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Degirmencioglu S, Öğüt S, Bahtiyar N, Aydemir B, Karaçetin D, Cinemre FB, Hacıosmanoğlu Aldoğan E, Güneş ME, Kural A, Bektaş M. Exploring the interplay of selenoproteins and mir-675 in breast cancer: a focus on radiotherapy effects. Int J Radiat Biol 2025; 101:572-580. [PMID: 40043235 DOI: 10.1080/09553002.2025.2473962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 01/31/2025] [Accepted: 02/19/2025] [Indexed: 05/24/2025]
Abstract
OBJECTIVES The present study aims to investigate the changes in the expression levels of miR-675 and some selenoproteins (Sel K, Sel W, and Sel P) in patients with breast cancer, before and after radiotherapy. SUBJECTS AND METHODS This study included 35 breast cancer patients who applied to the Department of Radiation Oncology for radiotherapy and 25 healthy female controls. miR-675 expressions were analyzed by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Western blot was conducted to determine Sel K, Sel W, and Sel P expression levels. Biochemical parameters and complete blood count were analyzed by autoanalyzer system and automatic cell counter, respectively. RESULTS Plasma Sel K protein expression levels were decreased in the after-radiotherapy group compared to the control and before-radiotherapy groups, but plasma miR-675 expression levels were lower in both before and after radiotherapy groups compared to the control group. CONCLUSION Our findings showed that miR-675 and Sel K expression levels changed after radiotherapy in breast cancer patients. These changes may have the potential to be biomarkers for the effectiveness of radiotherapy in breast cancer.
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Affiliation(s)
- Sevgin Degirmencioglu
- Department of Medical Biochemistry, Faculty of Medicine, Kırklareli University, Kırklareli, Turkiye
| | - Selim Öğüt
- Department of Biophysics, Faculty of Medicine, Bandirma Onyedi Eylul University, Balıkesir, Turkiye
| | - Nurten Bahtiyar
- Department of Biophysics, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkiye
| | - Birsen Aydemir
- Department of Biophysics, Faculty of Medicine, Sakarya University, Sakarya, Turkiye
| | - Didem Karaçetin
- Department of Radiation Oncology, University of Health Sciences/Bakirkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkiye
| | - Fatma Behice Cinemre
- Department of Medical Biochemistry, Faculty of Medicine, Sakarya University, Sakarya, Turkiye
| | | | - Mehmet Emin Güneş
- Department of Medical Services And Techniques, Vocational School of Health Services, Istanbul Esenyurt University, Istanbul, Turkiye
| | - Alev Kural
- Department of Medical Biochemistry, Faculty of Medicine, University of Health Sciences, Istanbul, Turkiye
| | - Muhammet Bektaş
- Department of Biophysics, Faculty of Medicine, Istanbul University, Istanbul, Turkiye
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2
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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Hassan D, Menges CW, Testa JR, Bellacosa A. AKT kinases as therapeutic targets. J Exp Clin Cancer Res 2024; 43:313. [PMID: 39614261 PMCID: PMC11606119 DOI: 10.1186/s13046-024-03207-4] [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: 07/24/2024] [Accepted: 10/03/2024] [Indexed: 12/01/2024] Open
Abstract
AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.
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Affiliation(s)
- Dalal Hassan
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, 901 Walnut St, Philadelphia, PA, 19107, USA
| | - Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
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Abdi E, Latifi-Navid S, Kholghi-Oskooei V, Mostafaiy B, Pourfarzi F, Yazdanbod A. Roles of the lncRNAs MEG3, PVT1 and H19 tagSNPs in gastric cancer susceptibility. BMC Cancer 2024; 24:1440. [PMID: 39578780 PMCID: PMC11583566 DOI: 10.1186/s12885-024-13209-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Improper expression of long noncoding RNAs (lncRNAs) can cause various cancers. Single nucleotide polymorphisms (SNPs) affect the expression and function of several key lncRNAs. We assessed the associations of MEG3, PVT1, and H19 lncRNA polymorphisms with susceptibility to gastric cancer (GC). METHODS In Ardabil (a high-risk area in North‒West Iran), 795 blood samples were collected from 396 cases and 399 controls. The control subjects were randomly selected from individuals receiving regular physical examinations in this hospital with no self-reported cancer history and were frequency-matched to the case group by sex and 5-year age intervals. All the samples were genotyped via the Infinium HTS platform, which was subsequently followed by rigorous data quality control, as well as statistical and bioinformatic analyses. RESULTS The H19 rs2107425 SNP was associated with GC risk in a recessive model of inheritance (TT vs. CC + CT: OR = 1.87). The PVT1 rs13255292 variant in the overdominant model significantly reduced GC risk (CT vs. CC + TT: OR = 0.74). There was no significant association between H19 rs2839698, MEG3 rs116907618, or rs11160608, or PVT1 rs7017386, rs13254990 tagSNPs and susceptibility to GC. The interaction between H19 rs2107425 TT and PVT1 rs7017386 TC increased GC risk (OR = 3.73; pbon < 0.05). The MEG3, PVT1, and H19 variants were not associated with clinicopathologic characteristics. CONCLUSIONS We revealed significant associations of the H19 rs2107425 and PVT1 rs13255292 genetic variants with GC. Interestingly, the novel SNP‒SNP interaction of H19 and PVT1 tagSNPs had a greater effect than single SNP impacts did on GC risk, providing us with invaluable data to identify potential biological mechanisms involved in the development of GC.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, 56199-11367, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, 56199-11367, Iran.
| | | | - Behdad Mostafaiy
- Department of Statistics, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, 5619911367, Iran
| | - Farhad Pourfarzi
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, 5618953141, Iran
| | - Abbas Yazdanbod
- Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, 5618953141, Iran
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Wang Q, Lu W, Lu L, Wu R, Wu D. miR-575/RIPK4 axis modulates cell cycle progression and proliferation by inactivating the Wnt/β-catenin signaling pathway through inhibiting RUNX1 in colon cancer. Mol Cell Biochem 2024; 479:1747-1766. [PMID: 38480605 DOI: 10.1007/s11010-024-04938-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 01/10/2024] [Indexed: 07/18/2024]
Abstract
Receptor interacting protein serine/threonine kinase 4 (RIPK4) is widely involved in human cancer development. Nevertheless, its role in colon cancer (COAD) has not been elucidated till now. Our research aimed at exploring the function and underlying molecular mechanism of RIPK4 in COAD progression. Through bioinformatic analyses and RT-qPCR, RIPK4 was discovered to be increased in COAD cells and tissues, and its high level predicted poor prognosis. Loss-of-function assays revealed that RIPK4 silencing suppressed COAD cell growth, induced cell cycle arrest, and enhanced cell apoptosis. In vivo experiments also proved that tumor growth was inhibited by silencing of RIPK4. Luciferase reporter assay validated that RIPK4 was targeted and negatively regulated by miR-575. Western blotting demonstrated that Wnt3a, phosphorylated (p)-GSK-3β, and cytoplasmic and nuclear β-catenin protein levels, β-catenin nuclear translocation, and Cyclin D1, CDK4, Cyclin E, and c-Myc protein levels were reduced by RIPK4 knockdown, which however was reversed by treatment with LiCl, the Wnt/β-catenin pathway activator. LiCl also offset the influence of RIPK4 knockdown on COAD cell growth, cell cycle process, and apoptosis. Finally, RIPK4 downregulation reduced RUNX1 level, which was upregulated in COAD and its high level predicted poor prognosis. RIPK4 is positively associated with RUNX1 in COAD. Overexpressing RUNX1 antagonized the suppression of RIPK4 knockdown on RUNX1, Wnt3a, p-GSK-3β, cytoplasmic β-catenin, nuclear β-catenin, Cyclin D1, CDK4, Cyclin E, and c-Myc levels. Collectively, miR-575/RIPK4 axis repressed COAD progression via inactivating the Wnt/β-catenin pathway through downregulating RUNX1.
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Affiliation(s)
- Qun Wang
- Department of Hepatopancreatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 16 Zhuodaoquan South Road, Hongshan District, Wuhan, 430079, China.
- Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, 430079, China.
- Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, 430079, China.
| | - Weijun Lu
- Department of Hepatopancreatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 16 Zhuodaoquan South Road, Hongshan District, Wuhan, 430079, China
- Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, 430079, China
| | - Li Lu
- Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, 430079, China
- Department of Gastrointestinal Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430079, China
| | - Ruopu Wu
- Tianjin Medical University, Tianjin, 300070, China
| | - Dongde Wu
- Department of Hepatopancreatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 16 Zhuodaoquan South Road, Hongshan District, Wuhan, 430079, China.
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He X, Huang T, Wang Q, Bao L, Wang Z, Song H, Li Y, Zhou J, Zhao Y, Xie Y. A prominent role of LncRNA H19 in H. pylori CagA induced DNA damage response and cell malignancy. Sci Rep 2024; 14:14185. [PMID: 38902391 PMCID: PMC11190245 DOI: 10.1038/s41598-024-65221-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/18/2024] [Indexed: 06/22/2024] Open
Abstract
Helicobacter pylori (H. pylori), together with its CagA, has been implicated in causing DNA damage, cell cycle arrest, apoptosis, and the development of gastric cancer. Although lncRNA H19 is abundantly expressed in gastric cancer and functions as a pro-oncogene, it remains unclear whether lncRNA H19 contributes to the oncogenic process of H. pylori CagA. This study investigates the role of H19 in the DNA damage response and malignancy induced by H. pylori. It was observed that cells infected with CagA+ H. pylori strain (GZ7/cagA) showed significantly higher H19 expression, resulting in increased γH2A.X and p-ATM expression and decreased p53 and Rad51 expression. Faster cell migration and invasion was also observed, which was reversed by H19 knockdown in H. pylori. YWHAZ was identified as an H19 target protein, and its expression was increased in H19 knockdown cells. GZ7/cagA infection responded to the increased YWHAZ expression induced by H19 knockdown. In addition, H19 knockdown stimulated cells to enter the G2-phase and attenuated the effect of GZ7/cagA infection on the cellular S-phase barrier. The results suggest that H. pylori CagA can upregulate H19 expression, participate in the DNA damage response and promote cell migration and invasion, and possibly affect cell cycle arrest via regulation of YWHAZ.
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Affiliation(s)
- Xiaofeng He
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China
- Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, 563003, Guizhou, People's Republic of China
| | - Tingting Huang
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China
| | - Qinrong Wang
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China
| | - Liya Bao
- Hepatitis Laboratory, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China
| | - Zhengrong Wang
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China
| | - Hui Song
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China
| | - Yanhong Li
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China
| | - Jianjiang Zhou
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China.
| | - Yan Zhao
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China.
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Minority Diseases, Ministry of Education and Key Laboratory of Molecular Biology, Guizhou Medical University, 4 Beijing Road, Guiyang, 550004, Guizhou, People's Republic of China.
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Darmadi D, Chugaeva UY, Saleh RO, Hjazi A, Saleem HM, Ghildiyal P, Alwaily ER, Alawadi A, Alnajar MJ, Ihsan A. Critical roles of long noncoding RNA H19 in cancer. Cell Biochem Funct 2024; 42:e4018. [PMID: 38644608 DOI: 10.1002/cbf.4018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/18/2024] [Accepted: 04/06/2024] [Indexed: 04/23/2024]
Abstract
Long noncoding RNAs (lncRNAs) are a category of noncoding RNAs characterized by their length, often exceeding 200 nucleotides. There is a growing body of data that indicate the significant involvement of lncRNAs in a wide range of disorders, including cancer. lncRNA H19 was among the initial lncRNAs to be identified and is transcribed from the H19 gene. The H19 lncRNA exhibits significant upregulation in a diverse range of human malignancies, such as breast, colorectal, pancreatic, glioma, and gastric cancer. Moreover, the overexpression of H19 is frequently associated with a worse prognosis among individuals diagnosed with cancer. H19 has been shown to have a role in facilitating several cellular processes, including cell proliferation, invasion, migration, epithelial-mesenchymal transition, metastasis, and apoptosis. This article summarizes the aberrant upregulation of H19 in human malignancies, indicating promising avenues for future investigations on cancer diagnostics and therapeutic interventions.
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Affiliation(s)
- Darmadi Darmadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia
| | - Uliana Y Chugaeva
- Department of Pediatric, Preventive Dentistry and Orthodontics, Institute of Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Hiba Muwafaq Saleem
- Department of Biology, College of Science, University of Anbar, Ramadi, Iraq
| | - Pallavi Ghildiyal
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Enas R Alwaily
- Microbiology Research Group, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Hillah, Iraq
| | | | - Ali Ihsan
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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8
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Liang H, Li H, Xia N, Chen J, Gao L, Liu H, Lyu P, Guo X, Yang Z. Circulating long noncoding RNA, Zfpm2-As1, and XIST based on medical data analysis are potential plasma biomarkers for gastric cancer diagnosis. Technol Health Care 2024; 32:4919-4928. [PMID: 38820035 PMCID: PMC11612959 DOI: 10.3233/thc-232033] [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: 12/27/2023] [Accepted: 02/19/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) participate in diseases, especially tumorigenesis, including gastric cancer (GC). Although lncRNAs in GC tissues have been extensively studied in previous research, the possible significance of circulating lncRNAs in diagnosing GC is still unknown. OBJECTIVE The present work investigated lncRNAs ZFPM2-AS1 and XIST with high expression in GC tissues proved as potential plasma biomarkers from 20 early GC cases, 100 GC cases, and 90 normal subjects. METHODS The possible correlation between ZFPM2-AS1 and XIST expression levels was analyzed with general characteristics and clinicopathological features. The performance in diagnosis was assessed according to receiver operating characteristic (ROC) analysis. RESULTS According to the results, XIST and ZFPM2-AS1 expression remarkably increased within GC plasma relative to normal subjects (P< 0.01); besides, lncRNA XIST expression after surgery had a tendency of downregulation compared with preoperative levels (P< 0.05). Moreover, the area under ROC curve (AUC) values were 0.62 for ZFPM2-AS1 and 0.68 for XIST, while the pooled AUC value of CA-724 and two lncRNAs was 0.751. CONCLUSION Circulating lncRNAs ZFPM2-AS1 and XIST can serve as the candidate plasma biomarkers used to diagnose GC.
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Affiliation(s)
- Han Liang
- Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hao Li
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Nan Xia
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jingjing Chen
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Linlin Gao
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Hao Liu
- Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ping Lyu
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaolin Guo
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ziwei Yang
- Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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9
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Li J, Yin Y, Huang H, Li M, Li H, Zhang M, Jiang C, Yang R. RUNX1 methylation as a cancer biomarker in differentiating papillary thyroid cancer from benign thyroid nodules. Epigenomics 2023; 15:1257-1272. [PMID: 38126720 DOI: 10.2217/epi-2023-0338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Aim: It remains a challenge to accurately identify malignancy of thyroid nodules when biopsy is indeterminate. The authors aimed to investigate the abnormal DNA methylation signatures in papillary thyroid cancer (PTC) compared with benign thyroid nodules (BTNs). Methods: The authors performed genome profiling by 850K array and RNA sequencing in early-stage PTC and BTN tissue samples. The identified gene was validated in two independent case-control studies using mass spectrometry. Results: Hypomethylation of RUNX1 in PTC was identified and verified (all odds ratios: ≥1.50). RUNX1 methylation achieved good accuracy in differentiating early-stage PTC from BTNs, especially for younger women. Conclusion: The authors disclosed a significant association between RUNX1 hypomethylation and PTC, suggesting RUNX1 methylation as a potential biomarker for companion diagnosis of malignant thyroid nodules.
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Affiliation(s)
- Junjie Li
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 210000, China
| | - Yifei Yin
- Department of Thyroid & Breast Surgery, Affiliated Huai'an Hospital of Xuzhou Medical University & Second People's Hospital of Huai'an, Huai'an, 223000, China
| | - Haixia Huang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 210000, China
| | - Mengxia Li
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 210000, China
| | - Hong Li
- Department of Pathology, Affiliated Huai'an Hospital of Xuzhou Medical University & Second People's Hospital of Huai'an, Huai'an, 223000, China
| | - Minmin Zhang
- Department of Thyroid & Breast Surgery, Affiliated Huai'an Hospital of Xuzhou Medical University & Second People's Hospital of Huai'an, Huai'an, 223000, China
| | - Chenxia Jiang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Rongxi Yang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 210000, China
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10
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Ebrahimi N, Hakimzadeh A, Bozorgmand F, Speed S, Manavi MS, Khorram R, Farahani K, Rezaei-Tazangi F, Mansouri A, Hamblin MR, Aref AR. Role of non-coding RNAs as new therapeutic targets in regulating the EMT and apoptosis in metastatic gastric and colorectal cancers. Cell Cycle 2023; 22:2302-2323. [PMID: 38009668 PMCID: PMC10730205 DOI: 10.1080/15384101.2023.2286804] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 05/11/2023] [Accepted: 08/01/2023] [Indexed: 11/29/2023] Open
Abstract
Colorectal cancer (CRC) and gastric cancer (GC), are the two most common cancers of the gastrointestinal tract, and are serious health concerns worldwide. The discovery of more effective biomarkers for early diagnosis, and improved patient prognosis is important. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), can regulate cellular processes such as apoptosis and the epithelial-mesenchymal transition (EMT) leading to progression and resistance of GC and CRC tumors. Moreover these pathways (apoptosis and EMT) may serve as therapeutic targets, to prevent metastasis, and to overcome drug resistance. A subgroup of ncRNAs is common to both GC and CRC tumors, suggesting that they might be used as biomarkers or therapeutic targets. In this review, we highlight some ncRNAs that can regulate EMT and apoptosis as two opposite mechanisms in cancer progression and metastasis in GC and CRC. A better understanding of the biological role of ncRNAs could open up new avenues for the development of personalized treatment plans for GC and CRC patients.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Hakimzadeh
- Department of Medical Biotechnologies, University of Siena, Tuscany, Italy
| | - Farima Bozorgmand
- Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Sepehr Speed
- Medical Campus, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | | | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kobra Farahani
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine group, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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11
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Mahdi Khanifar M, Zafari Z, Sheykhhasan M. Crosstalk between long non-coding RNAs and p53 signaling pathway in colorectal cancer: A review study. Pathol Res Pract 2023; 249:154756. [PMID: 37611430 DOI: 10.1016/j.prp.2023.154756] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/25/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and the third leading cause of cancer-related fatalities. Long non-coding RNAs (lncRNAs) are key regulators of diverse physiological processes and are dysregulated in a wide range of pathophysiological circumstances such as CRC. Studies revealed that aberrant expressions of lncRNAs clearly modulate the expression level of p53 gene in CRC, thereby transactivating multiple downstream pathways. P53 is regarded as a crucial tumor suppressor gene which promotes cell-cycle arrest, DNA repair, senescence or apoptosis in response to cellular stresses. P53 is also mutated in CRC as well as various types of human malignancies. Therefore, lncRNAs interact with the p53 signaling pathway in numerus ways and significantly influence CRC-related processes. The current findings in the investigation of the crosstalk between lncRNAs and the P53 pathway in controlling CRC carcinogenesis, tumor progression, and therapeutic resistance are summarized in the this review. A deeper knowledge of CRC carcinogenesis may also have implications in CRC prevention and treatment through more research.
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Affiliation(s)
- Mohammad Mahdi Khanifar
- School of Molecular Science, University of Western Australia, Perth, Western Australia, Australia; Department of Biology, Shahed University, Tehran, Iran
| | - Zahra Zafari
- Department of Biology, Shahed University, Tehran, Iran.
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran.
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12
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Bhattacharjee R, Prabhakar N, Kumar L, Bhattacharjee A, Kar S, Malik S, Kumar D, Ruokolainen J, Negi A, Jha NK, Kesari KK. Crosstalk between long noncoding RNA and microRNA in Cancer. Cell Oncol (Dordr) 2023; 46:885-908. [PMID: 37245177 PMCID: PMC10356678 DOI: 10.1007/s13402-023-00806-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2023] [Indexed: 05/29/2023] Open
Abstract
miRNAs and lncRNAs play a central role in cancer-associated gene regulations. The dysregulated expression of lncRNAs has been reported as a hallmark of cancer progression, acting as an independent prediction marker for an individual cancer patient. The interplay of miRNA and lncRNA decides the variation of tumorigenesis that could be mediated by acting as sponges for endogenous RNAs, regulating miRNA decay, mediating intra-chromosomal interactions, and modulating epigenetic components. This paper focuses on the influence of crosstalk between lncRNA and miRNA on cancer hallmarks such as epithelial-mesenchymal transition, hijacking cell death, metastasis, and invasion. Other cellular roles of crosstalks, such as neovascularization, vascular mimicry, and angiogenesis were also discussed. Additionally, we reviewed crosstalk mechanism with specific host immune responses and targeting interplay (between lncRNA and miRNA) in cancer diagnosis and management.
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Affiliation(s)
- Rahul Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Neeraj Prabhakar
- Centre for Structural System Biology, Department of Physics, University of Hamburg, c/o DESY, Building 15, Notkestr. 852267, Hamburg, Germany
- Pharmacy, Abo Akademi University, Tykistökatu 6A, Turku, Finland
| | - Lamha Kumar
- School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, India
| | - Arkadyuti Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Sulagna Kar
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Sumira Malik
- Amity Institute of Biotechnology, Amity University Jharkhand, Ranchi, Jharkhand, 834001, India
| | - Dhruv Kumar
- School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand, India
| | - Janne Ruokolainen
- Department of Applied Physics, School of Science, Aalto University, Espoo, 00076, Finland
| | - Arvind Negi
- Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University, Espoo, 00076, Finland.
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, 201310, UP, India.
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, 144411, India.
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India.
| | - Kavindra Kumar Kesari
- Department of Applied Physics, School of Science, Aalto University, Espoo, 00076, Finland.
- Faculty of Biological and Environmental Sciences, University of Helsinki, Biocentre 3, Helsinki, Finland.
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13
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Liao J, Chen B, Zhu Z, Du C, Gao S, Zhao G, Zhao P, Wang Y, Wang A, Schwartz Z, Song L, Hong J, Wagstaff W, Haydon RC, Luu HH, Fan J, Reid RR, He TC, Shi L, Hu N, Huang W. Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases. Genes Dis 2023; 10:1351-1366. [PMID: 37397543 PMCID: PMC10311118 DOI: 10.1016/j.gendis.2023.02.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/07/2023] [Accepted: 02/08/2023] [Indexed: 07/04/2023] Open
Abstract
Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.
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Affiliation(s)
- Junyi Liao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Bowen Chen
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Zhenglin Zhu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Chengcheng Du
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Shengqiang Gao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Piao Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Zander Schwartz
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Lily Song
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jeffrey Hong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- The Medical Scientist Training Program, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lewis Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Ning Hu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Wei Huang
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
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14
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Loe AKH, Zhu L, Kim TH. Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesis. Exp Mol Med 2023; 55:22-31. [PMID: 36653445 PMCID: PMC9898530 DOI: 10.1038/s12276-023-00926-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/08/2022] [Accepted: 11/22/2022] [Indexed: 01/20/2023] Open
Abstract
Gastric cancer (GC) is one of the most common and deadly cancers in the world. It is a multifactorial disease highly influenced by environmental factors, which include radiation, smoking, diet, and infectious pathogens. Accumulating evidence suggests that epigenetic regulators are frequently altered in GC, playing critical roles in gastric tumorigenesis. Epigenetic regulation involves DNA methylation, histone modification, and noncoding RNAs. While it is known that environmental factors cause widespread alterations in DNA methylation, promoting carcinogenesis, the chromatin- and noncoding RNA-mediated mechanisms of gastric tumorigenesis are still poorly understood. In this review, we focus on discussing recent discoveries addressing the roles of histone modifiers and noncoding RNAs and the mechanisms of their interactions in gastric tumorigenesis. A better understanding of epigenetic regulation would likely facilitate the development of novel therapeutic approaches targeting specific epigenetic regulators in GC.
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Affiliation(s)
- Adrian Kwan Ho Loe
- grid.42327.300000 0004 0473 9646Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4 Canada ,grid.17063.330000 0001 2157 2938Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 Canada
| | - Lexin Zhu
- grid.42327.300000 0004 0473 9646Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4 Canada ,grid.17063.330000 0001 2157 2938Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 Canada
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada. .,Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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15
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Qin X, Chen Y, Ma S, Shen L, Ju S. Immune-related gene TM4SF18 could promote the metastasis of gastric cancer cells and predict the prognosis of gastric cancer patients. Mol Oncol 2022; 16:4043-4059. [PMID: 36209368 PMCID: PMC9718113 DOI: 10.1002/1878-0261.13321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 09/04/2022] [Accepted: 10/07/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world, and the search for better markers has become one of the challenges today. It has been found that the L6 superfamily regulates the biological functions of numerous tumors, but transmembrane 4 L six family member 18 (TM4SF18) has been rarely reported. We found that TM4SF18 expression is upregulated in GC tissues and cells, which can be effectively diagnosed and dynamically monitored to assess the prognosis of GC patients. Furthermore, knockdown of TM4SF18 effectively inhibited proliferation, migration, and invasion of GC cells, and affected the epithelial-mesenchymal transition process. TM4SF18 was found to be an independent prognostic factor for GC by univariate and multifactorial Cox analyses as well as by establishing nomogram plots. In addition, in TM4SF18 and immune correlation analysis, TM4SF18 expression levels were found to be negatively correlated with most immune cell marker genes and associated with numerous immune cells and immune pathways, resulting in less benefit from treatment with immune checkpoint inhibitors. In summary, we found that TM4SF18 is a promising GC biomarker that promotes the proliferation, migration, and invasion abilities of GC cells, and is associated with immune response.
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Affiliation(s)
- Xinyue Qin
- Department of Laboratory MedicineAffiliated Hospital of Nantong University, Medical School of Nantong UniversityChina,Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityChina
| | - Yinhao Chen
- Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityChina
| | - Shuo Ma
- Department of Laboratory MedicineAffiliated Hospital of Nantong University, Medical School of Nantong UniversityChina,Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityChina,Medical School of Southeast UniversityNanjingChina
| | - Lei Shen
- Department of Laboratory MedicineAffiliated Hospital of Nantong University, Medical School of Nantong UniversityChina,Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityChina
| | - Shaoqing Ju
- Department of Laboratory MedicineAffiliated Hospital of Nantong University, Medical School of Nantong UniversityChina
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16
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Hashemi M, Moosavi MS, Abed HM, Dehghani M, Aalipour M, Heydari EA, Behroozaghdam M, Entezari M, Salimimoghadam S, Gunduz ES, Taheriazam A, Mirzaei S, Samarghandian S. Long non-coding RNA (lncRNA) H19 in human cancer: From proliferation and metastasis to therapy. Pharmacol Res 2022; 184:106418. [PMID: 36038043 DOI: 10.1016/j.phrs.2022.106418] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 02/07/2023]
Abstract
Initiation and development of cancer depend on multiple factors that mutations in genes and epigenetic level can be considered as important drivers. Epigenetic factors include a large family of members and understanding their function in cancer has been a hot topic. LncRNAs are RNA molecules with no capacity in synthesis of proteins, and they have regulatory functions in cells. LncRNAs are localized in nucleus and cytoplasm, and their abnormal expression is related to development of tumor. This manuscript emphasizes on the role of lncRNA H19 in various cancers and its association with tumor hallmarks. The function of lncRNA H19 in most tumors is oncogenic and therefore, tumor cells increase its expression for promoting their progression. LncRNA H19 contributes to enhancing growth and cell cycle of cancers and by EMT induction, it is able to elevate metastasis rate. Silencing H19 induces apoptotic cell death and disrupts progression of tumors. LncRNA H19 triggers chemo- and radio-resistance in cancer cells. miRNAs are dually upregulated/down-regulated by lncRNA H19 in increasing tumor progression. Anti-cancer agents reduce lncRNA H19 in impairing tumor progression and increasing therapy sensitivity. A number of downstream targets and molecular pathways for lncRNA H19 have been detected in cancers including miRNAs, RUNX1, STAT3, β-catenin, Akt2 and FOXM1. Clinical studies have revealed potential of lncRNA H19 as biomarker and its association with poor prognosis. LncRNA H19 can be transferred to cancer cells via exosomes in enhancing their progression.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marzieh Sadat Moosavi
- Department of Biochemistry, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Hedyeh Maghareh Abed
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Dehghani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Masoumeh Aalipour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Ali Heydari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Emine Selda Gunduz
- Vocational School of Health Services, Department of First and Emergency Aid, Akdeniz University, Antalya, Turkey.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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17
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Zhang X, Luo M, Zhang J, Guo B, Singh S, Lin X, Xiong H, Ju S, Wang L, Zhou Y, Zhou J. The role of lncRNA H19 in tumorigenesis and drug resistance of human Cancers. Front Genet 2022; 13:1005522. [PMID: 36246634 PMCID: PMC9555214 DOI: 10.3389/fgene.2022.1005522] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Systemic therapy is one of the most significant cancer treatments. However, drug resistance often appears and has become the primary cause of cancer therapy failure. Regulation of drug target, drug metabolism and drug efflux, cell death escape (apoptosis, autophagy, et al.), epigenetic changes, and many other variables are complicatedly involved in the mechanisms of drug resistance. In various types of cancers, long non-coding RNA H19 (lncRNA H19) has been shown to play critical roles in tumor development, proliferation, metastasis, and multiple drug resistance as well. The efficacy of chemotherapy, endocrine therapy, and targeted therapy are all influenced by the expression of H19, especially in breast cancer, liver cancer, lung cancer and colorectal cancer. Here, we summarize the relationship between lncRNA H19 and tumorigenesis, and illustrate the drug resistance mechanisms caused by lncRNA H19 as well. This review may provide more therapeutic potential targets for future cancer treatments.
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Affiliation(s)
- Xun Zhang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Mingpeng Luo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiahang Zhang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Bize Guo
- Zhejiang University School of Medicine, Hangzhou, China
| | - Shreya Singh
- Zhejiang University School of Medicine, Hangzhou, China
| | - Xixi Lin
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Hanchu Xiong
- Zhejiang University School of Medicine, Hangzhou, China
| | - Siwei Ju
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- Zhejiang University School of Medicine, Hangzhou, China
| | - Linbo Wang
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
| | - Yulu Zhou
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
| | - Jichun Zhou
- Department of Surgical Oncology, The Sir Run Run Shaw Affiliated Hospital, Zhejiang University, Hangzhou, China
- Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
- *Correspondence: Linbo Wang, ; Yulu Zhou, ; Jichun Zhou,
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18
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Najafi S, Khatami SH, Khorsand M, Jamali Z, Shabaninejad Z, Moazamfard M, Majidpoor J, Aghaei Zarch SM, Movahedpour A. Long non-coding RNAs (lncRNAs); roles in tumorigenesis and potentials as biomarkers in cancer diagnosis. Exp Cell Res 2022; 418:113294. [PMID: 35870535 DOI: 10.1016/j.yexcr.2022.113294] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/11/2022] [Accepted: 07/16/2022] [Indexed: 12/15/2022]
Abstract
New research has indicated that long non-coding RNAs (lncRNAs) play critical roles in a broad range of biological processes, including the pathogenesis of many complex human diseases, including cancer. The detailed regulation mechanisms of many lncRNAs in cancer initiation and progression have yet to be discovered, even though a few of lncRNAs' functions in cancer have been characterized. In the present study, we summarize recent advances in the mechanisms and functions of lncRNAs in cancer. We focused on the roles of newly-identified lncRNAs as oncogenes and tumor suppressors, as well as the potential pathways these molecules could play. The paper also discusses their potential uses as biomarkers for the diagnosis and prognosis of cancer.
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Affiliation(s)
- Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Seyyed Hossein Khatami
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marjan Khorsand
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Jamali
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Shabaninejad
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Jamal Majidpoor
- Department of Anatomy, Faculty of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Seyed Mohsen Aghaei Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Liu XY, Zhang TQ, Zhang Q, Guo J, Zhang P, Mao T, Tian ZB, Zhang CP, Li XY. Differential Long Non-Coding RNA Expression Analysis in Chronic Non-Atrophic Gastritis, Gastric Mucosal Intraepithelial Neoplasia, and Gastric Cancer Tissues. Front Genet 2022; 13:833857. [PMID: 35571069 PMCID: PMC9091194 DOI: 10.3389/fgene.2022.833857] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) has a high incidence worldwide, and when detected, the majority of patients have already progressed to advanced stages. Long non-coding RNAs (lncRNAs) have a wide range of biological functions and affect tumor occurrence and development. However, the potential role of lncRNAs in GC diagnosis remains unclear. We selected five high-quality samples from each group of chronic non-atrophic gastritis, gastric mucosal intraepithelial neoplasia, and GC tissues for analysis. RNA-seq was used to screen the differentially expressed lncRNAs, and we identified 666 differentially expressed lncRNAs between the chronic non-atrophic gastritis and GC groups, 13 differentially expressed lncRNAs between the gastric mucosal intraepithelial neoplasia and GC groups, and 507 differentially expressed lncRNAs between the chronic non-atrophic gastritis and gastric mucosal intraepithelial neoplasia groups. We also identified six lncRNAs (lncRNA H19, LINC00895, lnc-SRGAP2C-16, lnc-HLA-C-2, lnc-APOC1-1, and lnc-B3GALT2-1) which not only differentially expressed between the chronic non-atrophic gastritis and GC groups, but also differentially expressed between the gastric mucosal intraepithelial neoplasia and GC groups. Furthermore, RT-qPCR was used to verify the differentially co-expressed lncRNAs. LncSEA was used to conduct a functional analysis of differentially expressed lncRNAs. We also predicted the target mRNAs of the differentially expressed lncRNAs through bioinformatics analysis and analyzed targeting correlations between three differentially co-expressed lncRNAs and mRNAs (lncRNA H19, LINC00895, and lnc-SRGAP2C-16). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to explore the functions of target mRNAs of differentially expressed lncRNAs. In conclusion, our study provides a novel perspective on the potential functions of differentially expressed lncRNAs in GC occurrence and development, indicating that the differentially expressed lncRNAs might be new biomarkers for early GC diagnosis.
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Affiliation(s)
- Xin-Yuan Liu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tian-Qi Zhang
- Department of Gastroenterology, Qingdao Women and Children’s Hospital, Qingdao, China
| | - Qi Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Guo
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peng Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cui-Ping Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao-Yu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Xiao-Yu Li,
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20
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Xu Y, Peng Y, Shen M, Liu L, Lei J, Gao S, Wang Y, Lan A, Li H, Liu S. Construction and Validation of Angiogenesis-Related Prognostic Risk Signature to Facilitate Survival Prediction and Biomarker Excavation of Breast Cancer Patients. JOURNAL OF ONCOLOGY 2022; 2022:1525245. [PMID: 35498539 PMCID: PMC9045999 DOI: 10.1155/2022/1525245] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/05/2022] [Indexed: 02/06/2023]
Abstract
This study is aimed at exploring the potential mechanism of angiogenesis, a biological process-related gene in breast cancer (BRCA), and constructing a risk model related to the prognosis of BRCA patients. We used multiple bioinformatics databases and multiple bioinformatics analysis methods to complete our exploration in this research. First, we use the RNA-seq transcriptome data in the TCGA database to conduct a preliminary screening of angiogenesis-related genes through univariate Cox curve analysis and then use LASSO regression curve analysis for secondary screening. We successfully established a risk model consisting of seven angiogenesis-related genes in BRCA. The results of ROC curve analysis show that the risk model has good prediction accuracy. We can successfully divide BRCA patients into the high-risk and low-risk groups with significant prognostic differences based on this risk model. In addition, we used angiogenesis-related genes to perform cluster analysis in BRCA patients and successfully divided BRCA patients into three clusters with significant prognostic differences, namely, cluster 1, cluster 2, and cluster 3. Subsequently, we combined the clinical-pathological data for correlation analysis, and there is a significant correlation between the risk model and the patient's T and stage. Multivariate Cox regression curve analysis showed that the age of BRCA patients and the risk score of the risk model could be used as independent risk factors in the progression of BRCA. In particular, based on this angiogenesis-related risk model, we have drawn a matching nomogram that can predict the 5-, 7-, and 10-year overall survival rates of BRCA patients. Subsequently, we performed a series of pan-cancer analyses of CNV, SNV, OS, methylation, and immune infiltration for this risk model gene and used GDSC data to explore drug sensitivity. Subsequently, to gain insight into the protein expression of these risk model genes in BRCA, we used the immunohistochemical data in the THPA database for verification. The results showed that the protein expressions of IL18, RUNX1, SCG2, and THY1 molecules in BRCA tissues were significantly higher than those in normal breast tissues, while the protein expressions of PF4 and TNFSF12 molecules in BRCA tissues were significantly lower than those in normal breast tissues. Finally, we conducted multiple GSEA analyses to explore the biological pathways these risk model genes can cross in cancer progression. In summary, we believe that this study can provide valuable data and clues for future studies on angiogenesis in BRCA.
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Affiliation(s)
- Yingkun Xu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Yang Peng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Meiying Shen
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Li Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Jinwei Lei
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Shun Gao
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Yuan Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Ailin Lan
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Han Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
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21
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Bencivenga D, Stampone E, Vastante A, Barahmeh M, Della Ragione F, Borriello A. An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs. Cells 2022; 11:cells11081346. [PMID: 35456025 PMCID: PMC9028986 DOI: 10.3390/cells11081346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors’ (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control.
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22
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Wen X, Han W, Liu C. Long non-coding RNA TTTY15 silencing inhibits gastric cancer progression by sponging microRNA-98-5p to down-regulate cyclin D2 expression. Bioengineered 2022; 13:7380-7391. [PMID: 35266852 PMCID: PMC9208520 DOI: 10.1080/21655979.2022.2047398] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Gastric cancer is the most common malignant tumor in the digestive system. However, the detection rate of early gastric cancer is low, resulting in delayed prognosis and poor outcomes. The identification of effective therapeutic targets for gastric cancer is, therefore, of profound significance. Recently, various lncRNAs have been shown to be biomarkers for different cancers. This study investigated the role of long non-coding RNA (lncRNA) TTTY15 in gastric cancer. The expression level of TTTY15, miR-98-5p, and cyclin D2 (CCND2) were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot assay using tumor and non-tumor tissues collected from 30 patients with gastric cancer, gastric cancer cell lines (AGS, SNU-5, and NCI-N87), and the normal gastric epithelial cell line GES-1. The interaction between TTTY15 and miR-98-5p and between miR-98-5p and CCND2 were predicted by bioinformatics and then further verified by dual-luciferase and RNA pull-down analyses. Cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide (MTT) assay, and apoptosis was measured using flow cytometry and caspase-3 assay. The results indicate that TTTY15 and CCND2 expression increased and miR-98-5p expression decreased in gastric cancer tumor tissues and cell lines. TTTY15 knockdown inhibited gastric cancer cell proliferation but promoted apoptosis by sponging miR-98-5p, which acted as a tumor suppressor gene by reducing the expression of its target gene CCND2 in gastric cancer. In conclusion, lncRNA TTTY15 is a potential oncogene involved in gastric cancer and may be a novel therapeutic target for gastric cancer treatment.
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Affiliation(s)
- Xigang Wen
- Department of Gastrointestinal Surgery, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Wenling Han
- Department of Hospital Infection Office, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Chao Liu
- Department of Gastrointestinal Surgery, The Third People's Hospital of Hubei Province, Wuhan, China
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23
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Desai S, Dharavath B, Manavalan S, Rane A, Redhu A, Sunder R, Butle A, Mishra R, Joshi A, Togar T, Apte S, Bala P, Chandrani P, Chopra S, Bashyam M, Banerjee A, Prabhash K, Nair S, Dutt A. Fusobacterium nucleatum is associated with inflammation and poor survival in early-stage HPV-negative tongue cancer. NAR Cancer 2022; 4:zcac006. [PMID: 35252868 PMCID: PMC8894079 DOI: 10.1093/narcan/zcac006] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/03/2022] [Accepted: 02/16/2022] [Indexed: 02/05/2023] Open
Abstract
Persistent pathogen infection is a known cause of malignancy, although with sparse systematic evaluation across tumor types. We present a comprehensive landscape of 1060 infectious pathogens across 239 whole exomes and 1168 transcriptomes of breast, lung, gallbladder, cervical, colorectal, and head and neck tumors. We identify known cancer-associated pathogens consistent with the literature. In addition, we identify a significant prevalence of Fusobacterium in head and neck tumors, comparable to colorectal tumors. The Fusobacterium-high subgroup of head and neck tumors occurs mutually exclusive to human papillomavirus, and is characterized by overexpression of miRNAs associated with inflammation, elevated innate immune cell fraction and nodal metastases. We validate the association of Fusobacterium with the inflammatory markers IL1B, IL6 and IL8, miRNAs hsa-mir-451a, hsa-mir-675 and hsa-mir-486-1, and MMP10 in the tongue tumor samples. A higher burden of Fusobacterium is also associated with poor survival, nodal metastases and extracapsular spread in tongue tumors defining a distinct subgroup of head and neck cancer.
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Affiliation(s)
- Sanket Desai
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Bhasker Dharavath
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Sujith Manavalan
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Aishwarya Rane
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Archana Kumari Redhu
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Roma Sunder
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Ashwin Butle
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Rohit Mishra
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Asim Joshi
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Trupti Togar
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Shruti Apte
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India
| | - Pratyusha Bala
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad500039, Telangana, India
| | - Pratik Chandrani
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Supriya Chopra
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
- Department of Radiation Oncology, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Murali Dharan Bashyam
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad500039, Telangana, India
| | - Anirban Banerjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai 400012, Maharashtra, India
| | - Sudhir Nair
- Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai 400012, Maharashtra, India
| | - Amit Dutt
- Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research, and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
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24
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Guo XY, Liu TT, Zhu WJ, Liu HT, Zhang GH, Song L, Zhao RN, Chen X, Gao P. CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis. Oncogene 2022; 41:1895-1906. [PMID: 35145234 DOI: 10.1038/s41388-022-02232-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 01/21/2022] [Accepted: 02/03/2022] [Indexed: 02/07/2023]
Abstract
Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.
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Affiliation(s)
- Xiang-Yu Guo
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tian-Tian Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wen-Jie Zhu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hai-Ting Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guo-Hao Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lin Song
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Rui-Nan Zhao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xu Chen
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. .,Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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25
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Soltani R, Amini M, Mazaheri Moghaddam M, Jebelli A, Ahmadiyan S, Bidar N, Baradaran B, MotieGhader H, Asadi M, Mokhtarzadeh A. LncRNA DLGAP1-AS2 overexpression associates with gastric tumorigenesis: a promising diagnostic and therapeutic target. Mol Biol Rep 2022; 49:6817-6826. [PMID: 34981339 DOI: 10.1007/s11033-021-07038-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/29/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Aberrant expression of long noncoding RNAs (lncRNAs) is associated with the progression of human cancers, including gastric cancer (GC). The function of lncRNA DLGAP1-AS2, as a promising oncogene, has been identified in several human cancers. Therefore, this study was aimed to explore the association of DLGAP1-AS2 with gastric tumorigenesis, as well. METHODS AND RESULTS The expression level of DLGAP1-AS2 was initially pre-evaluated in GC datasets from Gene Expression Omnibus (GEO). Moreover, qRT-PCR experiment was performed on 25 GC and 25 adjacent normal tissue samples. The Cancer Genome Atlas (TCGA) data were also analyzed for further validation. Consistent with data obtained from GEO datasets, qRT-PCR results revealed that DLGAP1-AS2 was significantly (p < 0.0032) upregulated in GC specimens compared to normal samples, which was additionally confirmed using TCGA analysis (p < 0.0001). DLGAP1-AS2 expression level was also correlated with age (p = 0.0008), lymphatic and vascular invasion (p = 0.0415) in internal samples as well as poor survival of GC patients (p = 0.00074) in GEO datasets. Also, Gene Ontology analysis illustrated that DLGAP1-AS2 may be involved in the cellular process, including hippo signaling, regulated by YAP1, as its valid downstream target, in GC samples. Moreover, ROC curve analysis showed the high accuracy of the DLGAP1-AS2 expression pattern as a diagnostic biomarker for GC. CONCLUSION Our findings indicated that DLGAP1-AS2 might display oncogenic properties through gastric tumorigenesis and could be suggested as a therapeutic, diagnostic, and prognostic target.
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Affiliation(s)
- Rogayeh Soltani
- Department of Biology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Asiyeh Jebelli
- Department of Biology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Sahar Ahmadiyan
- Department of Biology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Negar Bidar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Habib MotieGhader
- Department of Bioinformatics, Biotechnology Research Center, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Milad Asadi
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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26
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Chen D, Ping S, Xu Y, Wang M, Jiang X, Xiong L, Zhang L, Yu H, Xiong Z. Non-Coding RNAs in Gastric Cancer: From Malignant Hallmarks to Clinical Applications. Front Cell Dev Biol 2021; 9:732036. [PMID: 34805143 PMCID: PMC8595133 DOI: 10.3389/fcell.2021.732036] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/18/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most lethal malignancies worldwide. However, the molecular mechanisms underlying gastric carcinogenesis remain largely unknown. Over the past decades, advances in RNA-sequencing techniques have greatly facilitated the identification of various non-coding RNAs (ncRNAs) in cancer cells, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Accumulating evidence has revealed that ncRNAs are essential regulators in GC occurrence and development. However, ncRNAs represent an emerging field of cancer research, and their complex functionality remains to be clarified. Considering the lack of viable biomarkers and therapeutic targets in GC, further studies should focus on elucidating the intricate relationships between ncRNAs and GC, which can be translated into clinical practice. In this review, we summarize recent research progress on how ncRNAs modulate the malignant hallmarks of GC, especially in tumor immune escape, drug resistance, and stemness. We also discuss the promising applications of ncRNAs as diagnostic biomarkers and therapeutic targets in GC, aiming to validate their practical value for clinical treatment.
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Affiliation(s)
- Di Chen
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Ping
- Department of Orthopaedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yushuang Xu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengmeng Wang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Jiang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lina Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Zhang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Honglu Yu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhifan Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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27
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Han J, Yang Z, Zhao S, Zheng L, Tian Y, Lv Y. Circ_0027599 elevates RUNX1 expression via sponging miR-21-5p on gastric cancer progression. Eur J Clin Invest 2021; 51:e13592. [PMID: 34032284 DOI: 10.1111/eci.13592] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/02/2021] [Accepted: 04/09/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Increasing evidence has shown that circular RNAs (circRNAs) serve as vital regulators in tumour progression. In this study, we focused on the functions of circ_0027599 in gastric cancer (GC) progression. METHODS The levels of circ_0027599, runt-related transcription factor 1 (RUNX1) mRNA and microRNA-21-5p (miR-21-5p) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The protein levels of RUNX1, E-Cadherin, vimentin and N-Cadherin were measured by Western blot assay. Cell viability, colony formation, metastasis and cell cycle process were evaluated by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assay and flow cytometry analysis, respectively. The interaction between circ_0027599 and miR-21-5p and the interaction between miR-21-5p and RUNX1 were verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The role of circ_0027599 in tumour growth in vivo was investigated by murine xenograft model assay. RESULTS Circ_0027599 and RUNX1 were downregulated in GC tissues and cells. Circ_0027599 level was associated with the overall survival of GC patients. Circ_0027599 or RUNX1 overexpression inhibited GC cell viability, colony formation, migration, invasion and cell cycle process in vitro. For mechanism analysis, circ_0027599 positively regulated RUNX1 expression via functioning as the sponge for miR-21-5p. RUNX1 inhibition reversed circ_0027599 overexpression mediated malignant behaviours of GC cells. Moreover, circ_0027599 overexpression repressed tumour growth in vivo. CONCLUSION Circ_0027599 overexpression repressed GC progression via modulation of miR-21-5p/RUNX1 axis, which might illumine a novel therapeutic target for GC.
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Affiliation(s)
- Jinzhu Han
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zixin Yang
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shan Zhao
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Likang Zheng
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanhua Tian
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yingqian Lv
- The Second Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Wu L, Li X, Chen X, Wu F, Sun G, Cheng Y, Tang W, Zhang W, Lv C. mRNA microarray profiling identifies a novel circulating HTRA2 for detection of gastric cancer. J Clin Lab Anal 2021; 35:e24054. [PMID: 34708890 PMCID: PMC8649374 DOI: 10.1002/jcla.24054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/31/2021] [Accepted: 10/02/2021] [Indexed: 11/28/2022] Open
Abstract
Background mRNAs have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a few of them have been studied as blood‐based biomarkers for gastric carcinoma (GC) detection. Methods mRNA expression profiles for GC were screened using plasma samples from 10 GC patients with different TNM stages and 5 healthy individuals as controls. One candidate tumor‐related mRNA named HTRA2 was then evaluated in GC samples with quantitative real‐time polymerase chain reaction (qRT‐PCR). TCGAportal, UALCAN, and TISCH database were used to explore the function of HTRA2 in GC. Finally, the effect generated by HTRA2 expression on cell proliferating, invading, and migrating processes was assessed in vitro with knockdown and over‐expression strategies. Results HTRA2 displayed noticeable increase inside GC plasma compared with control cases. Higher expression of HTRA2 displayed a correlation to higher clinicopathological stage and worse prognosis. HTRA2 knocking down down‐regulated GC cells' proliferating, invading, and migrating states, while HTRA2 over‐expression exerted the inconsistent influence. HTRA2 protein, which may interact with PINK1, PARL, and CYCS, was mainly located in the mitochondria of cells and primarily involved cellular response and metabolic signaling pathway. Immune factors may interact with HTRA2 in GC, and HTRA2 was found noticeably linked with immunosuppressor such as CD274, IDO1, and TIGIT. Conclusion One plasma HTRA2 can be an emerging diagnosis‐related biomarker to achieve GC detecting process, but the particular regulatory effect still needs to be further explored.
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Affiliation(s)
- Liangliang Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ye Cheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, Key Laboratory of Living Donor Transplantation, The First Affiliated Hospital of Nanjing Medical University, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wenling Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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29
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Tseng HH, Chen YZ, Chou NH, Chen YC, Wu CC, Liu LF, Yang YF, Yeh CY, Kung ML, Tu YT, Tsai KW. Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:180-194. [PMID: 34514098 PMCID: PMC8416970 DOI: 10.1016/j.omto.2021.08.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 08/13/2021] [Indexed: 12/30/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a group of nonprotein coding transcripts that play a critical role in cancer progression. However, the role of lncRNA in metformin-induced inhibition of cell growth and its biological function in gastric cancer remain largely unknown. In this study, we identified an oncogenic lncRNA, Loc100506691, the expression of which was decreased in gastric cancer cells with metformin treatment. Moreover, Loc100506691 was significantly overexpressed in gastric cancer compared with adjacent normal tissues (p < 0.001), and high Loc100506691 expression was significantly correlated with poor survival of patients with gastric cancer. Additionally, Loc100506691 knockdown could significantly suppress gastric cancer cell growth in vitro, and ectopic Loc100506691 expression accelerated tumor growth in an in vivo mouse model. Analysis of the cell cycle revealed that Loc100506691 knockdown induced cell cycle arrest at the G2/M phase by impairing cell entry from the G2/M to G1 phase. Loc100506691 negatively regulated CHAC1 expression by modulating miR-26a-5p/miR-330-5p expression, and CHAC1 knockdown markedly attenuated Loc100506691 knockdown-induced gastric cancer cell growth and motility suppression. We concluded that anti-proliferative effects of metformin in gastric cancer may be partially caused by suppression of the Loc100506691-miR-26a-5p/miR-330-5p-CHAC1 axis.
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Affiliation(s)
- Hui-Hwa Tseng
- Division of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - You-Zuo Chen
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.,Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Nan-Hua Chou
- Department of Surgery Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Yen-Chih Chen
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Chao-Chuan Wu
- Division of Gastrointestinal Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical of Foundation, New Taipei City 23124, Taiwan
| | - Li-Feng Liu
- Department of Biological Science and Technology, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yi-Fang Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Chung-Yu Yeh
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Ya-Ting Tu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23124, Taiwan
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Mutlu M, Tekin C, Ak Aksoy S, Taskapilioglu MO, Kaya S, Balcin RN, Ocak PE, Kocaeli H, Bekar A, Tolunay S, Tunca B. Long non-coding RNAs as a predictive markers of group 3 medulloblastomas. Neurol Res 2021; 44:232-241. [PMID: 34533098 DOI: 10.1080/01616412.2021.1975223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
ObjectiveThe appropriate treatments for the different molecular subgroups of medulloblastomas are challenging to determine. Hence, this study aimed to examine the expression profiles of long non-coding RNAs (LncRNAs) to determine a marker that may be important for treatment selection in these subgroups.MethodsChanges in the expression of LncRNAs in the tissues of patients with medulloblastoma, which are classified into four subgroups according to their clinical characteristics and gene expression profiles, were examined via reverse transcription polymerase chain reaction. Moreover, there association with patient prognosis was evaluated.ResultsThe expression levels of MALAT1 and SNGH16 were significantly higher in patients with group 3 medulloblastoma than in those with other subtypes. Patients with high expression levels of MALAT1 and SNGH16 had a relatively shorter overall survival than those with low expression levels.ConclusionsPatients with group 3 medulloblastoma have a high MALAT1 level, which is associated with poor prognosis. Therefore, MALAT1 can be a new therapeutic target in medulloblastoma.
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Affiliation(s)
- Melis Mutlu
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Cagla Tekin
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Secil Ak Aksoy
- Inegol Vocation School, Bursa Uludag University, Bursa, Turkey
| | | | - Seckin Kaya
- Department of Neurosurgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Rabia Nur Balcin
- Department of Neurosurgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Pınar Eser Ocak
- Department of Neurosurgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Hasan Kocaeli
- Department of Neurosurgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Ahmet Bekar
- Department of Neurosurgery, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Sahsine Tolunay
- Department of Pathology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Berrin Tunca
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
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Liu P, Huang X, Wu H, Yin G, Shen L. LncRNA-H19 gene plays a significant role in regulating glioma cell function. Mol Genet Genomic Med 2021; 9:e1480. [PMID: 34477331 PMCID: PMC8580082 DOI: 10.1002/mgg3.1480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/08/2020] [Accepted: 08/03/2020] [Indexed: 12/15/2022] Open
Abstract
Background Glioma is an aggressive adult primary cancer, and is characterized by low cure rate, poor prognosis, and high recurrence. The present study aimed to investigate the effect of lncRNA‐H19 gene silencing on glioma cell function. Methods lncRNA‐H19 interference vector (LV3‐si‐H19) and negative control vector (LV3‐NC) were stably transfected into U251 and U87‐MG cells, respectively. Quantitative real‐time PCR (qRT‐PCR) was performed to investigate the expression of lncRNA‐H19. Cell proliferation capacity was tested by adopting cell counting kit (CCK8), and propidium iodide (PI) was used for cell cycle analysis. Meanwhile, flow cytometry (FCM) method was used to investigate cell apoptosis, cell migration capacity was detected via wound healing and transwell experiments, and sphere‐forming ability was examined in serum‐free suspension culture. Additionally, glioma animal models were conducted through injecting U251 cells to estimate the effects of lncRNA‐H19 on glioma growth in vivo. Results Knocking down lncRNA‐H19 gene could effectively suppress the proliferation of U251 and U87‐MG cells. The knockdown of lncRNA‐H19 remarkably inhibited the migration and blocked cycle progressions of U251 and U87‐MG cells, yet, no obvious changes were observed in cell apoptosis. Besides, inhibiting lncRNA‐H19 expression could attenuate sphere‐forming function of U251 and U87‐MG cells. Additionally, tumor volume and weight were significantly reduced in rats injected with U251 LV‐si‐H19 cell line compared to untransfected and negative controls, when survival time was obviously prolonged in U251 LV‐si‐H19 injection groups. Conclusion LncRNA‐H19 gene plays a carcinogenic role in glioma progression via enhancing aggressive behavior of glioma cells.
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Affiliation(s)
- Ping Liu
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Xinqiong Huang
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Haijun Wu
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Guoling Yin
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
| | - Liangfang Shen
- Department of Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China
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Yang J, Qi M, Fei X, Wang X, Wang K. LncRNA H19: A novel oncogene in multiple cancers. Int J Biol Sci 2021; 17:3188-3208. [PMID: 34421359 PMCID: PMC8375239 DOI: 10.7150/ijbs.62573] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are a series of non-coding RNAs that lack open reading frameworks. Accumulating evidence suggests important roles for lncRNAs in various diseases, including cancers. Recently, lncRNA H19 (H19) became a research focus due to its ectopic expression in human malignant tumors, where it functioned as an oncogene. Subsequently, H19 was confirmed to be involved in tumorigenesis and malignant progression in many tumors and had been implicated in promoting cell growth, invasion, migration, epithelial-mesenchymal transition, metastasis, and apoptosis. H19 also sequesters some microRNAs, facilitating a multilayer molecular regulatory mechanism. In this review, we summarize the abnormal overexpression of H19 in human cancers, which suggests wide prospects for further research into the diagnosis and treatment of cancers.
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Affiliation(s)
- Jun Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Manlong Qi
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiang Fei
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Liu J, Wang G, Zhao J, Liu X, Zhang K, Gong G, Pan H, Jiang Z. LncRNA H19 Promoted the Epithelial to Mesenchymal Transition and Metastasis in Gastric Cancer via Activating Wnt/β-Catenin Signaling. Dig Dis 2021; 40:436-447. [PMID: 34348271 DOI: 10.1159/000518627] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 07/15/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Due to a combination of high morbidity and lack of effective treatments, gastric cancer (GC) remains a major cause of cancer-related death all over the world. H19, as a paternally imprinted long noncoding RNA (lncRNA), has been found dysregulated in GC. AIM The aim of this study is to elucidate the specific mechanism of H19 in GC. METHODS Bioinformatic analysis and quantitative real-time PCR analysis were utilized to test the expression pattern of H19 in GC tissues and cell lines. Wound healing, transwell, immunofluorescence assay, and Western blot assays were conducted to test cell malignant phenotypes. Meanwhile, TOP/FOP flash assay was to analyze the relationship of H19 and Wnt/β-catenin signaling. Also, mice xenograft models were to evaluate the influence of H19 on tumor growth. RESULTS H19 was overexpressed in GC tissues and cell lines and related to poor prognosis for GC patients. In vitro and in vivo assays verified the promotion of H19 on GC cell epithelial to mesenchymal transition (EMT) and metastasis. Mechanistically, H19 could induce β-catenin to transfer into nucleus and activate Wnt/β-catenin signaling, thus promoting EMT and metastasis of GC cells. CONCLUSION Our findings proved the mechanism of H19-mediated metastasis via activating Wnt/β-catenin signaling, which provides a promising target for developing new therapeutic strategies in GC.
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Affiliation(s)
- Jiang Liu
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Gang Wang
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jian Zhao
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinxin Liu
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Kai Zhang
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Guanwen Gong
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Huafeng Pan
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhiwei Jiang
- Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Farooqi AA, Gulnara K, Mukhanbetzhanovna AA, Datkhayev U, Kussainov AZ, Adylova A. Regulation of RUNX proteins by long non-coding RNAs and circular RNAs in different cancers. Noncoding RNA Res 2021; 6:100-106. [PMID: 34189363 PMCID: PMC8209647 DOI: 10.1016/j.ncrna.2021.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/05/2021] [Accepted: 05/25/2021] [Indexed: 12/27/2022] Open
Abstract
RUNX proteins have been shown to behave as "double-edge sword" in wide variety of cancers. Discovery of non-coding RNAs has played linchpin role in improving our understanding about the post-transcriptional regulation of different cell signaling pathways. Several new mechanistic insights and distinct modes of cross-regulation of RUNX proteins and non-coding RNAs have been highlighted by recent research. In this review we have attempted to provide an intricate interplay between non-coding RNAs and RUNX proteins in different cancers. Better conceptual and mechanistic understanding of layered regulation of RUNX proteins by non-coding RNAs will be helpful in effective translation of the laboratory findings to clinically effective therapeutics.
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Affiliation(s)
| | - Kapanova Gulnara
- Al-Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty, 050040, Kazakhstan
| | | | - Ubaidilla Datkhayev
- Asfendiyarov Kazakh National Medical University, KazNMU, Tole Bi St 94, Almaty, 050000, Kazakhstan
| | - Abay Z Kussainov
- Kazakh National Medical University Named After S. D. Asfendiyarov, Kazakhstan
| | - Aima Adylova
- Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, China
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Harari-Steinfeld R, Gefen M, Simerzin A, Zorde-Khvalevsky E, Rivkin M, Ella E, Friehmann T, Gerlic M, Zucman-Rossi J, Caruso S, Leveille M, Estall JL, Goldenberg DS, Giladi H, Galun E, Bromberg Z. The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD. Cancers (Basel) 2021; 13:cancers13030411. [PMID: 33499244 PMCID: PMC7866230 DOI: 10.3390/cancers13030411] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 01/13/2023] Open
Abstract
The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC (p = 0.014) as well as in human samples (p = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.
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Affiliation(s)
- Rona Harari-Steinfeld
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Maytal Gefen
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Alina Simerzin
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Elina Zorde-Khvalevsky
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Mila Rivkin
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Ezra Ella
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Tomer Friehmann
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Mordechay Gerlic
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France; (J.Z.-R.); (S.C.)
- Assistance Publique Hopitaux de Paris, AP-HP, Hopital Européen Georges Pompidou, HEGP, Service d’Oncologie, F-75015 Paris, France
| | - Stefano Caruso
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Equipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France; (J.Z.-R.); (S.C.)
| | - Mélissa Leveille
- Cardiovascular and Metabolic Disease Division, Institut de Recherches Cliniques de Montreal (IRCM), 110 Ave des Pins Ouest, Montreal, QC H2W 1R7, Canada; (M.L.); (J.L.E.)
| | - Jennifer L. Estall
- Cardiovascular and Metabolic Disease Division, Institut de Recherches Cliniques de Montreal (IRCM), 110 Ave des Pins Ouest, Montreal, QC H2W 1R7, Canada; (M.L.); (J.L.E.)
| | - Daniel S. Goldenberg
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Hilla Giladi
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
| | - Eithan Galun
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
- Correspondence: ; Tel.: +972-2-6777762
| | - Zohar Bromberg
- The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 9112001, Israel; (R.H.-S.); (M.G.); (A.S.); (E.Z.-K.); (M.R.); (E.E.); (T.F.); (D.S.G.); (H.G.); (Z.B.)
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Petkevicius V, Streleckiene G, Balciute K, Link A, Leja M, Malfertheiner P, Skieceviciene J, Kupcinskas J. Association of Long Non-Coding RNA Polymorphisms with Gastric Cancer and Atrophic Gastritis. Genes (Basel) 2020; 11:1505. [PMID: 33333725 PMCID: PMC7765138 DOI: 10.3390/genes11121505] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Long non-coding RNAs (lncRNA) play an important role in the carcinogenesis of various tumours, including gastric cancer. This study aimed to assess the associations of lncRNA ANRIL, H19, MALAT1, MEG3, HOTAIR single-nucleotide polymorphisms (SNPs) with gastric cancer and atrophic gastritis. SNPs were analyzed in 613 gastric cancer patients, 118 patients with atrophic gastritis and 476 controls from three tertiary centers in Germany, Lithuania and Latvia. Genomic DNA was extracted from peripheral blood leukocytes. SNPs were genotyped by the real-time polymerase chain reaction. Results showed that carriers of MALAT1 rs3200401 CT genotype had the significantly higher odds of atrophic gastritis than those with CC genotype (OR-1.81; 95% CI 1.17-2.80, p = 0.0066). Higher odds of AG were found in a recessive model (CC vs. TT + CT) for ANRIL rs1333045 (OR-1.88; 95% CI 1.19-2.95, p = 0.0066). Carriers of ANRIL (rs17694493) GG genotype had higher odds of gastric cancer (OR-4.93; 95% CI 1.28-19.00) and atrophic gastritis (OR-5.11; 95% CI 1.10-23.80) compared with the CC genotype, and carriers of HOTAIR rs17840857 TG genotype had higher odds of atrophic gastritis (OR-1.61 95% CI 1.04-2.50) compared with the TT genotype; however, the ORs did not reach the adjusted significance threshold (p < 0.007). In summary, our data provide novel evidence for a possible link between lncRNA SNPs and premalignant condition of gastric cancer, suggesting the involvement of lncRNAs in gastric cancer development.
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Affiliation(s)
- Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Greta Streleckiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Kotryna Balciute
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (A.L.); (P.M.)
| | - Marcis Leja
- Institute for Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia,1586 Riga, Latvia;
- Faculty of Medicine, University of Latvia, 1586 Riga, Latvia
- Department of Research, Riga East University Hospital, 1079 Riga, Latvia
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (A.L.); (P.M.)
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
- Institute for Digestive Research, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (G.S.); (K.B.); (J.S.)
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Zong Z, Li H, Yu ZM, Tang FX, Zhu XJ, Tian HK, Zhou TC, Wang H. Prognostic thirteen-long non-coding RNAs (IncRNAs) could improve the survival prediction of gastric cancer. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:598-606. [DOI: 10.1016/j.gastrohep.2020.01.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/20/2020] [Accepted: 01/23/2020] [Indexed: 12/24/2022]
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Kashyap MP, Sinha R, Mukhtar MS, Athar M. Epigenetic regulation in the pathogenesis of non-melanoma skin cancer. Semin Cancer Biol 2020; 83:36-56. [PMID: 33242578 DOI: 10.1016/j.semcancer.2020.11.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.
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Affiliation(s)
- Mahendra Pratap Kashyap
- UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Rajesh Sinha
- UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - M Shahid Mukhtar
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Mohammad Athar
- UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Wang B, Suen CW, Ma H, Wang Y, Kong L, Qin D, Lee YWW, Li G. The Roles of H19 in Regulating Inflammation and Aging. Front Immunol 2020; 11:579687. [PMID: 33193379 PMCID: PMC7653221 DOI: 10.3389/fimmu.2020.579687] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/05/2020] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence suggests that long non-coding RNA H19 correlates with several aging processes. However, the role of H19 in aging remains unclear. Many studies have elucidated a close connection between H19 and inflammatory genes. Chronic systemic inflammation is an established factor associated with various diseases during aging. Thus, H19 might participate in the development of age-related diseases by interplay with inflammation and therefore provide a protective function against age-related diseases. We investigated the inflammatory gene network of H19 to understand its regulatory mechanisms. H19 usually controls gene expression by acting as a microRNA sponge, or through mir-675, or by leading various protein complexes to genes at the chromosome level. The regulatory gene network has been intensively studied, whereas the biogenesis of H19 remains largely unknown. This literature review found that the epithelial-mesenchymal transition (EMT) and an imprinting gene network (IGN) might link H19 with inflammation. Evidence indicates that EMT and IGN are also tightly controlled by environmental stress. We propose that H19 is a stress-induced long non-coding RNA. Because environmental stress is a recognized age-related factor, inflammation and H19 might serve as a therapeutic axis to fight against age-related diseases.
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Affiliation(s)
- Bin Wang
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chun Wai Suen
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Haibin Ma
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Yan Wang
- Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Kong
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
| | - Dajiang Qin
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuk Wai Wayne Lee
- Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Gang Li
- The Chinese University of Hong Kong (CUHK)-Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL), Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.,Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Innovation Center for Translational Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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40
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Chen R, Lei S, Jiang T, She Y, Shi H. Regulation of Skeletal Muscle Atrophy in Cachexia by MicroRNAs and Long Non-coding RNAs. Front Cell Dev Biol 2020; 8:577010. [PMID: 33043011 PMCID: PMC7523183 DOI: 10.3389/fcell.2020.577010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 08/26/2020] [Indexed: 12/14/2022] Open
Abstract
Skeletal muscle atrophy is a common complication of cachexia, characterized by progressive bodyweight loss and decreased muscle strength, and it significantly increases the risks of morbidity and mortality in the population with atrophy. Numerous complications associated with decreased muscle function can activate catabolism, reduce anabolism, and impair muscle regeneration, leading to muscle wasting. microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), types of non-coding RNAs, are important for regulation of skeletal muscle development. Few studies have specifically identified the roles of miRNAs and lncRNAs in cellular or animal models of muscular atrophy during cachexia, and the pathogenesis of skeletal muscle wasting in cachexia is not entirely understood. To develop potential approaches to improve skeletal muscle mass, strength, and function, a more comprehensive understanding of the known key pathophysiological processes leading to muscular atrophy is needed. In this review, we summarize the known miRNAs, lncRNAs, and corresponding signaling pathways involved in regulating skeletal muscle atrophy in cachexia and other diseases. A comprehensive understanding of the functions and mechanisms of miRNAs and lncRNAs during skeletal muscle wasting in cachexia and other diseases will, therefore, promote therapeutic treatments for muscle atrophy.
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Affiliation(s)
- Rui Chen
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Si Lei
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Ting Jiang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanling She
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Huacai Shi
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
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41
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Sun Z, Xue S, Zhang M, Xu H, Hu X, Chen S, Liu Y, Guo M, Cui H. Aberrant NSUN2-mediated m 5C modification of H19 lncRNA is associated with poor differentiation of hepatocellular carcinoma. Oncogene 2020; 39:6906-6919. [PMID: 32978516 PMCID: PMC7644462 DOI: 10.1038/s41388-020-01475-w] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 08/21/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022]
Abstract
RNA methylation is an important epigenetic modification. Recent studies on RNA methylation mainly focus on the m6A modification of mRNA, but very little is known about the m5C modification. NSUN2 is an RNA methyltransferase responsible for the m5C modification of multiple RNAs. In this study, we knocked down the NSUN2 gene in HepG2 cells by CRISPR/Cas9 technology and performed high-throughput RNA-BisSeq. An important tumor-related lncRNA H19 was identified to be targeted by NSUN2. Studies have shown that the expression of H19 lncRNA is abnormally elevated and has a carcinogenic effect in many types of tumors. Our results demonstrated that m5C modification of H19 lncRNA can increase its stability. Interestingly, m5C-modified H19 lncRNA can be specifically bound by G3BP1, a well-known oncoprotein which further leads to MYC accumulation. This may be a novel mechanism by which lncRNA H19 exerts its oncogenic effect. Besides, both the m5C methylation level and the expression level of H19 lncRNA in hepatocellular carcinoma tissues were significantly higher than those in adjacent non-cancer tissues, which were closely associated with poor differentiation of hepatocellular carcinoma (HCC). In conclusion, we found that H19 RNA is a specific target for the NSUN2 modifier. The m5C-modified H19 lncRNA may promote the occurrence and development of tumors by recruiting the G3BP1 oncoprotein. Our findings may provide a potential target and biomarker for the diagnosis and treatment of HCC.
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Affiliation(s)
- Zhen Sun
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Songlei Xue
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Meiying Zhang
- The General Hospital of the People's Liberation Army (PLAGH), Beijing, China
| | - Hui Xu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Xuming Hu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Shihao Chen
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Yangyang Liu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China
| | - Mingzhou Guo
- The General Hospital of the People's Liberation Army (PLAGH), Beijing, China.
| | - Hengmi Cui
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China. .,Joint International Research Laboratory of Agricultural and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225009, Yangzhou, China. .,Institute of Comparative Medicine, Yangzhou University, 225009, Yangzhou, China. .,Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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Alipoor B, Parvar SN, Sabati Z, Ghaedi H, Ghasemi H. An updated review of the H19 lncRNA in human cancer: molecular mechanism and diagnostic and therapeutic importance. Mol Biol Rep 2020; 47:6357-6374. [PMID: 32743775 DOI: 10.1007/s11033-020-05695-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 07/26/2020] [Indexed: 12/24/2022]
Abstract
Accumulating evidence has reported that H19 long non-coding RNA (lncRNA) expression level is deregulated in human cancer. It has been also demonstrated that de-regulated levels of H19 could affect cancer biology by various mechanisms including microRNA (miRNA) production (like miR-675), miRNA sponging and epigenetic modifications. Furthermore, lncRNA could act as a potential diagnosis and prognosis biomarkers and also a candidate therapeutic approach for different human cancers. In this narrative review, we shed light on the molecular mechanism of H19 in cancer development and pathogenesis. Moreover, we discussed the expression pattern and diagnostic and therapeutic importance of H19 as a potential biomarker in a range of human malignancies from breast to osteosarcoma cancer.
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Affiliation(s)
- Behnam Alipoor
- Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Seyedeh Nasrin Parvar
- Department of Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Zolfaghar Sabati
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran
| | - Hamid Ghaedi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Ghasemi
- Department of Clinical Biochemistry, Abadan Faculty of Medical Sciences, Abadan, Iran.
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Zhang T, Lei F, Jiang T, Xie L, Huang P, Li P, Huang Y, Tang X, Gong J, Lin Y, Cheng A, Huang W. H19/miR-675-5p Targeting SFN Enhances the Invasion and Metastasis of Nasalpharyngeal Cancer Cells. Curr Mol Pharmacol 2020; 12:324-333. [PMID: 31677258 DOI: 10.2174/1874467212666190719120446] [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: 02/21/2019] [Revised: 05/27/2019] [Accepted: 06/18/2019] [Indexed: 12/25/2022]
Abstract
AIMS The aim is to study the role of miR-675-5p coded by long non-coding RNA H19 in the development of Nasopharyngeal Cancer (NPC) and whether miR-675-5p regulates the invasion and metastasis of NPC through targeting SFN (14-3-3σ). The study further validated the relationship between H19, miR-675-5p and SFN in NPC and their relationship with the invasion and metastasis of NPC. METHODS Western blot was used to detect the expression of 14-3-3σ protein in immortalized normal nasopharyngeal epithelial cells NP69 and different metastatic potential NPC cells, 6-10B and 5-8F. At the same time, to find out the relationship between 14-3-3σ protein and the expression of H19 and miR-675-5p, the expression of H19 and miR-675-5p in normal nasopharynx epithelial cells NP69 and varied nasopharyngeal carcinoma cells 6-10B and 5-8F were quantified by real-time PCR. MiR-675-5p mimic and inhibitor were transfected into NPC 6-10B to over-express and down-express miR-675-5p; miR-675-5p mimic negative control and inhibitor negative control were transfected into NPC 6-10B as control groups. The effect of over-expression and down-expression by miR-675-5p on the expression of 14-3-3σ protein was detected by Western blotting. The 3'-UTR segments of SFN, containing miR-675-5p binding sites were amplified by PCR and the luciferase activity in the transfected cells was assayed to detect whether SFN is the direct target of miR-675-5p. Transwell and scratch assays were used to verify the changes in NPC invasion and metastasis ability of mimics and inhibitors transfected with miR-675-5p. RESULTS The expression of 14-3-3σ protein in normal nasopharynx epithelial cells NP69 is significantly higher than in varied nasopharyngeal carcinoma cells, 6-10B and 5-8F (P<0.05), and the 14-3-3σ protein levels in low-metastatic nasopharyngeal carcinoma cell 6-10B is higher than in high-metastatic nasopharyngeal carcinoma cell 5-8F. The expression of H19 and miR-675-5p are significantly higher in NPC cells than in NP69 cell (P<0.05). The expression of H19 and miR-675-5p in high-Metastatic nasopharyngeal carcinoma cell 5-8F was higher than in low-Metastatic nasopharyngeal carcinoma cell 6-10B. The expression of 14-3-3σ protein in miR-675-5p mimic cells was significantly lower than in mimic NC (negative control) group and blank control group. However, compared with the blank control group, mimic NC showed no significant difference in 14-3-3σ protein between the two groups. The miR-675-5p inhibitor group was significantly higher than the inhibitor NC group and the blank control group (p<0.05), but there was no significant difference in the expression of 14-3-3σ protein in the inhibitor NC group and the blank control group (p>0.05). Dual-luciferase reporter assay system shows the 3'-UTR segments of SFN containing miR-675-5p binding sites. SFN was the target gene of miR-675-5p. CONCLUSION 14-3-3σ is downregulated in NPC and is involved in the development of NPC. H19 and miR- 675-5p are upregulated in NPC, which is related to the development of NPC. The over-expression of miR- 675-5p inhibits the expression of 14-3-3σ protein. SFN is the target gene of miR-675-5p. MiR-675-5p targets SFN, downregulates its protein expression and promotes the invasion and metastasis of NPC.
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Affiliation(s)
- Ting Zhang
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Fanghong Lei
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Tao Jiang
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Lisha Xie
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Pin Huang
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Pei Li
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Yun Huang
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Xia Tang
- Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Jie Gong
- Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Yunpeng Lin
- Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China
| | - Ailan Cheng
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China.,Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology (2016TP1015), Hengyang 421001, Hunan Province, China
| | - Weiguo Huang
- Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang 421001, Hunan Province, China.,Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology (2016TP1015), Hengyang 421001, Hunan Province, China
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Barwal TS, Sharma U, Vasquez KM, Prakash H, Jain A. A panel of circulating long non-coding RNAs as liquid biopsy biomarkers for breast and cervical cancers. Biochimie 2020; 176:62-70. [PMID: 32634463 DOI: 10.1016/j.biochi.2020.06.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/26/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022]
Abstract
The early detection and diagnosis of cancer is critical to optimize the treatment and management of cancer patients. Typical methods such as imaging and tissue biopsy are invasive, time-consuming, and often imprecise. Thus, recent technological advances of dependable, facile, and minimally invasive collectible oncogenic biomarkers using human biofluids and secretions have been an active area of research. Recently, circulating long non-coding RNAs (lncRNAs) have been identified as promising biomarkers that fulfill many recommended properties of successful biomarkers for cancer diagnosis and prognosis. LncRNAs play essential roles in many cellular processes including DNA repair, cell proliferation, and epithelial-to-mesenchymal transition (EMT) by regulating the expression of various genes associated with cancer development and progression. Herein, we discuss the regulatory functions/pathways associated with multiple cancer-associated lncRNAs and their potential as prognostic/diagnostic markers for breast and cervical cancers. Additionally, we provide a correlation between lncRNA levels in the blood and clinicopathological data, including sensitivity, specificity, and Area Under Curve (AUC) merits of model performance value.
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Affiliation(s)
- Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Karen M Vasquez
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA
| | - Hridayesh Prakash
- Amity Institute of Virology and Immunology, Amity University, Noida, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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Peperstraete E, Lecerf C, Collette J, Vennin C, Raby L, Völkel P, Angrand PO, Winter M, Bertucci F, Finetti P, Lagadec C, Meignan S, Bourette RP, Bourhis XL, Adriaenssens E. Enhancement of Breast Cancer Cell Aggressiveness by lncRNA H19 and its Mir-675 Derivative: Insight into Shared and Different Actions. Cancers (Basel) 2020; 12:cancers12071730. [PMID: 32610610 PMCID: PMC7407157 DOI: 10.3390/cancers12071730] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/11/2020] [Accepted: 06/28/2020] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is a major public health problem and the leading world cause of women death by cancer. Both the recurrence and mortality of breast cancer are mainly caused by the formation of metastasis. The long non-coding RNA H19, the precursor of miR-675, is involved in breast cancer development. The aim of this work was to determine the implication but, also, the relative contribution of H19 and miR-675 to the enhancement of breast cancer metastatic potential. We showed that both H19 and miR-675 increase the invasive capacities of breast cancer cells in xenografted transgenic zebrafish models. In vitro, H19 and miR-675 enhance the cell migration and invasion, as well as colony formation. H19 seems to induce the epithelial-to-mesenchymal transition (EMT), with a decreased expression of epithelial markers and an increased expression of mesenchymal markers. Interestingly, miR-675 simultaneously increases the expression of both epithelial and mesenchymal markers, suggesting the induction of a hybrid phenotype or mesenchymal-to-epithelial transition (MET). Finally, we demonstrated for the first time that miR-675, like its precursor H19, increases the stemness properties of breast cancer cells. Altogether, our data suggest that H19 and miR-675 could enhance the aggressiveness of breast cancer cells through both common and different mechanisms.
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Affiliation(s)
- Evodie Peperstraete
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Clément Lecerf
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Jordan Collette
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Constance Vennin
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Ludivine Raby
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Pamela Völkel
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Pierre-Olivier Angrand
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Marie Winter
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - François Bertucci
- Laboratoire d’Oncologie Prédictive, CRCM, Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR7258, Aix-Marseille Université, Département d’Oncologie Médicale, Institut Paoli-Calmettes, 13009 Marseille, France; (F.B.); (P.F.)
| | - Pascal Finetti
- Laboratoire d’Oncologie Prédictive, CRCM, Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR7258, Aix-Marseille Université, Département d’Oncologie Médicale, Institut Paoli-Calmettes, 13009 Marseille, France; (F.B.); (P.F.)
| | - Chann Lagadec
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Samuel Meignan
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Roland P. Bourette
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Xuefen Le Bourhis
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
| | - Eric Adriaenssens
- University Lille, CNRS, INSERM, CHU Lille, Centre Oscar Lambret, UMR 9020–UMR 1277–Canther–Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France; (E.P.); (C.L.); (J.C.); (C.V.); (L.R.); (P.V.); (P.-O.A.); (M.W.); (C.L.); (S.M.); (R.P.B.); (X.L.B.)
- Correspondence: ; Tel.: +33-(0)3-20-33-64-06
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Gao Y, Wang JW, Ren JY, Guo M, Guo CW, Ning SW, Yu S. Long noncoding RNAs in gastric cancer: From molecular dissection to clinical application. World J Gastroenterol 2020; 26:3401-3412. [PMID: 32655264 PMCID: PMC7327794 DOI: 10.3748/wjg.v26.i24.3401] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 04/24/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are important regulators of cell processes that are usually dysregulated in gastric cancer (GC). Based on their high specificity and ease of detection in tissues and body fluids, increasing attention has spurred the study of the roles of lncRNAs in GC patients. Thus, it is necessary to elucidate the molecular mechanisms and further explore the clinical applications of lncRNAs in GC. In this review, we summarize current knowledge to examine dysregulated lncRNAs in GC and their underlying molecular mechanisms and activities in GC, which involve microRNA sponging, mRNA stability, genetic variants, alternative splicing, transcription factor binding, and epigenetic modification. More significantly, the potential of lncRNAs as prognostic, circulating, and drug-resistant biomarkers for GC is also described. This review highlights the method of dissecting molecular mechanisms to explore the clinical application of lncRNAs in GC. Overall, this review offers assistance in using lncRNAs as novel candidates for molecular mechanisms and for the identification of revolutionary biomarkers for GC.
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Affiliation(s)
- Yue Gao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Jun-Wei Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Jia-Yi Ren
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Mian Guo
- Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Cheng-Wang Guo
- Department of Gastroenterology and Gastrosurgery, Gansu Wuwei Tumor Hospital, Wuwei 733000, Gansu Province, China
| | - Shang-Wei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Shan Yu
- Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, China
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Wang F, Rong L, Zhang Z, Li M, Ma L, Ma Y, Xie X, Tian X, Yang Y. LncRNA H19-Derived miR-675-3p Promotes Epithelial-Mesenchymal Transition and Stemness in Human Pancreatic Cancer Cells by targeting the STAT3 Pathway. J Cancer 2020; 11:4771-4782. [PMID: 32626524 PMCID: PMC7330704 DOI: 10.7150/jca.44833] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/25/2020] [Indexed: 12/17/2022] Open
Abstract
Objective: The functional role and mechanism of the long noncoding RNA (lncRNA) H19 in regulating human pancreatic cancer (PC) cell stemness and invasion have not been completely elucidated. This study aimed to evaluate the role of H19 in regulating the stemness, epithelial-mesenchymal transition (EMT), invasion and chemosensitivity of PC cells. Methods: The sphere-forming ability was assessed using serum-free floating-culture systems. Chemosensitivity was evaluated via CCK-8 and flow cytometry assays in vitro. Migration and invasion were evaluated by transwell assays. The expression of stemness and EMT markers was detected by flow cytometry, qRT-PCR and western blot analyses. Xenograft initiation, growth and sensitivity were examined; Ki-67 nuclear staining intensity was evaluated by immunohistochemistry; and in situ apoptosis was evaluated by a TUNEL assay. Results: H19 played an important role in maintaining PC cell stemness. Upregulated H19 expression in CAPAN-1 cells promoted tumor cell migration, invasion, EMT and chemoresistance. In contrast, downregulated H19 expression in PANC-1 cells yielded the opposite results. These effects were mediated by positively modulating the STAT3 pathway. Furthermore, SOCS5, an endogenous inhibitor of the STAT3 pathway, was a direct target of miR-675-3p, which was positively regulated by H19 in PC cells. Conclusions: The H19/miR-675-3p signaling axis plays a critical role in maintaining the EMT process and stemness of PC cells by directly targeting SOCS5 to activate the STAT3 pathway. These data provide new insights into the oncogenic function of H19 in human PC and reveal potential targets for the development of optimal treatment approaches for this disease.
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Affiliation(s)
- Feng Wang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China.,Department of Endoscopy Center, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Long Rong
- Department of Endoscopy Center, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Zhengkui Zhang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Mingzhe Li
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Ling Ma
- Department of Surgical Oncology, Peking University Ninth School of Clinical Medicine (Beijing Shijitan Hospital, Capital Medical University), Beijing 100038, People's Republic of China
| | - Yongsu Ma
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Xuehai Xie
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Xiaodong Tian
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
| | - Yinmo Yang
- Department of General Surgery, Peking University First Hospital, Beijing 100034, People's Republic of China
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Zhong X, Huang S, Liu D, Jiang Z, Jin Q, Li C, Da L, Yao Q, Wang D. Galangin promotes cell apoptosis through suppression of H19 expression in hepatocellular carcinoma cells. Cancer Med 2020; 9:5546-5557. [PMID: 32485786 PMCID: PMC7402821 DOI: 10.1002/cam4.3195] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/04/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Background Galangin has been extensively studied as the antitumor agent in various cancers. However, the effect of galangin in hepatocellular carcinoma (HCC) remains elusive. Methods Using RNA sequencing, the differential expression of lncRNA in human HCC cell line with highly metastatic potential (MHCC97H) cells treated with galangin was investigated. Furthermore, H19 expression pattern was also determined in MHCC97H cells following treatment with galangin. In addition, knockdown and overexpression of H19 was performed to analyze the effect of the expression pattern of H19 on cell apoptosis, cell cycle, migration, and invasion in HCC cells. Moreover, the in vivo effect of galangin on tumor development was also determined in nude mice. In order to analyze loss expression of H19 in vivo, clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) was used. Results Total of 50 lncRNAs were significantly differentially expressed in MHCC97H cells treated with galangin. Besides, the expression of H19 was markedly reduced following treatment with galangin in MHCC97H cells. Compared to the Control group, the galangin‐treated group inhibited cell migration and invasion. Knockdown of H19 expression showed increased cell apoptosis and decreased invasion. In addition, RNA‐seq data also identified 161 mRNA which was significantly differentially expressed following treatment with galangin. To further determine the underlying mechanism, p53 protein was analyzed. Notably, the results indicated that knockdown of H19 and miR675 induced the expression of p53, eventually promoting cell apoptosis in MHCC97H cells. These results indicated that galangin promoted cell apoptosis through reduced the expression of H19 and miR675 in MHCC97H cells. The in vivo result showed that compared to the Con, tumor growth was remarkably suppressed with loss expression of H19. Conclusion Our data suggested that galangin has a crucial role in hepatocarcinogenesis through regulating the expression pattern of H19.
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Affiliation(s)
- Xiaowei Zhong
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Siyi Huang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Dianfeng Liu
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Ziping Jiang
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
| | - Qinglong Jin
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Chengshun Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Liu Da
- Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Qunyan Yao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
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Hao J, Li C, Lin C, Hao Y, Yu X, Xia Y, Gao F, Jiang Z, Wang D. Targeted point mutations of the m6A modification in miR675 using RNA-guided base editing induce cell apoptosis. Biosci Rep 2020; 40:BSR20192933. [PMID: 32323721 PMCID: PMC7201566 DOI: 10.1042/bsr20192933] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 04/09/2020] [Accepted: 04/22/2020] [Indexed: 12/31/2022] Open
Abstract
Methylation of the adenine base at the nitrogen 6 position (m6A) is the most common post-transcriptional epigenetic modification of RNA, and it plays a very important role in regulating gene expression. To investigate the role of m6A methylation in the expression of non-coding RNA and miRNA, we used a system of adenine base editors (ABEs). Here, we mutated regions up- and downstream of miRNA 675 m6A modification sites in the H19 locus using HEK293T, L02, MHCC97L, MHCC97H, A549, and SGC-7901 cells. Our results showed that a T-A base transversion had occurred in all cell lines. Moreover, mutation of the regions upstream of the miRNA 675 m6A modification site led to reduced expression of H19 and the induction of cell apoptosis in HEK293T cells. To further confirm our results, L02 and MHCC97L cells were detected using ABEs system. The results indicated increased cell apoptosis and reduced expression of miR675 as well as H19. To confirm the relationship between H19 and miR675 expression, overexpression and knockdown studies were performed. The results showed that reduced HI9 expression induced cell apoptosis through miR675. Taken together, these results indicate that m6A modification can regulate the expression of H19 and miR675 which induce cell apoptosis.
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Affiliation(s)
- Jindong Hao
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chengshun Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chao Lin
- Department of Animal Science, Jilin Business and Technology College, Changchun, China
| | - Yang Hao
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Xianfeng Yu
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Yidan Xia
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
| | - Fei Gao
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Ziping Jiang
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
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Xu Z, Lv H, Wang Y, Hu C, Chen S, Du Y, Shi C, Cheng X. HAND2-AS1 Inhibits Gastric Adenocarcinoma Cells Proliferation and Aerobic Glycolysis via miRNAs Sponge. Cancer Manag Res 2020; 12:3053-3068. [PMID: 32431548 PMCID: PMC7200253 DOI: 10.2147/cmar.s222878] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/09/2020] [Indexed: 01/14/2023] Open
Abstract
Objective To study the effect of lncRNA HAND2-AS1 on gastric adenocarcinoma (GA) cell property and explore its specific mechanism. Methods Data on stomach adenocarcinoma (STAD) were analyzed to screen differentially expressed lncRNA HAND2-AS1. RNA22-HAS database and dual luciferase reporter assay were applied to confirm the target relationship between HAND2-AS1/HIF3A and miR-184. The HAND2-AS1 and miR-184 expressions in tissue or cells were determined by qRT-PCR and Western blot. Besides, after GA cells (AGS) cultured in normoxic and hypoxic condition, phosphoenolpyruvate (PEP) and lactic acid were quantified by Phosphoenolpyruvate Fluorometric Assay Kit and Lactic Acid Detection kit, respectively. Additionally, colony formation assay, transwell invasion and migration assays were used to evaluate the abilities of cell invasion, migration, and proliferation in distinct conditions. Results The HAND2-AS1 and HIF3A expressions were down-regulated and miR-184 expression was up-regulated in GA tissues and cells. Dual luciferase reporter assay confirmed HAND2-AS1 and HIF3A were targeted by miR-184. AGS cell proliferation abilities were restrained by HAND2-AS1 and HIF3A overexpression and enhanced by miR-184, as well as migration and invasion abilities. In addition, HAND2-AS1 rescued enhanced AGS cell proliferation, cell migration, cell invasion abilities and glycolytic process caused by hypoxia via miR-184/HIF3A. Conclusion LncRNA HAND2-AS1 could inhibit GA cell proliferation, migration and invasion abilities and glycolytic process induced by hypoxia through miR-184/HIF3A signaling.
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Affiliation(s)
- Zhiyuan Xu
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
| | - Hang Lv
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor, Hangzhou 300020, Zhejiang, People's Republic of China
| | - Yiping Wang
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor, Hangzhou 300020, Zhejiang, People's Republic of China
| | - Can Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Shangqi Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Yian Du
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
| | - Chengwei Shi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang, People's Republic of China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People's Republic of China
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