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Ruprecht NA, Singhal S, Sens D, Singhal SK. Translating genetic findings to epigenetics: identifying the mechanisms associated with aging after high-radiation exposure on earth and in space. Front Public Health 2024; 12:1333222. [PMID: 38584916 PMCID: PMC10995328 DOI: 10.3389/fpubh.2024.1333222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 02/27/2024] [Indexed: 04/09/2024] Open
Abstract
Purpose Exposure to radiation is a health concern within and beyond the Earth's atmosphere for aircrew and astronauts in their respective austere environments. The biological effects of radiation exposure from a multiomics standpoint are relatively unexplored and stand to shed light on tailored monitoring and treatment for those in these career fields. To establish a reference variable for genetic damage, biological age seems to be closely associated with the effect of radiation. Following a genetic-based study, this study explores the epigenetic landscape of radiation exposure along with its associative effects on aging processes. Methods We imported the results of the genetics-based study that was a secondary analysis of five publicly available datasets (noted as Data1). The overlap of these genes with new data involving methylation data from two datasets (noted as Data2) following similar secondary analysis procedures is the basis of this study. We performed the standard statistical analysis on these datasets along with supervised and unsupervised learning to create preranked gene lists used for functional analysis in Ingenuity Pathway Analysis (IPA). Results There were 664 genes of interest from Data1 and 577 genes from Data2. There were 40 statistically significant methylation probes within 500 base pairs of the gene's transcription start site and 10 probes within 100 base pairs, which are discussed in depth. IPA yielded 21 significant pathways involving metabolism, cellular development, cell death, and diseases. Compared to gold standards for gestational age, we observed relatively low error and standard deviation using newly identified biomarkers. Conclusion We have identified 17 methylated genes that exhibited particular interest and potential in future studies. This study suggests that there are common trends in oxidative stress, cell development, and metabolism that indicate an association between aging processes and the effects of ionizing radiation exposure.
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Affiliation(s)
- Nathan A. Ruprecht
- Department of Biomedical Engineering, University of North Dakota, Grand Forks, ND, United States
| | - Sonalika Singhal
- Department of Pathology, University of North Dakota, Grand Forks, ND, United States
| | - Donald Sens
- Department of Pathology, University of North Dakota, Grand Forks, ND, United States
| | - Sandeep K. Singhal
- Department of Biomedical Engineering, University of North Dakota, Grand Forks, ND, United States
- Department of Pathology, University of North Dakota, Grand Forks, ND, United States
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Trsova I, Hrustincova A, Krejcik Z, Kundrat D, Holoubek A, Staflova K, Janstova L, Vanikova S, Szikszai K, Klema J, Rysavy P, Belickova M, Kaisrlikova M, Vesela J, Cermak J, Jonasova A, Dostal J, Fric J, Musil J, Dostalova Merkerova M. Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1. Mol Oncol 2023; 17:2565-2583. [PMID: 37408496 PMCID: PMC10701770 DOI: 10.1002/1878-0261.13486] [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: 01/09/2023] [Revised: 04/27/2023] [Accepted: 07/04/2023] [Indexed: 07/07/2023] Open
Abstract
Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.
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Affiliation(s)
- Iva Trsova
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
- Department of Genetics and Microbiology, Faculty of ScienceCharles UniversityPragueCzech Republic
| | - Andrea Hrustincova
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Zdenek Krejcik
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - David Kundrat
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Aleš Holoubek
- Department of ProteomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Karolina Staflova
- Department of BiochemistryInstitute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic
| | - Lucie Janstova
- Department of Modern ImmunotherapyInstitute of Hematology and Blood TransfusionPragueCzech Republic
- Department of Cell Biology, Faculty of ScienceCharles UniversityPragueCzech Republic
| | - Sarka Vanikova
- Department of Immunomonitoring and Flow CytometryInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Katarina Szikszai
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Jiri Klema
- Department of Computer ScienceCzech Technical UniversityPragueCzech Republic
| | - Petr Rysavy
- Department of Computer ScienceCzech Technical UniversityPragueCzech Republic
| | - Monika Belickova
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Monika Kaisrlikova
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Jitka Vesela
- Department of GenomicsInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Jaroslav Cermak
- Laboratory of AnemiasInstitute of Hematology and Blood TransfusionPragueCzech Republic
| | - Anna Jonasova
- First Department of MedicineGeneral University HospitalPragueCzech Republic
| | - Jiri Dostal
- Department of BiochemistryInstitute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic
| | - Jan Fric
- Department of Modern ImmunotherapyInstitute of Hematology and Blood TransfusionPragueCzech Republic
- International Clinical Research Center of St. Anne's University Hospital (FNUSA‐ICRC)BrnoCzech Republic
| | - Jan Musil
- Department of Immunomonitoring and Flow CytometryInstitute of Hematology and Blood TransfusionPragueCzech Republic
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Jesenko T, Brezar SK, Cemazar M, Biasin A, Tierno D, Scaggiante B, Grassi M, Grassi C, Dapas B, Truong NH, Abrami M, Zanconati F, Bonazza D, Rizzolio F, Parisi S, Pastorin G, Grassi G. Targeting Non-Coding RNAs for the Development of Novel Hepatocellular Carcinoma Therapeutic Approaches. Pharmaceutics 2023; 15:1249. [PMID: 37111734 PMCID: PMC10145575 DOI: 10.3390/pharmaceutics15041249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.
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Affiliation(s)
- Tanja Jesenko
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
| | - Simona Kranjc Brezar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (T.J.); (S.K.B.); (M.C.)
- Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia
| | - Alice Biasin
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Domenico Tierno
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Bruna Scaggiante
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Mario Grassi
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Chiara Grassi
- Degree Course in Medicine, University of Trieste, I-34149 Trieste, Italy;
| | - Barbara Dapas
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City 70000, Vietnam;
| | - Michela Abrami
- Department of Engineering and Architecture, Trieste University, via Valerio 6, I-34127 Trieste, Italy; (A.B.); (M.G.); (M.A.)
| | - Fabrizio Zanconati
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I-34149 Trieste, Italy; (F.Z.)
| | - Deborah Bonazza
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I-34149 Trieste, Italy; (F.Z.)
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, I-33081 Aviano, Italy;
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I-30172 Venezia, Italy;
| | - Salvatore Parisi
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I-30172 Venezia, Italy;
- Doctoral School in Molecular Biomedicine, University of Trieste, I-34149 Trieste, Italy
| | - Giorgia Pastorin
- Pharmacy Department, National University of Singapore, Block S9, Level 15, 4 Science Drive 2, Singapore 117544, Singapore;
| | - Gabriele Grassi
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy; (D.T.); (B.S.); (B.D.)
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Wang C, Wang B, Liang W, Zhou C, Lin W, Meng Z, Wu W, Wu M, Liao Y, Li X, Zhao J, He Y. Hsa-miR-1248 suppressed the proliferation, invasion and migration of colorectal cancer cells via inhibiting PSMD10. BMC Cancer 2022; 22:922. [PMID: 36028821 PMCID: PMC9414407 DOI: 10.1186/s12885-022-10028-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/22/2022] [Indexed: 11/28/2022] Open
Abstract
Background Lymph node metastasis (LNM) is a critical event during the colorectal cancer (CRC) development and is indicative of poor prognosis. Identification of molecular markers of LNM may facilitate better therapeutic decision-making. Methods Six pairs of CRC tissues and corresponding adjacent tissues [3 pairs diagnosed as pT1N0M0 (M_Low group) and 3 pairs diagnosed as pT4N2M0 (M_High group)] collected from CRC patients who underwent surgical resection were used. MicroRNA sequencing was performed to screen differential microRNAs involved in CRC LNM. The selected microRNAs were validated in CRC tissues and cell lines using qRT-PCR. The functions of candidate hsa-miR-1248 were evaluated by CCK-8, colony formation, and Transwell assay. The binding of hsa-miR-1248 with its target PSMD10 was confirmed by luciferase activity assay, and the expression of PSMD10 in tissues was detected by droplet digital polymerase chain reaction. Results Ninety-five miRNAs were downregulated in carcinoma tissues (M_Low and M_high groups) compared with the normal group. Their expression in M_High group was significantly lower compared with M_Low group. The top 3 were hsa-miR-635, hsa-miR-1248, and hsa-miR-668-3p. After validation in tissues/cell lines, only hsa- hsa-miR-1248 was decreased in high metastatic tissues or SW620 cells compared to low metastatic tissues or SW480 cells. Hsa-miR-1248 was found to inhibit CRC cell viability, proliferation, invasion, and migration. The tumor suppressor effect of has-miR-1248 in CRC cells was attenuated or enhanced by up-regulating or down-regulating PSMD10, respectively. Conclusion Hsa-miR-1248 may act as a tumor suppressor gene in CRC by targeting and inhibiting PSMD10, which provides a clue for CRC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10028-1.
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Affiliation(s)
- Chengxing Wang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China
| | - Bin Wang
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Weijun Liang
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China
| | - Chaorong Zhou
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China
| | - Weixing Lin
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China
| | - Zijie Meng
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Wanting Wu
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Meimei Wu
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Yuehua Liao
- Department of Pathology, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Xiaoping Li
- Department of Breast, Jiangmen Central Hospital, Jiangmen, 529000, Guangdong, China
| | - Jinglin Zhao
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China.
| | - Yaoming He
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Haibang street NO.23, Jiangmen, 529000, Guangdong, China.
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Catanzaro G, Besharat ZM, Carai A, Jäger N, Splendiani E, Colin C, Po A, Chiacchiarini M, Citarella A, Gianno F, Cacchione A, Miele E, Diomedi Camassei F, Gessi M, Massimi L, Locatelli F, Jones DTW, Figarella-Branger D, Pfister SM, Mastronuzzi A, Giangaspero F, Ferretti E. MiR-1248: a new prognostic biomarker able to identify supratentorial hemispheric pediatric low-grade gliomas patients associated with progression. Biomark Res 2022; 10:44. [PMID: 35715818 PMCID: PMC9205050 DOI: 10.1186/s40364-022-00389-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/01/2022] [Indexed: 11/15/2022] Open
Abstract
Background Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways. Conclusions Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s40364-022-00389-x.
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Affiliation(s)
- Giuseppina Catanzaro
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Zein Mersini Besharat
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Andrea Carai
- Department of Neurosciences, Neurosurgery Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Natalie Jäger
- Division of Pediatric Neurooncology, Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elena Splendiani
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Carole Colin
- Institut de Neurophysiopathologie, Aix-Marseille Université, CNRS, Marseille, France
| | - Agnese Po
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Martina Chiacchiarini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Anna Citarella
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Francesca Gianno
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonella Cacchione
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Evelina Miele
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | | | - Marco Gessi
- Department of Women, Children and Public Health Sciences, Policlinico Universitario A. Gemelli, Catholic University Sacro Cuore, Rome, Italy
| | - Luca Massimi
- Pediatric Neurosurgery, Policlinico Universitario A. Gemelli, Catholic University Sacro Cuore, Rome, Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Department of Gynecology/Obstetrics & Pediatrics, Sapienza University of Rome, Rome, Italy
| | - David T W Jones
- Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
| | - Dominique Figarella-Branger
- Service d'Anatomie Pathologique Et de Neuropathologie, Hôpital de La Timone, Institut de Neurophysiopathologie, Aix-Marseille Université, AP-HM, CNRS, Marseille, France
| | - Stefan M Pfister
- Division of Pediatric Neurooncology, Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), and Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Angela Mastronuzzi
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Felice Giangaspero
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, IRCCS Neuromed, Pozzilli, Italy
| | - Elisabetta Ferretti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
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A Pleiotropic Role of Long Non-Coding RNAs in the Modulation of Wnt/β-Catenin and PI3K/Akt/mTOR Signaling Pathways in Esophageal Squamous Cell Carcinoma: Implication in Chemotherapeutic Drug Response. Curr Oncol 2022; 29:2326-2349. [PMID: 35448163 PMCID: PMC9031703 DOI: 10.3390/curroncol29040189] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/19/2022] [Accepted: 03/20/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of modern techniques for the treatment of esophageal squamous cell carcinoma (ESCC), tumor recurrence and metastasis are significant challenges in clinical management. Thus, ESCC possesses a poor prognosis and low five-year overall survival rate. Notably, the origin and recurrence of the cancer phenotype are under the control of complex cancer-related signaling pathways. In this review, we provide comprehensive knowledge about long non-coding RNAs (lncRNAs) related to Wnt/β-catenin and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in ESCC and its implications in hindering the efficacy of chemotherapeutic drugs. We observed that a pool of lncRNAs, such as HERES, TUG1, and UCA1, associated with ESCC, directly or indirectly targets various molecules of the Wnt/β-catenin pathway and facilitates the manifestation of multiple cancer phenotypes, including proliferation, metastasis, relapse, and resistance to anticancer treatment. Additionally, several lncRNAs, such as HCP5 and PTCSC1, modulate PI3K/Akt/mTOR pathways during the ESCC pathogenesis. Furthermore, a few lncRNAs, such as AFAP1-AS1 and LINC01014, block the efficiency of chemotherapeutic drugs, including cisplatin, 5-fluorouracil, paclitaxel, and gefitinib, used for ESCC treatment. Therefore, this review may help in designing a better therapeutic strategy for ESCC patients.
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Yue Q, Xu Y, Deng X, Wang S, Qiu J, Qian B, Zhang Y. Circ-PITX1 Promotes the Progression of Non-Small Cell Lung Cancer Through Regulating the miR-1248/CCND2 Axis. Onco Targets Ther 2021; 14:1807-1819. [PMID: 33727831 PMCID: PMC7955706 DOI: 10.2147/ott.s286820] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/28/2021] [Indexed: 12/15/2022] Open
Abstract
Background Circular RNA (circRNA) is a key regulator of cancer, and it has been proved to be involved in the regulation of cancer progression including non-small cell lung cancer (NSCLC). Circ-PITX1 was found to be a significantly upregulated circRNA in NSCLC, and its role and potential mechanism in NSCLC progression deserve further investigation. Methods The expression levels of circ-PITX1, microRNA (miR)-1248 and cyclin D2 (CCND2) were examined by quantitative real-time PCR (qRT-PCR). Cell proliferation, apoptosis, cell cycle process, migration and invasion were determined using cell counting kit 8 (CCK8) assay, colony formation assay, flow cytometry, wound healing assay and transwell assay. Xenograft models were built to explore the role of circ-PITX1 in NSCLC tumor growth in vivo. The glycolysis and glutamine metabolism of cells were assessed by detecting the consumptions of glucose and glutamine, cell extracellular acidification rate (ECAR), and the productions of lactate, α-ketoglutaric acid (α-KG) and ATP. The protein levels of hexokinase 2 (HK-2), glutaminase 1 (GLS1) and CCND2 were tested by Western blot (WB) analysis. Dual-luciferase reporter assay and RIP assay were employed to verify the interaction between miR-1248 and circ-PITX1 or CCND2. Results Circ-PITX1 was upregulated in NSCLC and its silencing could inhibit the proliferation, migration, invasion, cell cycle process, glycolysis, glutamine metabolism, and promote the apoptosis of NSCLC cells in vitro, as well as reduced tumor growth in vivo. In the terms of mechanism, we found that circ-PITX1 could act as a sponge of miR-1248, and miR-1248 could target CCND2. In addition, miR-1248 inhibitor reversed the inhibitory effect of circ-PITX1 knockdown on NSCLC progression. Similarly, CCND2 overexpression also reversed the suppressive effect of miR-1248 on NSCLC progression. Moreover, circ-PITX1 positively regulated CCND2 expression by sponging miR-1248. Conclusion Circ-PITX1 served as a sponge of miR-1248 to promote NSCLC progression by upregulating CCND2.
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Affiliation(s)
- Qianyu Yue
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Yanyan Xu
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Xiaoli Deng
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Shenglan Wang
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Jingman Qiu
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Baojiang Qian
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
| | - Yunhui Zhang
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, 650032, Yunnan, People's Republic of China
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Byun Y, Choi YC, Jeong Y, Yoon J, Baek K. Long Noncoding RNA Expression Profiling Reveals Upregulation of Uroplakin 1A and Uroplakin 1A Antisense RNA 1 under Hypoxic Conditions in Lung Cancer Cells. Mol Cells 2020; 43:975-988. [PMID: 33273139 PMCID: PMC7772508 DOI: 10.14348/molcells.2020.0126] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 10/15/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022] Open
Abstract
Hypoxia plays important roles in cancer progression by inducing angiogenesis, metastasis, and drug resistance. However, the effects of hypoxia on long noncoding RNA (lncRNA) expression have not been clarified. Herein, we evaluated alterations in lncRNA expression in lung cancer cells under hypoxic conditions using lncRNA microarray analyses. Among 40,173 lncRNAs, 211 and 113 lncRNAs were up- and downregulated, respectively, in both A549 and NCI-H460 cells. Uroplakin 1A (UPK1A) and UPK1A-antisense RNA 1 (AS1), which showed the highest upregulation under hypoxic conditions, were selected to investigate the effects of UPK1AAS1 on the expression of UPK1A and the mechanisms of hypoxia-inducible expression. Following transfection of cells with small interfering RNA (siRNA) targeting hypoxiainducible factor 1α (HIF-1α), the hypoxia-induced expression of UPK1A and UPK1A-AS1 was significantly reduced, indicating that HIF-1α played important roles in the hypoxiainduced expression of these targets. After transfection of cells with UPK1A siRNA, UPK1A and UPK1A-AS1 levels were reduced. Moreover, transfection of cells with UPK1A-AS1 siRNA downregulated both UPK1A-AS1 and UPK1A. RNase protection assays demonstrated that UPK1A and UPK1A-AS1 formed a duplex; thus, transfection with UPK1A-AS1 siRNA decreased the RNA stability of UPK1A. Overall, these results indicated that UPK1A and UPK1A-AS1 expression increased under hypoxic conditions in a HIF-1α-dependent manner and that formation of a UPK1A/UPK1A-AS1 duplex affected RNA stability, enabling each molecule to regulate the expression of the other.
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MESH Headings
- Cell Hypoxia/genetics
- Cell Line, Tumor
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Lung Neoplasms/genetics
- Methylation
- RNA Stability/genetics
- RNA, Antisense/genetics
- RNA, Antisense/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Reproducibility of Results
- Ribonucleases/metabolism
- Up-Regulation/genetics
- Uroplakin Ia/genetics
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Affiliation(s)
- Yuree Byun
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea
| | - Young-Chul Choi
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea
| | - Yongsu Jeong
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea
| | - Jaeseung Yoon
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea
| | - Kwanghee Baek
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea
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9
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Zhang DY, Sun QC, Zou XJ, Song Y, Li WW, Guo ZQ, Liu SS, Liu L, Wu DH. Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:229. [PMID: 33121524 PMCID: PMC7596966 DOI: 10.1186/s13046-020-01748-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/22/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. METHODS Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. RESULTS We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. CONCLUSIONS Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.
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Affiliation(s)
- Dong-Yan Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Qing-Can Sun
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Xue-Jing Zou
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Yang Song
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Wen-Wen Li
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Ze-Qin Guo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Shan-Shan Liu
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Li Liu
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - De-Hua Wu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
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10
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Zhao M, Cui H, Zhao B, Li M, Man H. Long intergenic non‑coding RNA LINC01232 contributes to esophageal squamous cell carcinoma progression by sequestering microRNA‑654‑3p and consequently promoting hepatoma‑derived growth factor expression. Int J Mol Med 2020; 46:2007-2018. [PMID: 33125097 PMCID: PMC7595671 DOI: 10.3892/ijmm.2020.4750] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Long intergenic non-coding RNA 01232 (LINC01232) was identified as a critical regulator of the development of pancreatic adenocarcinoma. The present study investigated the expression and regulatory roles of LINC01232 in esophageal squamous cell carcinoma (ESCC). The main aim of the present study was to elucidate the underlying mechanisms through which LINC01232 affects the malignancy of ESCC. Initially, LINC01232 expression in ESCC was analyzed using the TCGA and GTEx databases and was confirmed using reverse transcription-quantitative polymerase chain reaction. ESCC cell proliferation, apoptosis and migration and invasion were assessed using the Cell Counting kit-8 assay, flow cytometric analysis, and migration and invasion assays, respectively. ESCC tumor growth in vivo was examined using a xenograft mouse model. As shown by the results, a high LINC01232 expression was detected in ESCC tissues and cell lines. LINC01232 downregulation suppressed the proliferation, migration and invasion of ESCC cells, and promoted cell apoptosis in vitro. In addition, LINC01232 depletion restricted tumor growth in vivo. Mechanistically, LINC01232 was shown to function as an microRNA-654-3p (miR-654-3p) sponge in ESCC cells, and hepatoma-derived growth factor (HDGF) was identified as a direct target of miR-654-3p. LINC01232 could bind competitively to miR-654-3p and decrease its expression in ESCC cells, thereby promoting HDGF expression. Rescue experiments reconfirmed that the effects of LINC01232 deficiency in ESCC cells were restored by increasing the output of the miR-654-3p/HDGF axis. On the whole, the present study demonstrates that LINC01232 plays a tumor-promoting role during the progression of ESCC by regulating the miR-654-3p/HDGF axis. The LINC01232/miR-654-3p/HDGF pathway may thus provide a novel theoretical basis for the management of ESCC.
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Affiliation(s)
- Meihua Zhao
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 028007, P.R. China
| | - Haishan Cui
- Department of Endoscopy, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 028007, P.R. China
| | - Baisui Zhao
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 028007, P.R. China
| | - Mei Li
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 028007, P.R. China
| | - Haiqing Man
- Department of Endoscopy, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 028007, P.R. China
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11
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Liu X, Zhao W, Wang X. Inhibition of long non-coding RNA MALAT1 elevates microRNA-429 to suppress the progression of hypopharyngeal squamous cell carcinoma by reducing ZEB1. Life Sci 2020; 262:118480. [PMID: 32980391 DOI: 10.1016/j.lfs.2020.118480] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Hypopharyngeal squamous cell carcinoma (HSCC) is a common type of malignant tumor. Long non-coding RNAs (lncRNAs) are known to participate in HSCC development, while the role of lncRNA MALAT1 in HSCC remains largely unknown. We aimed to explore function of the lncRNA MALAT1/miR-429/ZEB1 axis in HSCC progression. METHODS Levels of MALAT1, miR-429 and ZEB1 in HSCC tissues samples were assessed. The FaDu cells were respectively treated with relative sequence or plasmid of MALAT1, miR-429, or ZEB1. Then, CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were used to determine the cell proliferation, apoptosis, cell cycle, migration and invasion of the cells. The PI3K/Akt/mTOR signaling pathway-related proteins, proliferation-related proteins, cell cycle-related proteins, apoptosis-related proteins, and migration-related proteins were detected using Western blot analysis. The cell growth in vivo was observed. The targeting relationships between MALAT1 and miR-429, and between miR-429 and ZEB1 were confirmed. RESULTS MALAT1 and ZEB1 expression in HSCC was upregulated while miR-429 expression was downregulated. Reduced MALAT1 and ZEB1, and upregulated miR-429 inactivated the PI3K/Akt/mTOR signaling pathway, suppressed in vitro viability, colony formation ability, migration and invasion, as well as cell growth in vivo, and promoted the apoptosis of FaDu cells. Downregulated miR-429 reversed the role of MALAT1 inhibition in FaDu cell growth. LncRNA MALAT1 served as a sponge of miR-429, thus regulating ZEB1 expression. CONCLUSION Inhibition of MALAT1 was able to elevate miR-429 to suppress the progression of HSCC via reducing ZEB1. Our research provided a potential therapeutic target for HSCC.
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Affiliation(s)
- Xiuling Liu
- Department of Otolaryngology Head and Neck Surgery, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai 264200, Shandong, PR China.
| | - Weixia Zhao
- Department of Otolaryngology, Weihai Central Hospital, Weihai 264200, Shandong, PR China
| | - Xuehai Wang
- Department of Otolaryngology Head and Neck Surgery, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai 264200, Shandong, PR China
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