1
|
Hosseini N, Forghanifard MM. MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma. BMC Med Genomics 2025; 18:69. [PMID: 40211274 PMCID: PMC11983858 DOI: 10.1186/s12920-025-02134-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 03/27/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/β-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway. RESULTS The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased. CONCLUSIONS Our data suggest that MEIS1 gene probably induces WNT/β-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.
Collapse
Affiliation(s)
- Nayyerehalsadat Hosseini
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mahdi Forghanifard
- Department of Biology, Da.C., Islamic Azad University, Cheshmeh-Ali Boulevard, Sa'dei square, P.O.Box: 3671639998, Damghan, Iran.
| |
Collapse
|
2
|
Mathuram TL. GSK-3: An "Ace" Among Kinases. Cancer Biother Radiopharm 2024; 39:619-631. [PMID: 38746994 DOI: 10.1089/cbr.2024.0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2024] Open
Abstract
Background: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase known to participate in the regulation of β-catenin signaling (Wnt signaling). This aids in the establishment of a multicomponent destruction complex that stimulates phosphorylation, leading to the destruction of β-catenin. Evidence about the role of increasingly active β-catenin signaling is involved in many forms of human cancer. The understanding of GSK-3 remains elusive as recent research aims to focus on developing potent GSK-3 inhibitors to target this kinase. Objective: This short review aims to highlight the regulation of GSK-3 with emphasis on Wnt signaling while highlighting its interaction with miRNAs corresponding to pluripotency and epithelial mesenchymal transition substantiating this kinase as an "Ace" among kinases in regulation of cellular processes. Result: Significant findings of miRNA regulation by GSK-3 exemplify the underpinnings of kinase-mediated transcriptional regulation in cancers. Conclusion: The review provides evidence on the role of GSK-3 as a possible master regulator of proteins and noncoding RNA, thereby implicating the fate of a cell.
Collapse
|
3
|
Karpagavalli M, Sivagurunathan S, Panda TS, Srikakulam N, Arora R, Dohadwala L, Tiwary BK, Sadras SR, Arunachalam JP, Pandi G, Chidambaram S. piRNAs in the human retina and retinal pigment epithelium reveal a potential role in intracellular trafficking and oxidative stress. Mol Omics 2024; 20:248-264. [PMID: 38314503 DOI: 10.1039/d3mo00122a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2024]
Abstract
Long considered active only in the germline, the PIWI/piRNA pathway is now known to play a significant role in somatic cells, especially neurons. In this study, piRNAs were profiled in the human retina and retinal pigment epithelium (RPE). Furthermore, RNA immunoprecipitation with HIWI2 (PIWIL4) in ARPE19 cells yielded 261 piRNAs, and the expression of selective piRNAs in donor eyes was assessed by qRT-PCR. Intriguingly, computational analysis revealed complete and partial seed sequence similarity between piR-hsa-26131 and the sensory organ specific miR-183/96/182 cluster. Furthermore, the expression of retina-enriched piR-hsa-26131 was positively correlated with miR-182 in HIWI2-silenced Y79 cells. In addition, the lnc-ZNF169 sequence matched with two miRNAs of the let-7 family, and piRNAs, piR-hsa-11361 and piR-hsa-11360, which could modulate the regulatory network of retinal differentiation. Interestingly, we annotated four enriched motifs among the piRNAs and found that the piRNAs containing CACAATG and CTCATCAKYG motifs were snoRNA-derived piRNAs, which are significantly associated with developmental functions. However, piRNAs consisting of ACCACTANACCAC and AKCACGYTCSC motifs were mainly tRNA-derived fragments linked to stress response and sensory perception. Additionally, co-expression network analysis revealed cell cycle control, intracellular transport and stress response as the important biological functions regulated by piRNAs in the retina. Moreover, loss of piRNAs in HIWI2 knockdown ARPE19 confirmed altered expression of targets implicated in intracellular transport, circadian clock, and retinal degeneration. Moreover, piRNAs were dysregulated under oxidative stress conditions, indicating their potential role in retinal pathology. Therefore, we postulate that piRNAs, miRNAs, and lncRNAs might have a functional interplay during retinal development and functions to regulate retinal homeostasis.
Collapse
Affiliation(s)
| | - Suganya Sivagurunathan
- RS Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Chennai, India
| | - T Sayamsmruti Panda
- Department of Bioinformatics, Pondicherry University, Puducherry-605014, India
| | - Nagesh Srikakulam
- Laboratory of RNA Biology and Epigenomics, Department of Plant Biotechnology, School of Biotechnology, Madurai Kamaraj University, Madurai, India
| | - Reety Arora
- National Centre for Biological Sciences, TIFR, Bangalore, India
| | | | - Basant K Tiwary
- Department of Bioinformatics, Pondicherry University, Puducherry-605014, India
| | - Sudha Rani Sadras
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry-605014, India.
| | - Jayamuruga Pandian Arunachalam
- Central Inter-Disciplinary Research Facility, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry-607402, India
| | - Gopal Pandi
- Laboratory of RNA Biology and Epigenomics, Department of Plant Biotechnology, School of Biotechnology, Madurai Kamaraj University, Madurai, India
| | - Subbulakshmi Chidambaram
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry-605014, India.
| |
Collapse
|
4
|
Alitongbieke G, Zhang X, Zhu F, Wu Q, Lin Z, Li X, Xue Y, Lai X, Feng J, Huang R, Pan Y. Glucan from Oudemansiella raphanipes suppresses breast cancer proliferation and metastasis by regulating macrophage polarization and the WNT/β-catenin signaling pathway. J Cancer 2024; 15:1169-1181. [PMID: 38356709 PMCID: PMC10861828 DOI: 10.7150/jca.89873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/16/2023] [Indexed: 02/16/2024] Open
Abstract
Background: The glucan extract of Oudemansiella raphanipes (Orp) has multiple biological properties, similar to extracts of other natural edible fungi. Drugs traditionally used in cancer treatment are associated with several drawbacks, such as side effects, induction of resistance, and poor prognosis, and many recent studies have focused on polysaccharides extracted from natural sources as alternatives. Our study focuses on the therapeutic role and molecular mechanism of action of Orp in breast cancer progression. Methods: MMTV-PyMT transgenic mice were used as the spontaneous breast cancer mice model. Immunoblotting, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were used to evaluate the tumor behaviors in breast cancer. The inflammatory cell model was constructed using TNF-α. Macrophage activation and WNT/β-catenin signaling were assayed using western blotting and immunofluorescence. Results: Orp management significantly inhibited tumor growth and promoted tumor cell apoptosis in MMTV-PyMT transgenic mice. Besides, the Orp challenge also attenuated the ability of breast tumors to metastasize into lung tissues. Mechanistically, Orp treatment restrained the polarization of M1 macrophages to M2 macrophages and suppressed WNT/β-catenin signaling in mouse tumor tissues, which implied that Orp-mediated tumor inhibition partly occurred via regulating the inflammatory response. Findings from in vitro experiments confirmed that Orp inhibited the TNF-α-induced nuclear transportation of β-catenin, thus preventing inflammation signaling and the expression of c-Myc in MCF-7 cells. Conclusion: Orp inhibits breast cancer growth and metastasis by regulating macrophage polarization and the WNT/β-catenin signaling axis. The findings of this study suggest that Orp may be a promising therapeutic strategy for breast cancer.
Collapse
Affiliation(s)
- Gulimiran Alitongbieke
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xiuru Zhang
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Fukai Zhu
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Qici Wu
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Zhichao Lin
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xiumin Li
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Yu Xue
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xuebin Lai
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Jiexin Feng
- Department of Breast Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363099, People's Republic of China
| | - Rongjie Huang
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363099, People's Republic of China
| | - Yutian Pan
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| |
Collapse
|
5
|
Zheng Y, Sukocheva O, Tse E, Neganova M, Aleksandrova Y, Zhao R, Chubarev V, Fan R, Liu J. MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies. Am J Cancer Res 2023; 13:6147-6175. [PMID: 38187051 PMCID: PMC10767355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/29/2023] [Indexed: 01/09/2024] Open
Abstract
Small non-coding RNAs (microRNA, miR), powerful epigenetic regulators, were found involved in the regulation of most biological functions via post-translational inhibition of protein expression. Increased expression of pro-oncogenic miRs (known as miR cancer biomarkers) and inhibition of pro-apoptotic miR expression have been demonstrated in different tumors. The recently identified miR-183 was found implicated in gastrointestinal tumor metabolism regulation. Elevated miR-183 expression and cancer-promoting effects were reported in esophageal and colorectal cancers, which was partially contradicted by controversial data observed in gastric cancers. Anti-cancer effect of miR-183 in gastric cancer cells was associated with the Bim-1 and Ezrin genes regulation. Many studies indicated that miR-183 can inhibit tumor suppressor genes in most cell lines, promoting tumor cell proliferation and migration. Increased miR-183 level results in the downregulation of FOXO1, PDCD4, and other tumor suppressor genes in gastrointestinal tumor cells. MiR-183 also influences the signaling of PI3K/AKT/mTOR, Wnt/β-catenin, and Bcl-2/p53 signaling pathways. Mir-183 inhibits apoptosis and autophagy, and promotes epithelial-to-mesenchymal transition, cancer cell proliferation, and migration. Accordingly, gastrointestinal cancer occurrence, development of chemoradiotherapy resistance, recurrence/metastasis, and prognosis were associated with miR-183 expression. The current study assessed reported miR-183 functions and signaling, providing new insights for the diagnosis and treatment of gastrointestinal malignancies.
Collapse
Affiliation(s)
- Yufei Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Olga Sukocheva
- Department of Hepatology, Royal Adelaide HospitalAdelaide, SA 5000, Australia
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide HospitalAdelaide, SA 5000, Australia
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of SciencesSevernij Pr. 1, Chernogolovka 142432, Russia
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of SciencesAkad. Arbuzov St. 8, Kazan 420088, Russia
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of SciencesSevernij Pr. 1, Chernogolovka 142432, Russia
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of SciencesAkad. Arbuzov St. 8, Kazan 420088, Russia
| | - Ruiwen Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Vladimir Chubarev
- Sechenov First Moscow State Medical University (Sechenov University)8-2 Trubetskaya St., Moscow 119991, Russia
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052, Henan, China
| |
Collapse
|
6
|
Yan W, Chen Y, Hu G, Shi T, Liu X, Li J, Sun L, Qian F, Chen W. MiR-200/183 family-mediated module biomarker for gastric cancer progression: an AI-assisted bioinformatics method with experimental functional survey. J Transl Med 2023; 21:163. [PMID: 36864416 PMCID: PMC9983275 DOI: 10.1186/s12967-023-04010-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/18/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major cancer burden throughout the world with a high mortality rate. The performance of current predictive and prognostic factors is still limited. Integrated analysis is required for accurate cancer progression predictive biomarker and prognostic biomarkers that help to guide therapy. METHODS An AI-assisted bioinformatics method that combines transcriptomic data and microRNA regulations were used to identify a key miRNA-mediated network module in GC progression. To reveal the module's function, we performed the gene expression analysis in 20 clinical samples by qRT-PCR, prognosis analysis by multi-variable Cox regression model, progression prediction by support vector machine, and in vitro studies to elaborate the roles in GC cells migration and invasion. RESULTS A robust microRNA regulated network module was identified to characterize GC progression, which consisted of seven miR-200/183 family members, five mRNAs and two long non-coding RNAs H19 and CLLU1. Their expression patterns and expression correlation patterns were consistent in public dataset and our cohort. Our findings suggest a two-fold biological potential of the module: GC patients with high-risk score exhibited a poor prognosis (p-value < 0.05) and the model achieved AUCs of 0.90 to predict GC progression in our cohort. In vitro cellular analyses shown that the module could influence the invasion and migration of GC cells. CONCLUSIONS Our strategy which combines AI-assisted bioinformatics method with experimental and clinical validation suggested that the miR-200/183 family-mediated network module as a "pluripotent module", which could be potential marker for GC progression.
Collapse
Affiliation(s)
- Wenying Yan
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China. .,Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China.
| | - Yuqi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Guang Hu
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China.,Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215021, China
| | - Xingyi Liu
- Department of Bioinformatics, School of Biology and Basic Medical Sciences, Suzhou Medical College of Soochow University, 199 Renai Road, Suzhou, 215123, China
| | - Juntao Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Linqing Sun
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China
| | - Fuliang Qian
- Center for Systems Biology, Soochow University, 199 Renai Road, Suzhou, 215123, China. .,Medical Center of Soochow University, Suzhou, 215000, China.
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, China. .,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Suzhou Key Laboratory for Tumor Immunology of Digestive Tract, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215021, China. .,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215021, China.
| |
Collapse
|
7
|
miR-183/96/182 Cluster Regulates the Development of Bovine Myoblasts through Targeting FoxO1. Animals (Basel) 2022; 12:ani12202799. [PMID: 36290185 PMCID: PMC9597811 DOI: 10.3390/ani12202799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/16/2022] [Accepted: 10/08/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary In this work, we identified that the miR-183/96/182 cluster was highly expressed in bovine embryonic muscle; meanwhile, it widely existed in other organizations. Functional assays indicated that the miR-183/96/182 cluster targets the FoxO1 gene to regulate the proliferation and differentiation of bovine myoblasts. Abstract Muscle development is an important factor affecting meat yield and quality and is coordinated by a variety of the myogenic genes and signaling pathways. Recent studies reported that miRNA, a class of highly conserved small noncoding RNA, is actively involved in regulating muscle development, but many miRNAs still need to be further explored. Here, we identified that the miR-183/96/182 cluster exhibited higher expression in bovine embryonic muscle; meanwhile, it widely existed in other organizations. Functionally, the results of the RT-qPCR, EdU, CCK8 and immunofluorescence assays demonstrated that the miR-183/96/182 cluster promoted proliferation and differentiation of bovine myoblast. Next, we found that the miR-183/96/182 cluster targeted FoxO1 and restrained its expression. Meanwhile, the expression of FoxO1 had a negative correlation with the expression of the miR-183/96/182 cluster during myoblast differentiation. In a word, our findings indicated that the miR-183/96/182 cluster serves as a positive regulator in the proliferation and differentiation of bovine myoblasts through suppressing the expression of FoxO1.
Collapse
|
8
|
Wei M, Ye C, Huang H, Yang C, Zhang L, Huang Y, Wang Y, Luo X, Luo J. Acacetin inhibits the tumor growth of human osteosarcoma cells through regulating Wnt/β-catenin and JNK signaling pathways. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
|
9
|
Dawood AF, Younes S, Alzamil NM, Alradini FA, Saja MF. Inhibition of glycogen synthase kinase-3β protects against collagen type II-induced arthritis associated with the inhibition of miR155/24 and inflammation and upregulation of apoptosis in rats. Arch Physiol Biochem 2022; 128:679-687. [PMID: 31994915 DOI: 10.1080/13813455.2020.1716021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA) and their syntheses are modulated by glycogen synthase kinase-3β (GSK-3β). Therefore, we hypothesised that the GSK-3β inhibitor, TDZD-8 can protect against collagen-induced arthritis (CIA) via downregulating miR155 and miR-24 expression. Rats were randomly allocated into four groups (n = 6) as follows: Control, Control + TDZD-8 (1 mg/kg), CIA, and CIA + TDZD-8. Rats were sacrificed after 6 weeks. We observed in the model group (CIA) significant (p<.05) increase in arthritis score and serum levels of RA biomarkers, which were significantly (p < .05) inhibited by TDZD-8. TDZD-8 also significantly (p<.05) inhibited CIA-induced synovial tissue levels of miR155, miR-24, and inflammation. In addition, a significant (p<.05) modulation of biomarkers of survival (Bcl-2) and apoptosis (cleaved caspase-3) by TDZD-8 was observed. Thus, TDZD-8 protects against CIA in rats for a period of 6 weeks, which is associated with the inhibition of miR155/24 and inflammation, and apoptosis augmentation.
Collapse
Affiliation(s)
- Amal F Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sheren Younes
- Department of Pathology, Faculty of Medicine, Menoufia University, Egypt
| | - Norah M Alzamil
- Department of Clinical Sciences, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Faten A Alradini
- Department of Clinical Sciences, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Maha Fahad Saja
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
10
|
Transcriptional and post-transcriptional control of epithelial-mesenchymal plasticity: why so many regulators? Cell Mol Life Sci 2022; 79:182. [PMID: 35278142 PMCID: PMC8918127 DOI: 10.1007/s00018-022-04199-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/18/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
The dynamic transition between epithelial-like and mesenchymal-like cell states has been a focus for extensive investigation for decades, reflective of the importance of Epithelial-Mesenchymal Transition (EMT) through development, in the adult, and the contributing role EMT has to pathologies including metastasis and fibrosis. Not surprisingly, regulation of the complex genetic networks that underlie EMT have been attributed to multiple transcription factors and microRNAs. What is surprising, however, are the sheer number of different regulators (hundreds of transcription factors and microRNAs) for which critical roles have been described. This review seeks not to collate these studies, but to provide a perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.
Collapse
|
11
|
Gharib AF, Eed EM, Khalifa AS, Raafat N, Shehab-Eldeen S, Alwakeel HR, Darwiesh E, Essa A. Value of Serum miRNA-96-5p and miRNA-99a-5p as Diagnostic Biomarkers for Hepatocellular Carcinoma. Int J Gen Med 2022; 15:2427-2436. [PMID: 35264879 PMCID: PMC8901257 DOI: 10.2147/ijgm.s354842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/15/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose Circulatory microRNAs (miRNAs) have the potential to be employed as markers for cancer detection and as prognostic tools for disease management. As a result, our goal was to explore the effectiveness of serum miRNA-96-5p and miRNA-99a-5p as diagnostic tools in hepatocellular carcinoma (HCC). Patients and methods Blood samples were collected from 55 patients with HCV-induced HCC, 55 patients with HCV-induced liver cirrhosis, and 55 healthy controls. The expression levels of miRNA-96-5p and miRNA-99a-5p were measured using quantitative RT-PCR. Results miRNA-96-5p expression levels were increased in HCC patient sera, while miRNA-99a-5p levels were reduced. According to ROC curve analysis, using a combination of circulating miRNA-96-5p, miRNA-99a-5-, and alpha-fetoprotein (AFP) improves the accuracy of diagnoses for HCC, with an area under the curve (AUC) of 0.97, compared to AUCs of 0.82, 0.86, and 0.73, respectively, for the individual biomarkers. Furthermore, the present data suggested that higher serum miRNA-96-5p levels were linked to larger tumors and metastasis, whereas lower serum miRNA-99a-5p levels were exclusively linked to HCC metastasis. Conclusion Using miRNA-96-5p and miRNA-99a-5p in combination with AFP increased both sensitivity and specificity for the diagnosis of HCC. Furthermore, serum levels were linked to tumor size and metastasis. These findings suggested that serum miRNA-96-5p and miRNA-99a-5p could be used as non-invasive biomarkers for the diagnosis of HCC.
Collapse
Affiliation(s)
- Amal F Gharib
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, 21944, Saudi Arabia
| | - Emad M Eed
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, 21944, Saudi Arabia
| | - Amany S Khalifa
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Nermin Raafat
- Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Somaia Shehab-Eldeen
- Tropical Medicine Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
- Department of Internal Medicine, College of Medicine, King Faisal University, Al-Ahsaa, Saudi Arabia
- Correspondence: Somaia Shehab-Eldeen, Tropical Medicine Department, Faculty of Medicine, Menoufia University, Yassen Abd Al Ghafar Street, Shebin El-Kom, 32511, Egypt, Tel +20 1117251523, Email
| | - Hany R Alwakeel
- Department of Hepatology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ehab Darwiesh
- Department of Tropical Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Abdallah Essa
- Tropical Medicine Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
- Department of Internal Medicine, College of Medicine, King Faisal University, Al-Ahsaa, Saudi Arabia
| |
Collapse
|
12
|
Fu R, Dou Z, Li N, Zhang J, Li Z, Yang P. Avenanthramide C induces cellular senescence in colorectal cancer cells via suppressing β-catenin-mediated the transcription of miR-183/96/182 cluster. Biochem Pharmacol 2022; 199:115021. [DOI: 10.1016/j.bcp.2022.115021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/06/2022] [Accepted: 03/23/2022] [Indexed: 12/13/2022]
|
13
|
Rahimi HR, Mojarrad M, Moghbeli M. MicroRNA-96: A therapeutic and diagnostic tumor marker. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:3-13. [PMID: 35656454 DOI: 10.22038/ijbms.2021.59604.13226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/19/2021] [Indexed: 12/17/2022]
Abstract
Cancer has been always considered as one of the main human health challenges worldwide. One of the main causes of cancer-related mortality is late diagnosis in the advanced stages of the disease, which reduces the therapeutic efficiency. Therefore, novel non-invasive diagnostic methods are required for the early detection of tumors and improving the quality of life and survival in cancer patients. MicroRNAs (miRNAs) have pivotal roles in various cellular processes such as cell proliferation, motility, and neoplastic transformation. Since circulating miRNAs have high stability in body fluids, they can be suggested as efficient noninvasive tumor markers. MiR-96 belongs to the miR-183-96-182 cluster that regulates cell migration and tumor progression as an oncogene or tumor suppressor by targeting various genes in solid tumors. In the present review, we have summarized all of the studies that assessed the role of miR-96 during tumor progression. This review clarifies the molecular mechanisms and target genes recruited by miR-96 to regulate tumor progression and metastasis. It was observed that miR-96 mainly affects tumorigenesis by targeting the structural proteins and FOXO transcription factors.
Collapse
Affiliation(s)
- Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarrad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
14
|
Wang X, Sipila P, Si Z, Rosales JL, Gao X, Lee KY. CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway. Cell Death Dis 2021; 13:9. [PMID: 34930892 PMCID: PMC8688469 DOI: 10.1038/s41419-021-04457-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/23/2021] [Accepted: 12/07/2021] [Indexed: 12/03/2022]
Abstract
Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.
Collapse
Affiliation(s)
- Xidi Wang
- grid.22072.350000 0004 1936 7697Department of Cell Biology & Anatomy, Arnie Charbonneau Cancer and Alberta Children’s Hospital Research Institutes, Cumming School of Medicine, University of Calgary, Calgary, AB Canada ,grid.410736.70000 0001 2204 9268Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, China
| | - Patrick Sipila
- grid.22072.350000 0004 1936 7697Department of Cell Biology & Anatomy, Arnie Charbonneau Cancer and Alberta Children’s Hospital Research Institutes, Cumming School of Medicine, University of Calgary, Calgary, AB Canada
| | - Zizhen Si
- grid.410736.70000 0001 2204 9268Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, China
| | - Jesusa L. Rosales
- grid.22072.350000 0004 1936 7697Department of Cell Biology & Anatomy, Arnie Charbonneau Cancer and Alberta Children’s Hospital Research Institutes, Cumming School of Medicine, University of Calgary, Calgary, AB Canada
| | - Xu Gao
- grid.410736.70000 0001 2204 9268Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, China
| | - Ki-Young Lee
- Department of Cell Biology & Anatomy, Arnie Charbonneau Cancer and Alberta Children's Hospital Research Institutes, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| |
Collapse
|
15
|
Xie G, Dong P, Chen H, Xu L, Liu Y, Ma Y, Zheng Y, Yang J, Zhou Y, Chen L, Shen L. Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP. Exp Mol Med 2021; 53:1706-1722. [PMID: 34728784 PMCID: PMC8639750 DOI: 10.1038/s12276-021-00694-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/09/2021] [Accepted: 08/24/2021] [Indexed: 01/04/2023] Open
Abstract
ATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients. New treatments for gastric cancer could involve controlling the activity of a regulatory gene and associated signaling pathway. Over-activation of the Wnt signaling pathway, which regulates many cellular functions, occurs in around half of gastric cancers. Further, the activating transcription factor 3 gene (ATF3) is thought to influence tumorigenesis, although its role in gastric cancer is unclear. Guohua Xie and co-workers at Shanghai Jiao Tong University, China, explored the function of ATF3 in human gastric cancer tissues. Patients with low ATF3 expression had poorer prognosis and shorter life expectancy. The team discovered that reduced expression of ATF3 triggered the increased expression of two of its target genes, which then altered Wnt signaling. Reduced ATF3 expression also boosted the invasiveness of gastric cancer cells. Initial results suggest that overexpression of ATF3 could suppress gastric cancer progression.
Collapse
Affiliation(s)
- Guohua Xie
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ping Dong
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Xu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingxia Zheng
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junyao Yang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Chen
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Faculty of Medical Laboratory Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
16
|
Epigenetic Silencing of SOX15 Is Controlled by miRNAs rather than Methylation in Papillary Thyroid Cancer. DISEASE MARKERS 2021; 2021:1588220. [PMID: 34603557 PMCID: PMC8486500 DOI: 10.1155/2021/1588220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/11/2021] [Accepted: 09/11/2021] [Indexed: 11/17/2022]
Abstract
Methods In this study, qRT-PCR was used to investigate the expression levels of the SOX15 gene and of miR-182, miR-183, miR-375, and miR-96 in thyroid tumors and adjacent noncancerous tissues. We also investigated the methylation status of the SOX15 promoter by methylation-specific PCR in tumors and adjacent noncancerous tissues. Results We observed a statistically significant downregulation of SOX15 expression in tumors compared to noncancerous tissue samples. The methylation levels of tumors and matched noncancerous tissues were similar, but miR-182, miR-183, and miR-375 expression levels were elevated in tumor tissues compared to noncancerous tissue samples. Conclusions Our results indicate that SOX15 gene expression is associated with the pathogenesis of papillary thyroid carcinoma (PTC), and the epigenetic control of the SOX15 gene is regulated by miRNAs rather than by promoter methylation.
Collapse
|
17
|
Shan MJ, Meng LB, Guo P, Zhang YM, Kong D, Liu YB. Screening and Identification of Key Biomarkers of Gastric Cancer: Three Genes Jointly Predict Gastric Cancer. Front Oncol 2021; 11:591893. [PMID: 34485109 PMCID: PMC8416116 DOI: 10.3389/fonc.2021.591893] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most common cancers all over the world, causing high mortality. Gastric cancer screening is one of the effective strategies used to reduce mortality. We expect that good biomarkers can be discovered to diagnose and treat gastric cancer as early as possible. Methods We download four gene expression profiling datasets of gastric cancer (GSE118916, GSE54129, GSE103236, GSE112369), which were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between gastric cancer and adjacent normal tissues were detected to explore biomarkers that may play an important role in gastric cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of overlap genes were conducted by the Metascape online database; the protein-protein interaction (PPI) network was constructed by the STRING online database, and we screened the hub genes of the PPI network using the Cytoscape software. The survival curve analysis was conducted by km-plotter and the stage plots of hub genes were created by the GEPIA online database. PCR, WB, and immunohistochemistry were used to verify the expression of hub genes. A neural network model was established to quantify the predictors of gastric cancer. Results The relative expression level of cadherin-3 (CDH3), lymphoid enhancer-binding factor 1 (LEF1), and matrix metallopeptidase 7 (MMP7) were significantly higher in gastric samples, compared with the normal groups (p<0.05). Receiver operator characteristic (ROC) curves were constructed to determine the effect of the three genes’ expression on gastric cancer, and the AUC was used to determine the degree of confidence: CDH3 (AUC = 0.800, P<0.05, 95% CI =0.857-0.895), LEF1 (AUC=0.620, P<0.05, 95%CI=0.632-0.714), and MMP7 (AUC=0.914, P<0.05, 95%CI=0.714-0.947). The high-risk warning indicator of gastric cancer contained 8<CDH3<15 and 10<expression of LEF1<16. Conclusions CDH3, LEF1, and MMP7 can be used as candidate biomarkers to construct a neural network model from hub genes, which may be helpful for the early diagnosis of gastric cancer.
Collapse
Affiliation(s)
- Meng-Jie Shan
- Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China.,Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ling-Bing Meng
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Cardiology Department, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Peng Guo
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuan-Meng Zhang
- Department of Cardiology, The Third Medical Centre of Chinese PLA General Hospital, Beijing, China
| | - Dexian Kong
- Department of Endocrinology, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ya-Bin Liu
- Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
18
|
Yao W, Wang S, Du X, Lin C, Zhang J, Pan Z, Li Q. SMAD4 Inhibits Granulosa Cell Apoptosis via the miR-183-96-182 Cluster and FoxO1 Axis. Reprod Sci 2021; 29:1577-1585. [PMID: 34287793 DOI: 10.1007/s43032-021-00690-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 07/04/2021] [Indexed: 12/21/2022]
Abstract
The miR-183-96-182 cluster is a polycistronic miRNA cluster necessary for ovarian functions in mammals. However, its transcriptional regulation in the ovary is largely unclear. In this study, we characterized the promoter region of the porcine miR-183-96-182 cluster, and showed that SMAD4 may function as a transcriptional activator of the miR-183-96-182 cluster in GCs through direct binding to SBE motifs in its promoter. SMAD4 may inhibit GC apoptosis via suppression of FoxO1, an effector of GC apoptosis and a direct target of the miR-183-96-182 cluster, by inducing the miR-183-96-182 cluster, and this process may be regulated by the TGF-β/SMAD signaling pathway. Our findings uncovered the regulatory mechanism of miR-183-96-182 cluster expression in GCs and demonstrated that TGF-β1/SMAD4/miR-183-96-182 cluster/FoxO1 may be a potential pathway for regulating follicular atresia and female reproduction.
Collapse
Affiliation(s)
- Wang Yao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Siqi Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xing Du
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Chenggang Lin
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jinbi Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Zengxiang Pan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Qifa Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| |
Collapse
|
19
|
Zhou C, Jin H, Li W, Zhao R, Chen C. CTNNB1 S37C mutation causing cells proliferation and migration coupled with molecular mechanisms in lung adenocarcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:681. [PMID: 33987379 PMCID: PMC8106026 DOI: 10.21037/atm-21-1146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background This study aimed to investigate the potential cytological effects and molecular mechanisms of β-catenin (CTNNB1) S37C mutation in lung adenocarcinoma (LUAD). Methods CTNNB1 with S37C mutation were transfected into LUAD cell lines. The expression of β-catenin were determined using Western blot. Cell proliferation and migration were detected using cell counting kit-8 (CCK-8) assay and wound healing assay, respectively. Transcriptome sequencing was performed on LUAD cells with CTNNB1 S37C mutation (CTNNB1 mutation group) and LUAD cells without treatment (Control group), followed by the screening of differentially expressed genes (DEGs). Functional enrichment analysis and protein-protein interaction (PPI) analysis were performed for the DEGs. Finally, the expression of key DEGs were validated by quantitative real-time PCR (qRT-PCR). Results CTNNB1 with S37C mutation was successful expressed in 2 cell lines. Cells proliferation and migration were significantly promoted in mutation group in comparison with that of Control group (P<0.05). A total of 180 DEGs were revealed between Control and CTNNB1 mutation groups. These DEGs were mainly enriched in extracellular matrix function and nicotine addiction pathway. PPI network contained 51 DEGs and 45 interactions. PTPRD, GNG7 and CNTN1 were hub genes in PPI network with higher degree. CGB5 interacted with PTPRU, while IGFBP3 showed interaction with MMP1. Results of qRT-PCR confirmed the expression of several key DEGs in transcriptome analysis. Conclusions CTNNB1 S37C mutation contributed the LUAD cells proliferation and migration. PTPRD, IGFBP-3, MMP1 and PTPRU might play roles in the effect of CTNNB1 S37C mutation in LUAD.
Collapse
Affiliation(s)
- Chao Zhou
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Haizhen Jin
- The Central Lab, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wentao Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruiying Zhao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
20
|
Zi Shen Decoction Inhibits Growth and Metastasis of Lung Cancer via Regulating the AKT/GSK-3 β/ β-Catenin Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6685282. [PMID: 33777320 PMCID: PMC7969097 DOI: 10.1155/2021/6685282] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/15/2020] [Accepted: 02/10/2021] [Indexed: 12/11/2022]
Abstract
Lung cancer has become the leading cause of cancer-related death worldwide. Oxidative stress plays important roles in the pathogenesis of lung cancer. Many natural products show antioxidative activities in cancer treatment. Zi Shen decoction (ZSD) is a classic prescription for the treatment of lung disease. However, its effect on lung cancer lacks evidence-based efficacy. In this study, we investigated the anticancer effects of ZSD on lung cancer in vivo and in vitro. Our results showed that oral administration of ZSD suppressed the Lewis lung cancer (LLC) growth in a subcutaneous allograft model and promoted necrosis and inflammatory cell infiltration in the tumor tissues. Furthermore, ZSD not only inhibited tumor cell proliferation and migration but also induced cell apoptosis in lung cancer cells. PI3K/AKT signaling is well characterized in response to oxidative stress. The bioinformatics analysis and western blot assays suggested that ZSD decreased the enzyme activity of PI3K and AKT in vivo and in vitro. We also found that the AKT/GSK-3β/β-catenin pathway medicated anticancer effect of ZSD in lung cancer cells. In conclusion, we demonstrate for the first time that ZSD possesses antitumor properties, highlighting its potential use as an alternative strategy or adjuvant treatment for lung cancer therapy.
Collapse
|
21
|
Fan S, Zhao S, Gao X, Qin Q, Guo Y, Yuan Z, Zhang M, Liu Q, Li H. Circular RNA circGSE1 Promotes Cervical Cancer Progression Through miR-138-5p/Vimentin. Onco Targets Ther 2021; 13:13371-13386. [PMID: 33408484 PMCID: PMC7781114 DOI: 10.2147/ott.s282425] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/04/2020] [Indexed: 01/01/2023] Open
Abstract
Background A growing number of studies have identified that circular RNAs (circRNAs) play a vital role in the progression of various tumors. However, the underlying functions and mechanisms of circRNAs in cervical cancer have not been clarified. Methods qRT-PCR was used to detect the level of circGSE1 in cervical cancer tissues and matched normal tissues. In vitro cell wound healing, transwell migration and invasion assays were employed to assess the effects of circGSE1 on cell mobility. The pull-down, luciferase reporter, RIP and rescue assays were performed to evaluate the interaction between circGSE1and miR-138-5p and the regulation of miR-138-5p on Vimentin. Results We found that circGSE1 was significantly higher in cervical cancer tissues than that in matched normal tissues. Further analyses revealed that the level of circGSE1 was positively correlated with tumor differentiation, FIGUREO stage, depth of stromal invasion, lymph node metastasis and infiltration of parauterine organ. Kaplan–Meier survival analysis showed that high circGSE1 predicted worse overall survival and disease-free survival. Down-regulated circGSE1 evidently inhibited cell migration and metastasis of cervical cancer, while up-regulated circGSE1 significantly promoted cell migration and metastasis. The pull-down, luciferase reporter and RIP assays revealed that circGSE1 directly bound to and sponge miR-138-5p. MiR-138-5p inhibited the expression of Vimentin through directly binding to 3ʹUTR of Vimentin mRNA. In addition, miR-138-5p suppressed cell migration and invasion through inhibiting Vimentin expression, and circGSE1 promoted cell migration and invasion through sponging miR-138-5p and enhancing Vimentin expression. Conclusion CircGSE1 promotes the progression and may act as a novel diagnostic biomarker for disease progression of cervical cancer.
Collapse
Affiliation(s)
- Suzhen Fan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Shujun Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Xiang Gao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Qiaohong Qin
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Yan Guo
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Zhongfu Yuan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Min Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Qing Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Hongyu Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| |
Collapse
|
22
|
Nguyen MT, Min KH, Lee W. MiR-96-5p Induced by Palmitic Acid Suppresses the Myogenic Differentiation of C2C12 Myoblasts by Targeting FHL1. Int J Mol Sci 2020; 21:ijms21249445. [PMID: 33322515 PMCID: PMC7764195 DOI: 10.3390/ijms21249445] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 12/31/2022] Open
Abstract
Skeletal myogenesis is a multi-stage process that includes the cell cycle exit, myogenic transcriptional activation, and morphological changes to form multinucleated myofibers. Recent studies have shown that saturated fatty acids (SFA) and miRNAs play crucial roles in myogenesis and muscle homeostasis. Nevertheless, the target molecules and myogenic regulatory mechanisms of miRNAs are largely unknown, particularly when myogenesis is dysregulated by SFA deposition. This study investigated the critical role played by miR-96-5p on the myogenic differentiation in C2C12 myoblasts. Long-chain SFA palmitic acid (PA) significantly reduced FHL1 expression and inhibited the myogenic differentiation of C2C12 myoblasts but induced miR-96-5p expression. The knockdown of FHL1 by siRNA stimulated cell proliferation and inhibited myogenic differentiation of myoblasts. Interestingly, miR-96-5p suppressed FHL1 expression by directly targeting the 3’UTR of FHL1 mRNA. The transfection of an miR-96-5p mimic upregulated the expressions of cell cycle-related genes, such as PCNA, CCNB1, and CCND1, and increased myoblast proliferation. Moreover, the miR-96-5p mimic inhibited the expressions of myogenic factors, such as myoblast determination protein (MyoD), myogenin (MyoG), myocyte enhancer factor 2C (MEF2C), and myosin heavy chain (MyHC), and dramatically impeded differentiation and fusion of myoblasts. Overall, this study highlights the role of miR-96-5p in myogenesis via FHL1 suppression and suggests a novel regulatory mechanism for myogenesis mediated by miRNA in a background of obesity.
Collapse
Affiliation(s)
- Mai Thi Nguyen
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Korea; (M.T.N.); (K.-H.M.)
| | - Kyung-Ho Min
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Korea; (M.T.N.); (K.-H.M.)
| | - Wan Lee
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Korea; (M.T.N.); (K.-H.M.)
- Channelopathy Research Center (CRC), Dongguk University College of Medicine, 32 Dongguk-ro, Ilsan Dong-gu, 10326 Goyang, Korea
- Correspondence: ; Tel.: +82-54-770-2409; Fax: +82-54-770-2447
| |
Collapse
|
23
|
Chang TS, Lu CK, Hsieh YY, Wei KL, Chen WM, Tung SY, Wu CS, Chan MWY, Chiang MK. 2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis. Int J Mol Sci 2020; 21:ijms21165901. [PMID: 32824603 PMCID: PMC7460562 DOI: 10.3390/ijms21165901] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/12/2020] [Accepted: 08/15/2020] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/β-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/β-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.
Collapse
Affiliation(s)
- Te-Sheng Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chung-Kuang Lu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
- Correspondence: (C.-K.L.); (M.-K.C.); Tel.: +886-5-3621000 (ext. 2077) (C.-K.L.); +886-5-2720411 (ext. 66505) (M.-K.C.); Fax: +886-5-3623005 (C.-K.L.); +886-5-2722871 (M.-K.C.)
| | - Yung-Yu Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
| | - Kuo-Liang Wei
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wei-Ming Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
| | - Sui-Yi Tung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
| | - Cheng-Shyong Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61303, Taiwan; (T.-S.C.); (Y.-Y.H.); (K.-L.W.); (W.-M.C.); (S.-Y.T.); (C.-S.W.)
| | - Michael W. Y. Chan
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi 62102, Taiwan;
| | - Ming-Ko Chiang
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi 62102, Taiwan;
- Correspondence: (C.-K.L.); (M.-K.C.); Tel.: +886-5-3621000 (ext. 2077) (C.-K.L.); +886-5-2720411 (ext. 66505) (M.-K.C.); Fax: +886-5-3623005 (C.-K.L.); +886-5-2722871 (M.-K.C.)
| |
Collapse
|
24
|
Duda P, Akula SM, Abrams SL, Steelman LS, Gizak A, Rakus D, McCubrey JA. GSK-3 and miRs: Master regulators of therapeutic sensitivity of cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118770. [PMID: 32524999 DOI: 10.1016/j.bbamcr.2020.118770] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 01/04/2023]
Abstract
Glycogen synthetase kinase-3 (GSK-3) and microRNAs (miRs) affect many critical signaling pathways important in cell growth. GSK-3 is a serine/threonine (S/T) protein kinase. Often when GSK-3 phosphorylates other proteins, they are inactivated and the signaling pathway is shut down. The PI3K/PTEN/AKT/GSK3/mTORC1 pathway plays key roles in regulation of cell growth, apoptosis, drug resistance, malignant transformation and metastasis and is often deregulated in cancer. When GSK-3 is phosphorylated by AKT it is inactivated and this often leads to growth promotion. When GSK-3 is not phosphorylated by AKT or other kinases at specific negative-regulatory residues, it can modify the activity of many proteins by phosphorylation, some of these proteins promote while others inhibit cell proliferation. This is part of the conundrum regarding GSK-3. The central theme of this review is the ability of GSK-3 to serve as either a tumor suppressor or a tumor promoter in cancer which is likely due to its diverse protein substrates. The effects of multiple miRs which bind mRNAs encoding GSK-3 and other signaling molecules and how they affect cell growth and sensitivity to various therapeutics will be discussed as they serve to regulate GSK-3 and other proteins important in controlling proliferation.
Collapse
Affiliation(s)
- Przemysław Duda
- Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland
| | - Shaw M Akula
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
| | - Agnieszka Gizak
- Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland
| | - Dariusz Rakus
- Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA; Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Brody Building 5N98C, Greenville, NC 27858, USA.
| |
Collapse
|
25
|
Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
| |
Collapse
|
26
|
LINC00163 inhibits the invasion and metastasis of gastric cancer cells as a ceRNA by sponging miR-183 to regulate the expression of AKAP12. Int J Clin Oncol 2020; 25:570-583. [PMID: 31894433 DOI: 10.1007/s10147-019-01604-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/11/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Gastric cancer (GC) is the most common and aggressive cancer of the digestive system and poses a serious threat to human health. Since genes do not work alone, our aim was to elucidate the potential network of mRNAs and noncoding RNAs (ncRNAs) in this study. METHODS Transcriptome data of GC were obtained from TCGA. R and Perl were used to obtain the differentially expressed RNAs and construct a competing endogenous RNA (ceRNA) regulatory network. To investigate the biological functions of differentially expressed RNAs, loss-of-function and gain-of-function experiments were performed. Real-time PCR (RT-qPCR), western blot analysis, dual-luciferase reporter assays and fluorescence in situ hybridization were conducted to explore the underlying mechanisms of competitive endogenous RNAs (ceRNAs). RESULTS Based on TCGA data and bioinformatics analysis, we identified the LINC00163/miR-183/A-Kinase Anchoring Protein 12 (AKAP12) axis. We observed that AKAP12 was weakly expressed in GC and suppressed invasion and metastasis in GC cells, which could be abolished by miR-183. In addition, LINC00163 can be used as a ceRNA to inhibit the expression of miR-183, thus enhancing the anticancer effect of AKAP12. CONCLUSION Our results demonstrated that weak LINC00163 expression in GC can sponge miR-183 to promote AKAP12. We established that the LINC00163/miR-183/AKAP12 axis plays an important role in GC invasion and metastasis and may be a potential biomarker and target for GC treatment.
Collapse
|
27
|
Cao D, Di M, Liang J, Shi S, Tan Q, Wang Z. MicroRNA-183 in Cancer Progression. J Cancer 2020; 11:1315-1324. [PMID: 32047538 PMCID: PMC6995398 DOI: 10.7150/jca.39044] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/16/2019] [Indexed: 12/15/2022] Open
Abstract
MicroRNA-183(miR-183) is abnormally expressed in many kinds of tumors. It participates in the initiation and development of tumors. There are many pathways regulate the expression of miR-183. The action mechanism of miR-183 in cancer is very extensive, and contradictory conclusions are often drawn. It was upregulated in 18 kinds of cancer, downregulated in 6 kinds of cancer. In addition, there are seven types of cancer, both upregulated and downregulated reports can be found. Evidence showed that miR-183 can not only directly play the role of oncogene or antioncogene, but also regulate the expression of other oncogene or antioncogene in different cancer types. In this review, we discuss the regulator of miR-183 and summarized the expression of miR-183 in different cancers. We also counted the target genes of miR-183 and the functional roles they play. Furthermore, we focused on the roles of miR-183 in cell migration, cell invasion, epithelial-mesenchymal transition (EMT) and microangiogenesis, which play the most important roles in cancer processes. It sheds light on the likely reasons why miR-183 plays different roles in various cancers. In addition, miR-183 and its downstream effectors have the potential to be promising prognostic markers and therapeutic targets in cancer.
Collapse
Affiliation(s)
- Dingren Cao
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Min Di
- Sir Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, 310058, P. R. China
| | - Jingjie Liang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Shuang Shi
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Qiang Tan
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
| | - Zhengguang Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
| |
Collapse
|
28
|
miR-1185-1 and miR-548q Are Biomarkers of Response to Weight Loss and Regulate the Expression of GSK3B. Cells 2019; 8:cells8121548. [PMID: 31801236 PMCID: PMC6953011 DOI: 10.3390/cells8121548] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of the present investigation was to identify putative miRNAs involved in the response to weight loss. Reverse-transcribed RNA isolated from white blood cells (WBCs) of a subpopulation from the Reduction of the Metabolic Syndrome in Navarra-Spain (RESMENA-S) study (low-responders (LR) and high-responders (HR)) was hybridized in a gene expression microarray. Moreover, miRNAs were sequenced by miRNA-Seq. It was found that miR-548q and miR-1185-1 were overexpressed in HR, both in the microarray and in the miRNA-Seq. A bioinformatic prediction of putative target genes of the selected miRNAs found that GSK3B, a putative target for miR-548q and miR-1185-1, was downregulated in HR. Particular 3′-UTR binding regions of GSK3B were cloned downstream of the firefly luciferase gene. HEK-293T cells were co-transfected with either 0.25 μg of empty pmiR-GLO or pmiR-GLO-548q-3′-UTR/pmiR-GLO-1185-1-3′-UTR, and 7.5 pmol of miR-548q/miR-1185-1 mimics, demonstrating that miR-1185-1 bound to the 3′-UTR region of GSK3B. THP-1 cells were transfected with either 20/40 nM of miR-548q/miR-1185-1 mimics, evidencing that miR-1185-1inhibited the expression of the gene when transfected at doses of 20/40 nM, whereas miR-548q inhibited GSK3B expression at a dose of 40 nM. As a conclusion, miR-548q and miR-1185-1 levels in WBCs are biomarkers of response to weight-loss diets and could be involved in the regulation of the proinflammatory gene GSK3B.
Collapse
|
29
|
Xiang W, Han L, Mo G, Lin L, Yu X, Chen S, Gao T, Huang C. MicroRNA-96 is a potential tumor repressor by inhibiting NPTX2 in renal cell carcinoma. J Cell Biochem 2019; 121:1504-1513. [PMID: 31498486 DOI: 10.1002/jcb.29385] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 08/28/2019] [Indexed: 12/22/2022]
Abstract
MicroRNA-96 (miR-96) is a vertebrate conserved microRNA which plays important roles in various cancers including renal cell carcinoma (RCC). However, its function and mechanism in RCC are still unclear. In this study, miR-96 was found to be downregulated in RCC based on The Cancer Genome Atlas datasets analyses, and its target genes, which predicted by TargetScan, were investigated. Among these target genes, neuronal pentraxin 2 (NPTX2) was upregulated more than 15-fold in RCC, and moreover, closely related to patient survival. To validate its targeting of NPTX2 experimentally, reverse transcription polymerase chain reaction, Western blot analysis, and dual-luciferase assays were performed, and results of these assays demonstrated that miR-96 inhibited expression of NPTX2 through a single 3'-untranslated region targeting site. Furthermore, transfection assays in RenCa and 786-O cells showed miR-96 and small interfering RNA of NPTX2 inhibited cell proliferation, migration, and invasion and overexpression of NPTX2 recovered the inhibition of miR-96. In conclusion, the present study reveals a novel regulatory mechanism of miR-96 on NPTX2 expression in RCC, and the potential of miR-96 as a RCC tumor repressor deserves further investigation.
Collapse
Affiliation(s)
- Wei Xiang
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Lintao Han
- China Key Laboratory of TCM Resource and Prescription, Hubei University of Chinese Medicine, Wuhan, China
| | - Guoyan Mo
- China Key Laboratory of TCM Resource and Prescription, Hubei University of Chinese Medicine, Wuhan, China
| | - Li Lin
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Xiaoming Yu
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Shaowen Chen
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Tiexiang Gao
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| | - Chunhua Huang
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, China
| |
Collapse
|
30
|
DC-SIGN-LEF1/TCF1-miR-185 feedback loop promotes colorectal cancer invasion and metastasis. Cell Death Differ 2019; 27:379-395. [PMID: 31217502 PMCID: PMC7205996 DOI: 10.1038/s41418-019-0361-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/31/2019] [Accepted: 05/28/2019] [Indexed: 02/07/2023] Open
Abstract
DC-SIGN is previously focused on its physiologic and pathophysiologic roles in immune cells. Little is known about whether DC-SIGN is expressed in malignant epithelial cells and how DC-SIGN participates in tumor progression. Here we showed that DC-SIGN expression was increased in metastatic colorectal cancer (CRC) cell lines and patient tissues. The overall survival in CRC patients with positive DC-SIGN was remarkably reduced. Gain of DC-SIGN function facilitated the CRC metastases both in vitro and in vivo, and this effect was reversed by miR-185. DC-SIGN and Lyn interacted physically, and Lyn maintained the stability of DC-SIGN in cells. DC-SIGN activation recruited Lyn and p85 to form the DC-SIGN-Lyn-p85 complex, which promoted CRC metastasis by increasing PI3K/Akt/β-catenin signaling in tyrosine kinase Lyn-dependent manner. Furthermore, activation of DC-SIGN promoted the transcription of MMP-9 and VEGF by increasing PI3K/Akt/β-catenin signaling, and induced TCF1/LEF1-mediated suppression of miR-185. Our findings reveal the presence of the DC-SIGN–TCF1/LEF1–miR-185 loop in cancer cells with metastatic traits, implying that it may represent a new pathogenic mechanism of CRC metastasis. This character of the loop promises to provide new targets for blocking CRC invasive and metastatic activity.
Collapse
|
31
|
Nagini S, Sophia J, Mishra R. Glycogen synthase kinases: Moonlighting proteins with theranostic potential in cancer. Semin Cancer Biol 2019; 56:25-36. [DOI: 10.1016/j.semcancer.2017.12.010] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 10/23/2017] [Accepted: 12/28/2017] [Indexed: 12/11/2022]
|
32
|
Xu B, Wang T, Xiao J, Dong W, Wen HZ, Wang X, Qin Y, Cai N, Zhou Z, Xu J, Wang H. FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/ β-catenin signaling pathway. Biochem Pharmacol 2019; 163:234-249. [DOI: 10.1016/j.bcp.2019.02.023] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/18/2019] [Indexed: 02/08/2023]
|
33
|
Sahin I, Eturi A, De Souza A, Pamarthy S, Tavora F, Giles FJ, Carneiro BA. Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses. Cancer Biol Ther 2019; 20:1047-1056. [PMID: 30975030 DOI: 10.1080/15384047.2019.1595283] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As a kinase at the crossroads of numerous metabolic and cell growth signaling pathways, glycogen synthase kinase-3 beta (GSK-3β) is a highly desirable therapeutic target in cancer. Despite its involvement in pathways associated with the pathogenesis of several malignancies, no selective GSK-3β inhibitor has been approved for the treatment of cancer. The regulatory role of GSK-3β in apoptosis, cell cycle, DNA repair, tumor growth, invasion, and metastasis reflects the therapeutic relevance of this target and provides the rationale for drug combinations. Emerging data on GSK-3β as a mediator of anticancer immune response also highlight the potential clinical applications of novel selective GSK-3β inhibitors that are entering clinical studies. This manuscript reviews the preclinical and early clinical results with GSK-3β inhibitors and delineates the developmental therapeutics landscape for this potentially important target in cancer therapy.
Collapse
Affiliation(s)
- Ilyas Sahin
- a Lifespan Cancer Institute, Division of Hematology/Oncology , The Warren Alpert Medical School of Brown University , Providence , RI , USA
| | - Aditya Eturi
- b Department of Medicine , The Warren Alpert Medical School of Brown University , Providence , RI , USA
| | - Andre De Souza
- a Lifespan Cancer Institute, Division of Hematology/Oncology , The Warren Alpert Medical School of Brown University , Providence , RI , USA
| | - Sahithi Pamarthy
- c Atrin Pharmaceuticals , Pennsylvania Biotechnology Center , Doylestown , PA , USA
| | - Fabio Tavora
- d Argos Laboratory/Messejana Heart and Lung Hospital , Fortaleza , Brazil
| | - Francis J Giles
- e Developmental Therapeutics Consortium , Chicago , IL , USA
| | - Benedito A Carneiro
- a Lifespan Cancer Institute, Division of Hematology/Oncology , The Warren Alpert Medical School of Brown University , Providence , RI , USA
| |
Collapse
|
34
|
Wu X, Shen J, Xiao Z, Li J, Zhao Y, Zhao Q, Cho CH, Li M. An overview of the multifaceted roles of miRNAs in gastric cancer: Spotlight on novel biomarkers and therapeutic targets. Biochem Pharmacol 2019; 163:425-439. [PMID: 30857828 DOI: 10.1016/j.bcp.2019.03.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/07/2019] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs that have displayed strong association with gastric cancer (GC). Through the repression of target mRNAs, miRNAs regulate many biological pathways that are involved in cell proliferation, apoptosis, migration, invasion, metastasis as well as drug resistance. The detection of miRNAs in tissues and in body fluids emerges as a promising method in the diagnosis and prognosis of GC, due to their unique expression pattern in correlation with GC. Notably, miRNAs are also identified as potential therapeutic targets for GC therapy. The present review is thus to highlight the multifaceted roles of miRNAs in GC and in GC therapies, which would give indications for future research.
Collapse
Affiliation(s)
- Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
| |
Collapse
|
35
|
Pan J, Fan Z, Wang Z, Dai Q, Xiang Z, Yuan F, Yan M, Zhu Z, Liu B, Li C. CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:52. [PMID: 30717785 PMCID: PMC6360779 DOI: 10.1186/s13046-019-1049-7] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/17/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. METHODS Immunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays. RESULTS PA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of β-catenin through inactivation of GSK-3β via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data. CONCLUSIONS Our experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3β/β-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.
Collapse
Affiliation(s)
- Jiaomeng Pan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Zhiyuan Fan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Zhenqiang Wang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Qingqiang Dai
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Zhen Xiang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Min Yan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Zhenggang Zhu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Bingya Liu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
| | - Chen Li
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
| |
Collapse
|
36
|
Trinh TL, Kandell WM, Donatelli SS, Tu N, Tejera MM, Gilvary DL, Eksioglu EA, Burnette A, Adams WA, Liu J, Teer JK, Djeu JY, Coppola D, Wei S. Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells. Oncoimmunology 2019; 8:e1557372. [PMID: 30906652 PMCID: PMC6422376 DOI: 10.1080/2162402x.2018.1557372] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 11/07/2018] [Accepted: 12/01/2018] [Indexed: 01/02/2023] Open
Abstract
Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8+ T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3'untranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3'UTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by antisense TGFβ transfection into H1355 or H1299 tumor cells which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8+ T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells.
Collapse
Affiliation(s)
- Thu Le Trinh
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Wendy M Kandell
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
| | | | - Nhan Tu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Melba M Tejera
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Erika A Eksioglu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Alexis Burnette
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - William A Adams
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jinhong Liu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jamie K Teer
- Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Julie Y Djeu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Sheng Wei
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| |
Collapse
|
37
|
Yang F, Fang E, Mei H, Chen Y, Li H, Li D, Song H, Wang J, Hong M, Xiao W, Wang X, Huang K, Zheng L, Tong Q. Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1. Cancer Res 2018; 79:557-571. [PMID: 30563889 DOI: 10.1158/0008-5472.can-18-1559] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/27/2018] [Accepted: 12/11/2018] [Indexed: 11/16/2022]
Abstract
Circular RNAs (circRNA), a subclass of noncoding RNA characterized by covalently closed continuous loops, play emerging roles in tumorigenesis and aggressiveness. However, the functions and underlying mechanisms of circRNA in regulating Wnt/β-catenin signaling and cancer progression remain elusive. Here, we screen cis-acting circRNA generated by β-catenin (CTNNB1)/transcription factor 7-like 2 genes and identify one intronic circRNA derived from CTNNB1 (circ-CTNNB1) as a novel driver of cancer progression. Circ-CTNNB1 was predominantly expressed in the nucleus, upregulated in cancer tissues and cell lines, and associated with unfavorable outcomes in patients with cancer. Circ-CTNNB1 promoted β-catenin activation, growth, invasion, and metastasis in cancer cells. Circ-CTNNB1 bound DEAD-box polypeptide 3 (DDX3) to facilitate its physical interaction with transcription factor Yin Yang 1 (YY1), resulting in the transactivation of YY1 and transcriptional alteration of downstream genes associated with β-catenin activation and cancer progression. Preclinically, administration of lentivirus-mediated short hairpin RNA targeting circ-CTNNB1 or a cell-penetrating inhibitory peptide blocking the circ-CTNNB1-DDX3 interaction inhibited downstream gene expression, tumorigenesis, and aggressiveness in cancer cells. Taken together, these results demonstrate cis-acting circ-CTNNB1 as a mediator of β-catenin signaling and cancer progression through DDX3-mediated transactivation of YY1. SIGNIFICANCE: These findings reveal the oncogenic functions of a cis-acting circular RNA in β-catenin activation and cancer progression, with potential value as a therapeutic target for human cancers.
Collapse
Affiliation(s)
- Feng Yang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Erhu Fang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Hong Mei
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Yajun Chen
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Huanhuan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Dan Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Huajie Song
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Jianqun Wang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Mei Hong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Wenjing Xiao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Xiaojing Wang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Kai Huang
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China. .,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Qiangsong Tong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China. .,Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| |
Collapse
|
38
|
The role of miR-183 cluster in immunity. Cancer Lett 2018; 443:108-114. [PMID: 30529154 DOI: 10.1016/j.canlet.2018.11.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 10/25/2018] [Accepted: 11/21/2018] [Indexed: 12/22/2022]
Abstract
MicroRNAs (miRNAs) are essential factors of an extensively conserved post-transcriptional process to regulate gene expression. MiRNAs play a pivotal role in immunity, including controlling the differentiation of various immune cells as well as their immunological functions. The miR-183 cluster, which is comprised of miR-183, -96 and -182, is a miRNA family with sequence homology. These miRNAs are usually transcribed together as a polycistronic miRNA cluster during development and are required for maturation of sensory organs. In comparison to defined sensory-specific role of these miRNAs in normal development, they are frequently over-expressed in several non-sensory diseases, including autoimmune diseases and cancers. Because individual miRNAs of miR-183 cluster have both common and unique targets within functionally interrelated pathways, they can show cooperative or opposing effects on biological processes, implying the complexity of this miR cluster-mediated gene regulation. Therefore, a better understanding of the molecular regulation of miR-183 cluster expression and its downstream networks is important for the therapeutic applications. In this review, we will discuss the characteristics of miR-183 cluster and a wide variety of evidence on its function in immune system. Newer knowledge summarized here will help readers understand the versatile role of miR-183 cluster in this field.
Collapse
|
39
|
Kabekkodu SP, Shukla V, Varghese VK, D' Souza J, Chakrabarty S, Satyamoorthy K. Clustered miRNAs and their role in biological functions and diseases. Biol Rev Camb Philos Soc 2018; 93:1955-1986. [PMID: 29797774 DOI: 10.1111/brv.12428] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 04/20/2018] [Accepted: 04/26/2018] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are endogenous, small non-coding RNAs known to regulate expression of protein-coding genes. A large proportion of miRNAs are highly conserved, localized as clusters in the genome, transcribed together from physically adjacent miRNAs and show similar expression profiles. Since a single miRNA can target multiple genes and miRNA clusters contain multiple miRNAs, it is important to understand their regulation, effects and various biological functions. Like protein-coding genes, miRNA clusters are also regulated by genetic and epigenetic events. These clusters can potentially regulate every aspect of cellular function including growth, proliferation, differentiation, development, metabolism, infection, immunity, cell death, organellar biogenesis, messenger signalling, DNA repair and self-renewal, among others. Dysregulation of miRNA clusters leading to altered biological functions is key to the pathogenesis of many diseases including carcinogenesis. Here, we review recent advances in miRNA cluster research and discuss their regulation and biological functions in pathological conditions.
Collapse
Affiliation(s)
- Shama P Kabekkodu
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Vaibhav Shukla
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Vinay K Varghese
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Jeevitha D' Souza
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| |
Collapse
|
40
|
Liu ZQ, Du JJ, Ren JJ, Zhang ZY, Guo XB, Yan YE, Jia XT, Gu NB, Di ZL, Li SZ. miR-183-96-182 clusters alleviated ox-LDL-induced vascular endothelial cell apoptosis in vitro by targeting FOXO1. RSC Adv 2018; 8:35031-35041. [PMID: 35547044 PMCID: PMC9087689 DOI: 10.1039/c8ra06866f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 09/17/2018] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the role of FOXO1 and miR-183-96-182 clusters in ox-LDL induced endothelial cell apoptosis. METHODS FOXO1 overexpression (OE) and knockdown (KD) as well as AKT1 OE in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were achieved by lentiviral transduction. Upregulation of miR-183-5p, miR-182-5p or miR-96-5p was mimicked by agomir treatment. FOXO1 gene transcription was monitored by FOXO1 promotor reporter assay. Cell apoptosis in culture was monitored by TiterTACS in situ detection. Regulation of FOXO1 gene expression by an miRNA targeting mechanism was monitored by AGO2-RNA immunoprecipitation assay. RESULTS FOXO1 mRNA and protein expression levels in ox-LDL treated HUVECs or HAECs were significantly upregulated due to transcriptional and miRNA targeting mechanisms. MiR-183-5p, miR-182-5p and miR-96-5p expression levels in HUVECs or HAECs were significantly reduced by ox-LDL treatment, the overexpression of which by agomir treatment partially reduced the FOXO1 mRNA/protein expression levels and cell apoptosis which was upregulated by ox-LDL treatment. FOXO1 overexpression antagonized the effect of the agomir treatment indicated above. MiR-183-5p, miR-182-5p and miR-96-5p agomir treatment partially rescued the FOXO1 pSer256/total FOXO1 protein ratio and the AKT1 pSer473 level that were reduced by ox-LDL treatment in the HUVECs or HAECs. AKT1 overexpression significantly reduced FOXO1 protein expression, increased miR-182-5p and miR-183-5p expression, and partially alleviated ox-LDL induced HUVEC or HAEC apoptosis in an miR-183-5p and miR-182-5p-dependent manner. CONCLUSION miR-183-96-182 clusters could partially alleviate ox-LDL-induced apoptosis in HUVECs or HAECs by targeting FOXO1.
Collapse
Affiliation(s)
- Zhi-Qin Liu
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Jing-Jing Du
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Jing-Jing Ren
- Department of Hematology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Zhi-Yong Zhang
- Department of Neurology, China-Japan Friendship Hospital Beijing 100029 China
| | - Xiao-Bo Guo
- Department of Hematology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Yu-E Yan
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Xiao-Tao Jia
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Nai-Bing Gu
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - Zheng-Li Di
- Department of Neurology, Xi'an Central Hospital, Xi'an Jiaotong University, School of Medicine Xi'an 710003 Shaanxi China
| | - San-Zhong Li
- Department of Neurosurgery, Xi-jing Hospital Fourth Military Medical University No. 127, Changle Xi Road Xi'an 710032 Shaanxi China +86-185-9140-9510
| |
Collapse
|
41
|
Abstract
Intestinal-type gastric carcinoma exhibits a multistep carcinogenic sequence from adenoma to carcinoma with a gradual increase in genomic alterations. But the roles of microRNAs (miRNA) in this multistage cascade are not fully explored. To identify differentially expressed miRNA (DEM) during early gastric carcinogenesis, we performed miRNA microarray profiling with 24 gastric cancers and precursor lesions (7 early gastric cancer [EGC], 3 adenomas with high-grade dysplasia, 4 adenomas with low-grade dysplasia, and 10 adjacent normal tissues). Alterations in the expression of 132 miRNA were detected; these were categorized into three groups based on their expression patterns. Of these, 42 miRNAs were aberrantly expressed in EGC. Five miRNA (miR-26a, miR-375, miR-574-3p, miR-145, and miR-15b) showed decreased expression since adenoma. Expression of two miRNA, miR-200C and miR-29a, was down-regulated in EGCs compared to normal mucosa or adenomas. Six miRNA (miR-601, miR-107, miR-18a, miR-370, miR-300, and miR-96) showed increased expression in gastric cancer compared to normal or adenoma samples. Five representative miRNAs were further validated with RT-qPCR in independent 77 samples. Taken together, these results suggest that the dysregulated miRNA show alterations at the early stages of gastric tumorigenesis and may be used as a candidate biomarker.
Collapse
|
42
|
Lu Z, Xu A, Yuan X, Chen K, Wang L, Guo T. Anticancer effect of resibufogenin on gastric carcinoma cells through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β signaling pathway. Oncol Lett 2018; 16:3297-3302. [PMID: 30127928 DOI: 10.3892/ol.2018.8979] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/24/2017] [Indexed: 01/20/2023] Open
Abstract
The aim of the present study was to investigate the anticancer effect of resibufogenin in gastric carcinoma cells through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) signaling pathway. MGC-803 cells were treated with 0, 1, 2, 4 and 8 µM resibufogenin for 12, 24 and 48 h. Cell viability and apoptosis were measured using an MTT assay and annexin V staining. Caspase-3 and caspase-8 activity were identified using caspase-3 and caspase-8 activity kits and a variety of protein expression [B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin] were quantified using western blot analysis. It was revealed that resibufogenin effectively inhibited cell proliferation, and induced apoptosis and caspase-3 and caspase-8 activity in MGC-803 cells. Furthermore, treatment with resibufogenin effectively increased Bax/Bcl-2 expression, and suppressed cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin protein expression in MGC-803 cells. These results suggest that the anticancer effect of resibufogenin induces gastric carcinoma cell death through the PI3K/AKT/GSK3β signaling pathway, offering a novel view of the mechanism by which resibufogenin functions as an agent to treat gastric carcinoma.
Collapse
Affiliation(s)
- Zhen Lu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Aman Xu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiao Yuan
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kaiwei Chen
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Likun Wang
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Tao Guo
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| |
Collapse
|
43
|
Gao D, Zhang J, Bai L, Li F, Dong Y, Li Q. Melittin induces NSCLC apoptosis via inhibition of miR-183. Onco Targets Ther 2018; 11:4511-4523. [PMID: 30122943 PMCID: PMC6078185 DOI: 10.2147/ott.s169806] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Non-small-cell lung cancer (NSCLC) has one of the highest mortality rates among cancers worldwide, with a poor prognosis. Previous studies have reported that melittin, an active component of apitoxin, exerts anti-inflammatory and antitumor effects via vascular endothelial growth factor or FoxO1. Methods CCK8, flow cytometry assay and Western blotting were performed to evaluate the effect of melittin on NSCLC. Results The present study demonstrates that melittin activated caspase-2 by inhibiting miR-183 expression and, thus, induced NSCLC apoptosis in both NCI-H441 cancer cell line assays and an in vivo xenograft model. The results of the cell-based assays showed that melittin (2 μg/mL) robustly suppressed miR-183 expression level and resulted in decreased invasion and migration abilities of NCI-H441 cells. Additionally, a flow cytometry assay and Western blotting showed that melittin induced NSCLC NCI-H441 cell apoptosis along with significant elevation of caspase-2 and Bax, which are regulators of cell apoptosis, and reduced Bcl-2 protein expression compared with dimethyl sulfoxide control. Furthermore, subcutaneous injection of melittin (5 mg/kg) significantly suppressed NSCLC tumor growth compared with vehicle group tumors, determined through tumor size and weight. Conclusion Taken together, the aforementioned findings contribute to identification of a novel therapeutic target in the treatment of NSCLC, in patients diagnosed with a high expression of miR-183. Moreover, this article provides solid evidence for the inhibitory effect of melittin on NSCLC cancer cell growth.
Collapse
Affiliation(s)
- Dongqi Gao
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| | - Jingjing Zhang
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| | - Lu Bai
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| | - Fubo Li
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| | - Yi Dong
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| | - Qingshan Li
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde 067000, China,
| |
Collapse
|
44
|
Hu Y, Lin X, Zuo S, Luo R, Fang W. Elevated GSK3β expression predicts good prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2776-2783. [PMID: 31938395 PMCID: PMC6958282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 02/07/2018] [Indexed: 06/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. The role of GSK-3β in cancer progression is considered critical. However, the prognostic value of total GSK-3β protein levels in HCC remains undetermined. In this study, the expression and biologic significance of total GSK-3β in HCC were evaluated at mRNA and protein levels. We showed that GSK-3β mRNA levels were significantly upregulated in HCC tissues relative to the levels in the adjacent non-tumor tissues as recorded on the TCGA database (P < 0.001). Notably, GSK-3β protein levels were significantly downregulated in HCC tissues relative to those in the adjacent non-tumor tissues by immunohistochemistry (P < 0.001). We found that GSK-3β was negatively associated with the American Joint Committee on Cancer (AJCC) stage (P = 0.030) and positively correlated with good prognosis for HCC patients (P = 0.036). The data further indicated that GSK3β expression tended to be an independent prognostic marker for HCC after surgical resection (HR = 1.658, 95% CI 0.945-2.909, P = 0.078) and can potentially serve as a biomarker for the clinical diagnosis and prognosis of HCC.
Collapse
Affiliation(s)
- Yingying Hu
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou, Guangdong, People’s Republic China
- Dongguan Health School of Guangdong ProvinceDongguan, Guangdong, People’s Republic China
| | - Xian Lin
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou, Guangdong, People’s Republic China
| | - Shi Zuo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical UniversityChina
| | - Rongcheng Luo
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou, Guangdong, People’s Republic China
| | - Weiyi Fang
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou, Guangdong, People’s Republic China
| |
Collapse
|
45
|
Chou CH, Tu HF, Kao SY, Chiang CYF, Liu CJ, Chang KW, Lin SC. Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis. Head Neck 2018; 40:808-817. [PMID: 29356167 DOI: 10.1002/hed.25063] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 08/07/2017] [Accepted: 11/28/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play crucial roles in head and neck squamous cell carcinoma (HNSCC). This study investigates whether miR-31, miR-96, and miR-182 are involved in targeting Numb during HNSCC. METHODS The expression of miR-31/96/182 in tumor tissues was analyzed. Reporter assay, knockdown, expression, and oncogenic analysis were carried out in cell lines. RESULTS Upregulation of miR-31/96/182 was detected in tumor tissues. In addition, advanced tumors showed higher expression levels of these miRNAs. The expression of these miRNAs was upregulated after treatment with areca ingredients (P < .01 or P < .001). These miRNAs directly targeted the 3' untranslated region (UTR) sequence of the Numb gene. An increased migration and invasion of HNSCC cells was associated with the exogenous expression of miR-31/96/182 (P < .01 or P < .001), and this was reverted by expression of Numb. CONCLUSION This study provides new evidence demonstrating that there is frequent and concordant upregulation of miR-31, miR-96, and miR-182 during HNSCC and these miRNAs co-target Numb.
Collapse
Affiliation(s)
- Chung-Hsien Chou
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Hsi-Feng Tu
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Shou-Yen Kao
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Yu Fan Chiang
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
| | - Chung-Ji Liu
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Dentistry, Taipei Mackay Memorial Hospital, Taipei, Taiwan
| | - Kuo-Wei Chang
- Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shu-Chun Lin
- Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
- Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan
| |
Collapse
|
46
|
Segura MF, Jubierre L, Li S, Soriano A, Koetz L, Gaziel-Sovran A, Masanas M, Kleffman K, Dankert JF, Walsh MJ, Hernando E. Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions. Oncotarget 2018; 8:26298-26311. [PMID: 28412746 PMCID: PMC5432258 DOI: 10.18632/oncotarget.15459] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 02/06/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases.The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Krüppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.
Collapse
Affiliation(s)
- Miguel F Segura
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA.,Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Luz Jubierre
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - SiDe Li
- Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aroa Soriano
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Lisa Koetz
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Avital Gaziel-Sovran
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Marc Masanas
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
| | - Kevin Kleffman
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - John F Dankert
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| | - Martin J Walsh
- Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eva Hernando
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
| |
Collapse
|
47
|
Ma D, Li S, Cui Y, Li L, Liu H, Chen Y, Zhou X. Paclitaxel increases the sensitivity of lung cancer cells to lobaplatin via PI3K/Akt pathway. Oncol Lett 2018; 15:6211-6216. [PMID: 29616103 PMCID: PMC5876435 DOI: 10.3892/ol.2018.8086] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 01/09/2018] [Indexed: 12/18/2022] Open
Abstract
The effect of paclitaxel combined with lobaplatin on the sensitivity of lung cancer cell line NCI-H446 through influencing the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated. The sensitivity of lobaplatin to NCI-H446 and the effect of paclitaxel and PI3K inhibitor LY294002 combined with lobaplatin on the sensitivity to NCI-H446 were detected via methyl thiazolyltetrazolium (MTT) assay. The effect of paclitaxel combined with lobaplatin on cell apoptosis was detected using flow cytometry, the effect of paclitaxel combined with lobaplatin on the cell migration was detected via cell wound scratch assay, and the effect of paclitaxel combined with lobaplatin on the cell invasion was detected via Transwell assay. Finally, the effect of paclitaxel on PI3K/Akt pathway was detected via western blotting. MTT assay showed that 30 µg/ml lobaplatin could significantly inhibit the growth of NCI-H446 (p<0.01). Lobaplatin group (group L), 2 µg/ml paclitaxel combined with lobaplatin group (group LP) and lobaplatin combined with 10 µmol/ml LY294002 group (group LL) were set up. The cell survival rates in group LP and group LL were significantly lower than that in group L (p<0.01), and the cell survival rate in group LP was similar to that in group LL (p>0.05). Flow cytometry revealed that the cell apoptotic levels in group LP and group LL were obviously higher than that in group L (p<0.01), and there was no statistically significant difference in the cell apoptotic level between group LP and group LL (p>0.05). Cell wound scratch assay showed that the cell migration capacity in group LP was significantly lower than those in group L and group LL (p<0.01, p<0.05), and the cell migration capacity in group LL was lower than that in group L (p<0.05). Besides, Transwell assay revealed that the cell invasion capacity in group LP was obviously lower than those in group L and group LL (p<0.01, p<0.05), and the cell invasion capacity in group LL was lower than that in group L (p<0.01). Finally, western blotting showed that the levels of PI3K, phosphorylated-Akt (p-Akt) and phosphorylated-glycogen synthase kinase 3β (p-GSK3β) in group LP and group LL were significantly lower than those in group L, and the differences were statistically significant (p<0.01). Paclitaxel can significantly increase the sensitivity of lobaplatin to lung cancer cell line NCI-H446. Moreover, paclitaxel can enhance the effect of lobaplatin on lung cancer cells and reduce the drug resistance through inhibiting PI3K/Akt pathway.
Collapse
Affiliation(s)
- Dongjie Ma
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Shanqing Li
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Yushang Cui
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Li Li
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Hongsheng Liu
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Yeye Chen
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Xiaoyun Zhou
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| |
Collapse
|
48
|
Cao MQ, You AB, Zhu XD, Zhang W, Zhang YY, Zhang SZ, Zhang KW, Cai H, Shi WK, Li XL, Li KS, Gao DM, Ma DN, Ye BG, Wang CH, Qin CD, Sun HC, Zhang T, Tang ZY. miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol 2018; 11:12. [PMID: 29361949 PMCID: PMC5782375 DOI: 10.1186/s13045-018-0555-y] [Citation(s) in RCA: 154] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 01/15/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND High frequency of recurrence is the major cause of the poor outcomes for patients with hepatocellular carcinoma (HCC). microRNA (miR)-182-5p emerged as a high-priority miRNA in HCC and was found to be related to HCC metastasis. Whether the expression of miR-182-5p in tumor tissue correlated with early recurrence in HCC patients underwent curative surgery was unknown. METHODS Real-time PCR (RT-PCR) and in situ hybridization (ISH) were conducted to assess the expression of miR-182-5p in HCC cells and tissues. Cell Counting Kit-8 (CCK-8), transwell assays were performed to detected cells proliferation and migration ability. Flow cytometry assays were used to detect cell apoptosis rate, and xenograft model was employed to study miR-182-5p in HCC growth and lung metastasis. The target of miR-182-5p was validated with a dual-luciferase reporter assay and western blotting. Immunohistochemistry, immumoblotting, and immunoprecipitation were performed to test relative protein expression. RESULTS We showed that high expression of miR-182-5p in tumor tissues correlated with poor prognosis as well as early recurrence in HCC patients underwent curative surgery. miR-182-5p enhanced motility and invasive ability of HCC cells both in vitro and in vivo. miR-182-5p directly targets 3'-UTR of FOXO3a and repressed FOXO3a expression, activating AKT/FOXO3a pathway to promote HCC proliferation. Notably, miR-182-5p activated Wnt/β-catenin signaling by inhibiting the degradation of β-catenin and enhancing the interaction between β-catenin and TCF4 which was mediated by repressed FOXO3a. CONCLUSIONS Consistently, miR-182-5p can be a potential predictor of early recurrence for HCC patients underwent curative surgery, and FOXO3a plays a key mediator in miR-182-5p induced HCC progression.
Collapse
Affiliation(s)
- Man-Qing Cao
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - A-Bin You
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Haidian District, Beijing, 100142, China
| | - Xiao-Dong Zhu
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - Yuan-Yuan Zhang
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Shi-Zhe Zhang
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Ke-Wei Zhang
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Hao Cai
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Wen-Kai Shi
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Xiao-Long Li
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Kang-Shuai Li
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Dong-Mei Gao
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - De-Ning Ma
- Department of Colorectal Cancer Surgery, Zhejiang Cancer Hospital, Zhejiang, Hangzhou, 310022, China
| | - Bo-Gen Ye
- Department of Organ Transplantation, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
| | - Cheng-Hao Wang
- Department of Liver Surgery, Fudan University Shanghai Cancer Center, Cancer Hospital, Shanghai, 200032, China
| | - Cheng-Dong Qin
- Department of Breast Cancer Surgery, Zhejiang Cancer Hospital, Zhejiang, Hangzhou, 310022, China
| | - Hui-Chuan Sun
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
| | - Zhao-You Tang
- Department of Hepatobiliary Surgery, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| |
Collapse
|
49
|
Guo YH, Wang LQ, Li B, Xu H, Yang JH, Zheng LS, Yu P, Zhou AD, Zhang Y, Xie SJ, Liang ZR, Zhang CM, Zhou H, Qu LH. Wnt/β-catenin pathway transactivates microRNA-150 that promotes EMT of colorectal cancer cells by suppressing CREB signaling. Oncotarget 2018; 7:42513-42526. [PMID: 27285761 PMCID: PMC5173152 DOI: 10.18632/oncotarget.9893] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/09/2016] [Indexed: 12/11/2022] Open
Abstract
A hallmark of aberrant activation of the Wnt/β-catenin signaling pathway has been observed in most colorectal cancers (CRC), but little is known about the role of non-coding RNAs regulated by this pathway. Here, we found that miR-150 was the most significantly upregulated microRNA responsive to elevated of Wnt/β-catenin signaling activity in both HCT116 and HEK293T cells. Mechanistically, the β-catenin/LEF1 complex binds to the conserved TCF/LEF1-binding element in the miR-150 promoter and thereby transactivates its expression. Enforced expression of miR-150 in HCT116 cell line transformed cells into a spindle shape with higher migration and invasion activity. miR-150 markedly suppressed the CREB signaling pathway by targeting its core transcription factors CREB1 and EP300. Knockdown of CREB1 or EP300 and knockout of CREB1 by CRISPR/Cas9 phenocopied the epithelial-mesenchymal transition (EMT) observed in HCT116 cells in response to miR-150 overexpression. In summary, our data indicate that miR-150 is a novel Wnt effector that may significantly enhance EMT of CRC cells by targeting the CREB signaling pathway.
Collapse
Affiliation(s)
- Yan-Hua Guo
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China.,Present address: Guangzhou Quality Supervision and Testing Institute, Guangzhou, P. R. China
| | - Lu-Qin Wang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Bin Li
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Hui Xu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Jian-Hua Yang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Li-Si Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Peng Yu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Ai-Dong Zhou
- Present address: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yin Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Shu-Juan Xie
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zi-Rui Liang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Chen-Min Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Hui Zhou
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Liang-Hu Qu
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P. R. China
| |
Collapse
|
50
|
Ma Y, Liang AJ, Fan YP, Huang YR, Zhao XM, Sun Y, Chen XF. Dysregulation and functional roles of miR-183-96-182 cluster in cancer cell proliferation, invasion and metastasis. Oncotarget 2018; 7:42805-42825. [PMID: 27081087 PMCID: PMC5173173 DOI: 10.18632/oncotarget.8715] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 03/31/2016] [Indexed: 02/07/2023] Open
Abstract
Previous studies have reported aberrant expression of the miR-183-96-182 cluster in a variety of tumors, which indicates its' diagnostic or prognostic value. However, a key characteristic of the miR-183-96-182 cluster is its varied expression levels, and pleomorphic functional roles in different tumors or under different conditions. In most tumor types, the cluster is highly expressed and promotes tumorigenesis, cancer progression and metastasis; yet tumor suppressive effects have also been reported in some tumors. In the present study, we discuss the upstream regulators and the downstream target genes of miR-183-96-182 cluster, and highlight the dysregulation and functional roles of this cluster in various tumor cells. Newer insights summarized in this review will help readers understand the different facets of the miR-183-96-182 cluster in cancer development and progression.
Collapse
Affiliation(s)
- Yi Ma
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - A-Juan Liang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yu-Ping Fan
- Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi-Ran Huang
- Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Ming Zhao
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Yun Sun
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Xiang-Feng Chen
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.,Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|