da Wang
- Department of Ultrasound, Tianjin Dongli Hospital, 300192, Tianjin, China
| | - Ying Tang
- Department of Ultrasound, Tianjin First Center Hospital, 300300, Tianjin, China.
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RUNX3 inhibits glioma survival and invasion via suppression of the β-catenin/TCF-4 signaling pathway. J Neurooncol 2018; 140:15-26. [PMID: 29916101 DOI: 10.1007/s11060-018-2927-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 06/09/2018] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Runt-related transcription factor 3 (RUNX3) exerts a tumor suppressor gene associated with gastric and other cancers, including glioma. However, how its anti-tumor mechanism in functions glioma is unclear. METHODS We assayed expression of RUNX3 with a tissue microarray (TMA), frozen cancer tissues and malignant glioma cell lines using immunohistochemistry, qRT-PCR and Western bolt analysis. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm the effect of RUNX3 medicated malignant phenotype. TOP/FOP experiment was used to detect the β-catenin/Tcf-4 transcription activity by RUNX3. RESULTS Enforced RUNX3 expression inhibited proliferation and invasion, induced cell cycle arrest and promoted apoptosis in vitro and in vivo, Bim siRNA partically reversed the effect of RUNX3-induced apoptosis in LN229 and U87 cells, suggesting a dependent role of Bim-caspase pathway. Moreover, Mechanism investigations revealed that restoration of RUNX3 suppressed β-catenin/Tcf-4 transcription activity. CONCLUSIONS RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.
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Li Z, Fan P, Deng M, Zeng C. The roles of RUNX3 in cervical cancer cells in vitro. Oncol Lett 2018; 15:8729-8734. [PMID: 29805611 DOI: 10.3892/ol.2018.8419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 03/21/2018] [Indexed: 01/28/2023] Open
Abstract
RUNX3 serves an important role in development of various types of human cancer. The purpose of the present study was to investigate the potential biological function of RUNX3 in cervical cancer cells. In the present study, a RUNX3 overexpressed model was constructed in Hce1 cells by PCDNA3.1-RUNX3 transfection. Western blot analysis was used to measure RUNX3 expression in cervical cancer cells. Immunofluorescence analysis was performed to examine subcellular localization of RUNX3 in cervical cancer cells. Effects of RUNX3 expression on proliferation, migration and invasion of cervical cancer cells were detected by colony formation assay, wound healing assay and Transwell assay, respectively. Immunofluorescence confirmed the nuclear location of RUNX3 in cervical cancer cell. Result sindicated that upregulation of RUNX3 expression inhibited proliferation, migration and invasion of cervical cancer cells. However, knockdown of RUNX3 expression promoted the proliferation, migration and invasion of cervical cancer cells. Hence, RUNX3 may serve as a tumor suppressor gene in cervical cancer.
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Affiliation(s)
- Zhen Li
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Pan Fan
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Min Deng
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China
| | - Chao Zeng
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Chen H, Yang Y, Wang J, Shen D, Zhao J, Yu Q. miR-130b-5p promotes proliferation, migration and invasion of gastric cancer cells via targeting RASAL1. Oncol Lett 2018; 15:6361-6367. [PMID: 29731849 PMCID: PMC5921226 DOI: 10.3892/ol.2018.8174] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 12/22/2017] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to investigate the targeted interaction between microRNA (miR)-130b-5p and RAS protein activator like 1 (RASAL1) gene and elucidate the function of miR-130b-5p in cell proliferation, migration and invasion in gastric cancer. Expression of miR-130b-5p and RASAL1 in seven gastric cell lines was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). MGC803 cells were selected for further study since they exhibited a marked increase in expression of miR-130b-5p accompanied by decreased expression of RASAL1. MGC803 cells were transfected with miR-130b-5p mimics and miR-130b-5p inhibitor using Lipofectamine 2000 for over- and underexpression, respectively, with cells transfected with negative control (NC) sequence as the control. In addition, a luciferase reporter gene assay was performed to evaluate the targeted interaction between miR-130b-5p and RASAL1. Then, alterations in RASAL1 expression were detected by RT-qPCR and western blot analysis following transfection with miR-130b-5p mimics and miR-130b-5p inhibitor. Cell proliferation, colony formation, and migration and invasion ability were detected by MTT, colony formation and Transwell assays, respectively. RASAL1 was demonstrated to be a target gene of miR-130b-5p by luciferase reporter gene assay. In addition, the expression of RASAL1 was significantly lower in MGC803 cells that were transfected with miR-130b-5p mimics and significantly higher in cells transfected with miR-130b-5p inhibitor in comparison with cells transfected with NC (P<0.05). Furthermore, the experimental group transfected with miR-130b-5p mimics manifested significantly higher cell proliferation, increased colony formation and increased migratory and invasive capacities (P<0.05). By contrast, cells transfected with miR-130b-5p inhibitor exhibited significantly lower cell proliferation, decreased colony formation and decreased migratory and invasive capacities, compared with cells transfected with NC (P<0.05). In conclusion, RASAL1 was demonstrated to be a target gene of miR-130b-5p. Overexpression of miR-130b-5p results in promoted proliferation, colony formation and migration and invasion abilities through targeted modulation of RASAL1.
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Affiliation(s)
- Hong Chen
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Yiqiong Yang
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Jing Wang
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Duo Shen
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Jiyi Zhao
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Qian Yu
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210000, P.R. China
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Zhang L, Zhang Y, Wong SH, Law PTY, Zhao S, Yu J, Chan MTV, Wu WKK. Common Deregulation of Seven Biological Processes by MicroRNAs in Gastrointestinal Cancers. Sci Rep 2018; 8:3287. [PMID: 29459716 PMCID: PMC5818544 DOI: 10.1038/s41598-018-21573-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 02/07/2018] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs are frequently dysregulated in human neoplasms, including gastrointestinal cancers. Nevertheless, the global influence of microRNA dysregulation on cellular signaling is still unknown. Here we sought to elucidate cellular signaling dysregulation by microRNAs in gastrointestinal cancers at the systems biology level followed by experimental validation. Signature dysregulated microRNAs in gastric, colorectal and liver cancers were defined based on our previous studies. Targets of signature dysregulated miRNAs were predicted using multiple computer algorithms followed by gene enrichment analysis to identify biological processes perturbed by dysregulated microRNAs. Effects of microRNAs on endocytosis were measured by epidermal growth factor (EGF) internalization assay. Our analysis revealed that, aside from well-established cancer-related signaling pathways, several novel pathways, including axon guidance, neurotrophin/nerve growth factor signaling, and endocytosis, were found to be involved in the pathogenesis of gastrointestinal cancers. The regulation of EGF receptor (EGFR) endocytosis by two predicted miRNAs, namely miR-17 and miR-145, was confirmed experimentally. Functionally, miR-145, which blocked EGFR endocytosis, prolonged EGFR membrane signaling and altered responsiveness of colon cancer cells to EGFR-targeting drugs. In conclusion, our analysis depicts a comprehensive picture of cellular signaling dysregulation, including endocytosis, by microRNAs in gastrointestinal cancers.
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Affiliation(s)
- Lin Zhang
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Yuchen Zhang
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Sunny H Wong
- Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Priscilla T Y Law
- Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Shan Zhao
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China. .,Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
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Gu JJ, Fan KC, Zhang JH, Chen HJ, Wang SS. Suppression of microRNA-130b inhibits glioma cell proliferation and invasion, and induces apoptosis by PTEN/AKT signaling. Int J Mol Med 2017; 41:284-292. [PMID: 29115407 PMCID: PMC5746316 DOI: 10.3892/ijmm.2017.3233] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Accepted: 10/24/2017] [Indexed: 12/29/2022] Open
Abstract
Glioblastoma is the most common malignant brain tumor in adults and is characterized by extensive proliferation and the diffused invasion of tumor cells. Due to the intricate signaling pathways involved in glioma progression, more effective targeted therapies and prognostic biomarkers in clinical practice are required. The suppression of proto-oncogene function or recovery of tumor suppressor gene function remains one of the primary approaches in gene therapy. The close association between the abnormal expression or mutation of microRNA (miRNA) and the tumorigenesis, progression and staging in glioma have been demonstrated previously. However, the expression pattern and specific role of microRNA‑130b (miR‑130b) in the tumor occurrence and progression of glioma are unclear. In the present study, quantitative polymerase chain reaction was performed to determine the expression level of miR-130b in 30 brain glioma patients and 3 glioma cell lines. An miR‑130b inhibitor was transfected into U87 cells to downregulate the expression of miR-130b, and assessments of cell proliferation, cell cycle, apoptosis, cell invasion and migration in vitro and nude mouse tumorigenicity in vivo were conducted. Western blotting and luciferase reporter gene technology were used to verify the downstream target gene of miR-130b, namely phosphatase and tensin homolog (PTEN). The results demonstrated that miR-130b expression was increased in glioma tissues and cell lines in comparison with non-glioma tissues or cells. The downregulated expression of miR-130b inhibited the proliferation and invasion of glioma cells, induced apoptosis of the cells in vitro and inhibited their tumorigenicity in vivo. Western blotting and luciferase reporter assays demonstrated that the PTEN gene is a direct target of miR‑130b. Western blotting revealed that the miR-130b inhibitor upregulated the expression of PTEN, inhibited AKT pathway activation, upregulated the tumor suppressor gene p27, and suppressed cyclin D1, matrix metalloproteinase 2 and 9 expression. These results suggest that the miR-130b inhibitor suppressed glioma cell proliferation and invasion via the PTEN/AKT pathway. Therefore, miR‑130b is suggested to be an effective therapeutic target for glioma.
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Affiliation(s)
- Jian-Jun Gu
- Stroke Center, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450000, P.R. China
| | - Kai-Chun Fan
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jian-He Zhang
- Department of Neurosurgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, P.R. China
| | - Hong-Jie Chen
- Department of Neurosurgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, P.R. China
| | - Shou-Sen Wang
- Department of Neurosurgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, P.R. China
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Yang H, Fu J, Yao L, Hou A, Xue X. Runx3 is a key modulator during the epithelial-mesenchymal transition of alveolar type II cells in animal models of BPD. Int J Mol Med 2017; 40:1466-1476. [PMID: 28949375 PMCID: PMC5627869 DOI: 10.3892/ijmm.2017.3135] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 08/31/2017] [Indexed: 01/01/2023] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a major challenge for premature infants; however, the underlying mechanisms remain unclear. We previously reported that epithelial-mesenchymal transition (EMT) in alveolar type II (AT2) epithelial cells influences the normal alveolar development process. In this study, we wished to examine whether Runx3 is an important factor for BPD by regulating EMT in AT2 cells. In vivo, animal models of BPD were established by placing newborn rats in hyperoxia tanks. Lung tissue and isolated AT2 cells were collected on different days following exposure to oxygen. The pathological changes in lung tissue, alveolar development and Runx3 expression were then investigated. In vitro, RLE-6TN cells were divided into 5 groups as follows: the cont-rol, Runx3, siRunx3, transforming growth factor-β1 (TGF-β1) and Runx3 + TGF-β1 groups, and the biomarkers of EMT were investigated. In the newborn rat model of BPD, Runx3 protein and mRNA levels in both lung tissue and BPD-derived AT2 cells were significantly lower than those in the control group. The correlation between Runx3 protein expression and pulmonary development indicators was analyzed; Runx3 expression positively correlated with the radial alveolar count (RAC) and the percentage of smooth muscle actin-positive secondary septa, but negatively correlated with alveolar wall thickness. EMT was observed in the RLE-6TN cells in which the Runx3 gene was knocked down and follwoing TGF-β1‑induced EMT stimulation; however, TGF-β1 failed to induce EMT in the RLE-6TN cells overexpressing Runx3. On the whole, our data indicte that low Runx3 levels may promote EMT, while high Runx3 levels inhibit TGF-β1-induced EMT. Therefore, we predict that low levels of Runx3 in BPD lung tissue may promote EMT in AT2 cells, thus affecting alveolar development.
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Affiliation(s)
- Haiping Yang
- Department of Pediatrics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Jianhua Fu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Li Yao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ana Hou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xindong Xue
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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29
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Sinha PB, Tesfaye D, Rings F, Hossien M, Hoelker M, Held E, Neuhoff C, Tholen E, Schellander K, Salilew-Wondim D. MicroRNA-130b is involved in bovine granulosa and cumulus cells function, oocyte maturation and blastocyst formation. J Ovarian Res 2017. [PMID: 28629378 PMCID: PMC5477299 DOI: 10.1186/s13048-017-0336-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Oocyte maturation and preimplantation embryo development are controlled by array of genes that are post-transcriptionally regulated by microRNAs. With respect to this, previously, we identified altered expression of microRNA-130b (miR-130b) during oocyte maturation. Here, we aimed to investigate the role of miR-130b in bovine granulosa and cumulus cell function, oocyte maturation and preimplantation embryo development using gain- and loss-of- function approach. Methods For this study, the granulosa cells, cumulus cells and the oocytes were collected from ovaries obtained from slaughterhouse. The genes targeted by miR-130b were identified using dual-luciferase reporter assay. The role of miR-130b in granulosa and cumulus cell function was investigated by increasing and inhibiting its expression in in vitro cultured cells using miR-130b precursor and inhibitor, respectively while the role of miR-130b on oocyte development, immature oocytes were microinjected with miR-130b precursor and inhibitor and the polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial were determined in each oocyte group 22 h after microinjection. Moreover, to investigate the role of miR-130b during preimplantation embryo development, zygote stage embryos were microinjected with miR-130b precursor or inhibitor and the cleavage rate, morula and blastocyst formation was analyzed in embryos derived from each zygote group after in vitro culture. Results The luciferase assay showed that SMAD5 and MSK1 genes were identified as the direct targets of miR-130b. Overexpression of miR-130b increased the granulosa and cumulus cell proliferation, while inhibition showed the opposite phenotype. Apart from these, modulation of miR-130b altered the lactate production and cholesterol biosynthesis in cumulus cells. Furthermore, inhibition of miR-130b expression during oocyte in vitro maturation reduced the first polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial activity, while inhibition of miR-130b during preimplantation embryo development significantly reduced morula and blastocyst formation. Conclusion This study demonstrated that in vitro functional modulation of miR-130b affected granulosa and cumulus cell proliferation and survival, oocyte maturation, morula and blastocyst formation suggesting that miR-130b is involved in bovine oocyte maturation and preimplantation embryo development. Electronic supplementary material The online version of this article (doi:10.1186/s13048-017-0336-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Pritam Bala Sinha
- Present address: Department of Biotechnology, Engineering and Applied Sciences, Amity University Ranchi, Ranchi, Jharkhand, 834002, India
| | - Dawit Tesfaye
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Franca Rings
- Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany
| | - Munir Hossien
- Present address: Department of Animal Breeding and Genetics, Bangladesh Agricultural University, Mymensingh, -2202, Bangladesh
| | - Michael Hoelker
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Eva Held
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany
| | - Christaine Neuhoff
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany
| | - Ernst Tholen
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany
| | - Karl Schellander
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Dessie Salilew-Wondim
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.
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30
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Liu Y, Sun Y, Zhao A. MicroRNA-134 suppresses cell proliferation in gastric cancer cells via targeting of GOLPH3. Oncol Rep 2017; 37:2441-2448. [DOI: 10.3892/or.2017.5488] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 11/25/2016] [Indexed: 11/05/2022] Open
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31
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Li C, Lu S, Shi Y. MicroRNA-187 promotes growth and metastasis of gastric cancer by inhibiting FOXA2. Oncol Rep 2017; 37:1747-1755. [PMID: 28098868 DOI: 10.3892/or.2017.5370] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 11/14/2016] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs) play an active role in the pathogenesis of gastric cancer. The expression and biological function for miR-187 in gastric cancer remains unknow. In the present study, we demonstrated that miR-187 expression was increased in gastric cancer (GC) tissues and cells. Increased expression level of miR-187 was associated with adverse clinical features including tumor size, lymph metastasis and TNM stage, and decreased overall survival and disease-free survival of GC patients. Functionally, overexpression miR-187 could promote while inhibition of miR-187 could suppress, the proliferation, migration and invasion of GC cells in vitro. In vivo experiments showed that overexpression of miR-187 promoted the growth and lung metastasis of SGC-7901 cells in nude mice. Mechanically, we confirmed that FOXA2 was the downstream target of miR-187 in GC cells using luciferase assay, qRT-PCR and western blot analysis. Moreover, overexpression of FOXA2 abrogated the promoting effects of miR-187 overexpression on SGC-7901 cell proliferation, migration and invasion, while inhibition of FOXA2 reversed the inhibitory effects of miR-187 downregulation on these biological functions of AGS cells, suggesting that FOXA2 was a functional mediator of miR-187 in GC. Therefore, this study indicates that miR-187 is potentially a biomarker and treatment target for GC patients.
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Affiliation(s)
- Cong Li
- Department of Emergency Internal Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Sumei Lu
- Department of Internal Neurology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Yubin Shi
- Department of Emergency Internal Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
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32
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Wang Y. Transcriptional Regulatory Network Analysis for Gastric Cancer Based on mRNA Microarray. Pathol Oncol Res 2017; 23:785-791. [PMID: 28078605 DOI: 10.1007/s12253-016-0159-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/14/2016] [Indexed: 12/27/2022]
Abstract
We aimed to screen the differential expressed genes (DEGs) and transcriptional factors (TFs) related to gastric cancer. GSE19826 microarray data downloaded from Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) and PPI network of DEGs were constructed by the Retrieval of Interacting Genes database. Pathway enrichment analysis of DEGs were performed by Gene Set Enrichment Analysis. Then, the transcriptional regulatory network was constructed based on TRANSFAC database. Finally, regulatory impact factor (RIF) of TF was calculated. We identified 446 DEGs including 209 up- and 237 down-regulated genes. These DEGs were mainly significantly enriched in 5 pathways including ECM receptor interaction (p = 0.013899), spliceosome (p = 0.025591), bladder cancer (p = 0.026316), focal adhesion (p = 0.047809) and WNT signaling pathway (p = 0.048077). PPI network with 247 nodes and 913 edges were constructed and COL5A2 was the hub node. Transcriptional regulatory network with 6 differently expressed TFs, 58 non-differently expressed TFs, 44 DEGs and 735 non-DEGs was constructed. Finally, top 5 TFs including CRX, TFAP4, NKX2-1, MYB and RARG with higher ZRIF were screened. The identified DEGs such as COL5A2 and TOP2A, and TFs including EGR2, FOXM1, NKX2-1 and TFAP4 might be the critical genes and TFs for gastric cancer.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, Shengjing Hospital, China Medical University, No.36 Sanhao Road, Shenyang, 110004, China.
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33
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Lv M, Zhong Z, Chi H, Huang M, Jiang R, Chen J. Genome-Wide Screen of miRNAs and Targeting mRNAs Reveals the Negatively Regulatory Effect of miR-130b-3p on PTEN by PI3K and Integrin β1 Signaling Pathways in Bladder Carcinoma. Int J Mol Sci 2016; 18:E78. [PMID: 28042869 PMCID: PMC5297712 DOI: 10.3390/ijms18010078] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 12/17/2016] [Accepted: 12/28/2016] [Indexed: 01/14/2023] Open
Abstract
miRNAs have emerged as promising markers for tumors. However, the underlying mechanism of specific miRNAs in bladder cancer (BC) remains largely unknown. Here, a comprehensive miRNA/mRNA expression profile was executed by microarray assay for four pairs of bladder carcinoma and para-carcinoma tissues from patients with grade 2 (G2) T2. A total of 99 miRNAs and 4416 mRNAs were discovered to be significantly differentially expressed in BC tissues compared with controls. Five microRNAs and two mRNAs were validated by qRT-PCR in 30 pairs of samples, including G1-G3/T1-T4. Subsequently, we constructed a network with the five miRNAs-target mRNAs; gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were utilized to recognize the functions and associated pathways. Moreover, we further found that miR-130b-3p was significantly up-regulated and negatively correlated with phosphatase and tensin homolog (PTEN) expression in bladder cancer tissues. Next, we demonstrated that miR-130b-3p might target PTEN through bioinformatics and dual-luciferase reporter assay. Finally, we showed that miR-130b-3p could down-regulate PTEN expression, which promoted proliferation, migration, invasion and rearranged cytoskeleton through the activation of the PI3K and integrin β1 signaling pathway in bladder cancer cells. Inversely, miR-130b-3p inhibitors induced apoptosis. Taken together, this research investigated, for the first time, miR-130b-3p by an incorporated analysis of microRNA/mRNA expressions of a genome-wide screen in BC. Our findings suggest that the miR-130b-3p/PTEN/integrin β1 axis could play a critical role in the progression and development of BC and that miR-130b-3p might be a valuable clinical marker and therapeutical target for BC patients.
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Affiliation(s)
- Mengxin Lv
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing 400016, China.
| | - Zhenyu Zhong
- The First Clinical College, Chongqing Medical University, Chongqing 400016, China.
| | - Hong Chi
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing 400016, China.
| | - Mengge Huang
- College of Clinical Medicine, Southwest Medical University, Luzhou 646000, China.
| | - Rong Jiang
- Laboratory of Stem Cells and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China.
| | - Junxia Chen
- Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing 400016, China.
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34
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Ponnurangam S, Dandawate PR, Dhar A, Tawfik OW, Parab RR, Mishra PD, Ranadive P, Sharma R, Mahajan G, Umar S, Weir SJ, Sugumar A, Jensen RA, Padhye SB, Balakrishnan A, Anant S, Subramaniam D. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget 2016; 7:3217-32. [PMID: 26673007 PMCID: PMC4823101 DOI: 10.18632/oncotarget.6560] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/21/2015] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1–4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.
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Affiliation(s)
- Sivapriya Ponnurangam
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Prasad R Dandawate
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Animesh Dhar
- Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Ossama W Tawfik
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | | | | | | | - Rajiv Sharma
- Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India
| | - Girish Mahajan
- Piramal Life Sciences Inc, Goregaon East, Mumbai 400063, India
| | - Shahid Umar
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Scott J Weir
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Aravind Sugumar
- Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Roy A Jensen
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Subhash B Padhye
- Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Interdisciplinary Science and Technology Research Academy, Abeda Inamdar Senior College, Azam Campus, Pune, 411001, India
| | | | - Shrikant Anant
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
| | - Dharmalingam Subramaniam
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160, USA.,The University of Kansas Cancer Center, Kansas City, KS 66160, USA
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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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Chen Y, Wang X, Cheng J, Wang Z, Jiang T, Hou N, Liu N, Song T, Huang C. MicroRNA-20a-5p targets RUNX3 to regulate proliferation and migration of human hepatocellular cancer cells. Oncol Rep 2016; 36:3379-3386. [PMID: 27748919 DOI: 10.3892/or.2016.5144] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 08/17/2016] [Indexed: 11/05/2022] Open
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37
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Paudel D, Zhou W, Ouyang Y, Dong S, Huang Q, Giri R, Wang J, Tong X. MicroRNA-130b functions as a tumor suppressor by regulating RUNX3 in epithelial ovarian cancer. Gene 2016; 586:48-55. [DOI: 10.1016/j.gene.2016.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 03/21/2016] [Accepted: 04/01/2016] [Indexed: 12/15/2022]
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38
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Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH, Lin KH. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int J Mol Sci 2016; 17:945. [PMID: 27322246 PMCID: PMC4926478 DOI: 10.3390/ijms17060945] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022] Open
Abstract
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Wei Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Pei-Hsuan Lu
- Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
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39
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Gu JJ, Zhang JH, Chen HJ, Wang SS. MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells. Int J Mol Med 2016; 37:1587-93. [PMID: 27122306 PMCID: PMC4866956 DOI: 10.3892/ijmm.2016.2580] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 04/25/2016] [Indexed: 12/20/2022] Open
Abstract
MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non-neoplastic brain specimens. Specifically, higher expression levels of miR-130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR-130b interacted with the 3′-untranslated region of peroxisome proliferator-activated receptor-γ (PPAR-γ), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR-130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR-130b in U251 glioma cells restored the expression of PPAR-γ and E-cadherin, and inhibited the expression of β-catenin. Notably, PPAR-γ knockdown abolished the inhibitory effect of miR-130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR-130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-γ.
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Affiliation(s)
- Jian-Jun Gu
- Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, Fuzhou, Fujian 350025, P.R. China
| | - Jian-He Zhang
- Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, Fuzhou, Fujian 350025, P.R. China
| | - Hong-Jie Chen
- Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, Fuzhou, Fujian 350025, P.R. China
| | - Shou-Sen Wang
- Department of Neurosurgery, Fuzhou General Hospital, Xiamen University Medical College, Fuzhou, Fujian 350025, P.R. China
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Ghosh RD, Ghuwalewala S, Das P, Mandloi S, Alam SK, Chakraborty J, Sarkar S, Chakrabarti S, Panda CK, Roychoudhury S. MicroRNA profiling of cisplatin-resistant oral squamous cell carcinoma cell lines enriched with cancer-stem-cell-like and epithelial-mesenchymal transition-type features. Sci Rep 2016; 6:23932. [PMID: 27045798 PMCID: PMC4820705 DOI: 10.1038/srep23932] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 03/14/2016] [Indexed: 12/30/2022] Open
Abstract
Oral cancer is of major public health problem in India. Current investigation was aimed to identify the specific deregulated miRNAs which are responsible for development of resistance phenotype through regulating their resistance related target gene expression in oral squamous cell carcinoma (OSCC). Cisplatin-resistant OSCC cell lines were developed from their parental human OSCC cell lines and subsequently characterised. The resistant cells exhibited enhanced proliferative, clonogenic capacity with significant up-regulation of P-glycoprotein (ABCB1), c-Myc, survivin, β-catenin and a putative cancer-stem-like signature with increased expression of CD44, whereas the loss of E-cadherin signifies induced EMT phenotype. A comparative analysis of miRNA expression profiling in parental and cisplatin-resistant OSCC cell lines for a selected sets (deregulated miRNAs in head and neck cancer) revealed resistance specific signature. Moreover, we observed similar expression pattern for these resistance specific signature miRNAs in neoadjuvant chemotherapy treated and recurrent tumours compared to those with newly diagnosed primary tumours in patients with OSCC. All these results revealed that these miRNAs play an important role in the development of cisplatin-resistance mainly through modulating cancer stem-cell-like and EMT-type properties in OSCC.
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Affiliation(s)
- Ruma Dey Ghosh
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sangeeta Ghuwalewala
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Pijush Das
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sapan Mandloi
- Structural Biology and Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Sk Kayum Alam
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Jayanta Chakraborty
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
| | - Sajal Sarkar
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
| | - Saikat Chakrabarti
- Structural Biology and Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Chinmoy Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
| | - Susanta Roychoudhury
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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41
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Ghosh RD, Ghuwalewala S, Das P, Mandloi S, Alam SK, Chakraborty J, Sarkar S, Chakrabarti S, Panda CK, Roychoudhury S. MicroRNA profiling of cisplatin-resistant oral squamous cell carcinoma cell lines enriched with cancer-stem-cell-like and epithelial-mesenchymal transition-type features. Sci Rep 2016; 6:23932. [DOI: doi.org/10.1038/srep23932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 03/14/2016] [Indexed: 04/05/2025] Open
Abstract
AbstractOral cancer is of major public health problem in India. Current investigation was aimed to identify the specific deregulated miRNAs which are responsible for development of resistance phenotype through regulating their resistance related target gene expression in oral squamous cell carcinoma (OSCC). Cisplatin-resistant OSCC cell lines were developed from their parental human OSCC cell lines and subsequently characterised. The resistant cells exhibited enhanced proliferative, clonogenic capacity with significant up-regulation of P-glycoprotein (ABCB1), c-Myc, survivin, β-catenin and a putative cancer-stem-like signature with increased expression of CD44, whereas the loss of E-cadherin signifies induced EMT phenotype. A comparative analysis of miRNA expression profiling in parental and cisplatin-resistant OSCC cell lines for a selected sets (deregulated miRNAs in head and neck cancer) revealed resistance specific signature. Moreover, we observed similar expression pattern for these resistance specific signature miRNAs in neoadjuvant chemotherapy treated and recurrent tumours compared to those with newly diagnosed primary tumours in patients with OSCC. All these results revealed that these miRNAs play an important role in the development of cisplatin-resistance mainly through modulating cancer stem-cell-like and EMT-type properties in OSCC.
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42
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Li Z, Li Y, Wang N, Yang L, Zhao W, Zeng X. miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells. Biochem Biophys Res Commun 2016; 471:479-85. [PMID: 26902120 DOI: 10.1016/j.bbrc.2016.02.050] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 02/14/2016] [Indexed: 12/17/2022]
Abstract
miR-130b was significantly up-regulated in osteosarcoma (OS) cells. Naked cuticle homolog 2 (NKD2) inhibited tumor growth and metastasis in OS by suppressing Wnt signaling. We used three miRNA target analysis tools to identify potential targets of miR-130b, and found that NKD2 is a potential target of miR-130b. Based on these findings, we hypothesize that miR-130b might target NKD2 and regulate the Wnt signaling to promote OS growth. We detected the expression of miR-130b and NKD2 mRNA and protein by quantitative Real-Time PCR (qRT-PCR) and western blot assays, respectively, and found up-regulation of miR-130b and down-regulation of NKD2 mRNA and protein exist in OS cell lines. MTT and flow cytometry assays showed that miR-130b inhibitors inhibit proliferation and promote apoptosis in OS cells. Furthermore, we showed that NKD2 is a direct target of miR-130b, and miR-130b regulated proliferation and apoptosis of OS cells by targeting NKD2. We further investigated whether miR-130b and NKD2 regulate OS cell proliferation and apoptosis by inhibiting Wnt signaling, and the results confirmed our speculation that miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis of OS cells. These findings will offer new clues for OS development and progression, and novel potential therapeutic targets for OS.
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Affiliation(s)
- Zhi Li
- Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University, China
| | - Youjun Li
- Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University, China.
| | - Nan Wang
- Central Hospital Affiliated to Shenyang Medical College, China
| | - Lifeng Yang
- Central Hospital Affiliated to Shenyang Medical College, China
| | - Wei Zhao
- Central Hospital Affiliated to Shenyang Medical College, China
| | - Xiandong Zeng
- Central Hospital Affiliated to Shenyang Medical College, China
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43
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Transforming growth factor (TGF) β1 acted through miR-130b to increase integrin α5 to promote migration of colorectal cancer cells. Tumour Biol 2016; 37:10763-73. [DOI: 10.1007/s13277-016-4965-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/02/2016] [Indexed: 11/25/2022] Open
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44
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Chang RM, Xu JF, Fang F, Yang H, Yang LY. MicroRNA-130b promotes proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Tumour Biol 2016; 37:10609-19. [PMID: 26861561 DOI: 10.1007/s13277-016-4919-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 01/27/2016] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths owing to its high rate of postoperative recurrence and metastasis. New research is continuously identifying novel metastasis-associated oncogenes and tumor suppressor genes. miRNAs are noncoding RNAs that regulate protein synthesis post-translationally. miR-130b is one of several miRNAs involved in tumor metastasis. However, the role of miR-130b in HCC remains controversial. Here, we demonstrate that miR-130b is highly expressed in HCC and that it correlates with tumor number, vascular invasion, and TNM stage-important predictors of postoperative recurrence and metastases. Moreover, high levels of miR-130b predicted poor overall and disease-free survival of HCC patients, and in vitro and in vivo research revealed that knockdown or overexpression of miR-130b inhibited and promoted proliferation and metastasis of HCC cells, respectively. We identified PTEN as a direct functional target of miR-130b using miRNA databases and a dual luciferase report assay. Next, using a gain and loss assay and epithelial-mesenchymal transition (EMT) relative assays, we show that miR-130b may promote proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Collectively, our data suggests that miR-130b may have prognostic value in HCC. Additionally, the miR-130b/PTEN/p-AKT/HIF-1α axis identified in this study provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
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Affiliation(s)
- Rui-Min Chang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiang-Feng Xu
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Feng Fang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Yang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lian-Yue Yang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Xiangya Road 87, Changsha, 410008, Hunan, China.
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45
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The miR-130 family promotes cell migration and invasion in bladder cancer through FAK and Akt phosphorylation by regulating PTEN. Sci Rep 2016; 6:20574. [PMID: 26837847 PMCID: PMC4738343 DOI: 10.1038/srep20574] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/06/2016] [Indexed: 02/08/2023] Open
Abstract
Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, currently used targeted therapy for malignant bladder cancer is still not efficient. We focused on the miR-130 family (miR-130b, miR-301a, and miR-301b) that was significantly upregulated in bladder cancer specimens than that of the normal urothelial specimens. We analyzed the functional significance of miR-130 family using a 5637 bladder cancer cell line and revealed that miR-130 family of inhibitors suppressed cell migration and invasion by downregulating focal adhesion kinase (FAK) and Akt phosphorylation. Mechanistic analyses indicate that the miR-130 family directly targets phosphatase and tensin homolog deleted from chromosome 10 (PTEN), resulting in the upregulation of FAK and Akt phosphorylation. In clinical bladder cancer specimens, downregulation of PTEN was found to be closely correlated with miR-130 family expression levels. Overall, the miR-130 family has a crucial role in malignant progression of bladder cancer and thus the miR-130 family could be a promising therapeutic target for invasive bladder cancer.
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46
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Browne G, Dragon JA, Hong D, Messier TL, Gordon JAR, Farina NH, Boyd JR, VanOudenhove JJ, Perez AW, Zaidi SK, Stein JL, Stein GS, Lian JB. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Tumour Biol 2016; 37:8825-39. [PMID: 26749280 DOI: 10.1007/s13277-015-4710-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 12/20/2015] [Indexed: 01/08/2023] Open
Abstract
The Runx1 transcription factor, known for its essential role in normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx1 increases concomitantly with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant downregulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mice and in human breast cancer cell lines MCF7 and triple-negative MDA-MB-231 that represent early- and late-stage diseases, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3' untranslated region (3'UTR) and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion, while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late-stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer.
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Affiliation(s)
- Gillian Browne
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Julie A Dragon
- Department of Microbiology and Molecular Genetics, University of Vermont, 95 Carrigan Avenue, Burlington, VT, 05405, USA
| | - Deli Hong
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Terri L Messier
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Jonathan A R Gordon
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Nicholas H Farina
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Joseph R Boyd
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Jennifer J VanOudenhove
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Andrew W Perez
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Sayyed K Zaidi
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Janet L Stein
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Gary S Stein
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA
| | - Jane B Lian
- Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA.
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Li Y, Chen D, Li Y, Jin L, Liu J, Su Z, Qi Z, Shi M, Jiang Z, Gui Y, Yang S, Mao X, Lai Y. Identification of miR‑130b as an oncogene in renal cell carcinoma. Mol Med Rep 2015; 13:1902-8. [PMID: 26717956 DOI: 10.3892/mmr.2015.4744] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 11/10/2015] [Indexed: 11/05/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common type of renal tumor, which has a poor prognosis. Improvements in understanding the underlying molecular biology of RCC has led to systemic treatments, which have markedly improved patient outcomes. Therefore, it is necessary and worthwhile to identify novel biomarkers for RCC. MicroRNAs (miRNAs) have been found to be important in a wide range of biological and pathological processes, including cell differentiation, migration, growth, proliferation, apoptosis and metabolism. Aberrant expression of miRNA‑130b has previously been reported in tumors, however, its role in RCC remains to be elucidated. In the present study, the upregulation of miR‑130b was observed in RCC tissues and cell lines using reverse transcription‑quantitative polymerase chain reaction analysis, which was consistent with previous microRNA profiling in RCC. Furthermore, the effects of miR‑130b on cell migration, proliferation and apoptosis were examined using a wound scratch assay, an MTT assay and flow cytometric analysis, respectively. The results demonstrated that the downregulation of miR‑130b by a synthesized inhibitor inhibited cell migration, suppressed cell proliferation and induced RCC cell apoptosis. The present study was the first, to the best of our knowledge, to suggest that miR‑130b may be a promising biomarker for diagnosis and a therapeutic target for the treatment of RCC. Further investigations are required to examine the roles and target genes of miR‑130b in RCC.
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Affiliation(s)
- Yifan Li
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Duqun Chen
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Yuchi Li
- Department of Urology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Lu Jin
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Jiaju Liu
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Zhengming Su
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Zhengyu Qi
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Min Shi
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Zhimao Jiang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Xiangming Mao
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen Hospital, Shenzhen PKU‑HKUST Medical Center, Shenzhen, Guangdong 518036, P.R. China
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Chen F, Liu X, Bai J, Pei D, Zheng J. The emerging role of RUNX3 in cancer metastasis (Review). Oncol Rep 2015; 35:1227-36. [PMID: 26708741 DOI: 10.3892/or.2015.4515] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/11/2015] [Indexed: 11/06/2022] Open
Abstract
Metastasis remains the major driver of mortality in patients with cancer. The multistep metastatic process starts with the dissemination of tumor cells from a primary site and leading to secondary tumor development in an anatomically distant location. Although significant progress has been made in understanding the molecular characteristics of metastasis, many questions remain regarding the intracellular mechanisms governing transition through the various metastatic stages. The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in the regulation of cell death by apoptosis, and in angiogenesis, epithelial-to-mesenchymal transition (EMT), cell migration and invasion. RUNX3 functions as a bona fide initiator of carcinogenesis by linking the Wnt oncogenic and TGF-β tumor suppressive pathways. RUNX3 is frequently inactivated in human cancer cell lines and cancer samples by hemizygous deletion of the Runx3 gene, hypermethylation of the Runx3 promoter, or cytoplasmic sequestration of RUNX3 protein. Inactivation of RUNX3 makes it a putative tumor suppressor in human neoplasia. In the present review, we summarize the proposed roles of RUNX3 in metastasis and, when applicable, highlight the mechanism by which they function.
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Affiliation(s)
- Feifei Chen
- Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Xin Liu
- Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Dongsheng Pei
- Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
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Sheng X, Chen H, Wang H, Ding Z, Xu G, Zhang J, Lu W, Wu T, Zhao L. MicroRNA-130b promotes cell migration and invasion by targeting peroxisome proliferator-activated receptor gamma in human glioma. Biomed Pharmacother 2015; 76:121-6. [PMID: 26653558 DOI: 10.1016/j.biopha.2015.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/28/2015] [Accepted: 10/13/2015] [Indexed: 12/30/2022] Open
Abstract
MircroRNA-130b (miR-130b) has been recognized as an oncogenic miRNA and is implicated in the initiation and development of human cancers. Deregulation of miR-130b has been reported in several tumors. However, the clinical significance and its underlying role in human glioma are poorly explored. Herein, we found that the expression of miR-130b was significantly up-regulated in glioma tissues as compared with that in normal brain (NB) tissues. Clinical association analysis disclosed that high-expression of miR-130b was evidently associated with advanced tumor stage (grade III+IV) in glioma. Moreover, we disclosed that the high-expression of miR-130b conferred an obviously reduced survival of glioma patients. Multivariate Cox regression analysis showed that miR-130b expression was an independent prognostic indicator for glioma patients. Our gain- or loss-of-function studies showed that miR-130b promoted invasion and migration of glioma cells. Notably, miR-130b regulated peroxisome proliferator-activated receptor gamma (PPARγ) abundance and epithelial-mesenchymal transition (EMT) in glioma cells. Hereby, PPARγ was identified as a functional target of miR-130b in glioma. Furthermore, an inverse correlation between miR-130b and PPARγ expression was observed in glioma tissues. In conclusion, miR-130b is an independent prognostic biomarker for indicating survival of glioma patients and promotes glioma cell migration and invasion by targeting PPARγ.
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Affiliation(s)
- Xudong Sheng
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Hu Chen
- Department of Neurosurgery, Tang-Du Hospital, Fourth Military Medical University, No. 1 Xinsi Road, Xi'an 710038, China
| | - Hui Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Zhibin Ding
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Gangzhu Xu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Junfeng Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Wenchao Lu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Tao Wu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China
| | - Ling Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Medical College, No. 48 Fenghao West Road, Xi'an 710077, China.
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50
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Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6:111-132. [PMID: 26468448 PMCID: PMC4600186 DOI: 10.5306/wjco.v6.i5.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/22/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
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