|
1
|
Gao H, Wang J, Liu J, Wang H, Wang T, Li S, Niu L, Wei Y. FOXD1 activates KIFC1 to modulate aerobic glycolysis and reinforce cisplatin resistance of breast cancer. Reprod Biol 2025; 25:100969. [PMID: 39541848 DOI: 10.1016/j.repbio.2024.100969] [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: 09/02/2024] [Revised: 10/24/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Breast cancer (BC) is the most prevalent invasive malignant tumor. Cisplatin (DDP) is a prototype of platinum-based chemotherapy drugs, its resistance severely hinders its clinical application. This project intended to figure out the exact mechanism of KIFC1 in the DDP resistance of BC. METHODS The levels of KIFC1 and FOXD1 in BC as well as their binding sites were investigated by bioinformatics analysis. The signaling pathways regulated by FOXD1 were analyzed. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays verified the binding relationship between the two. Through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB), we assessed the expression of FOXD1, KIFC1, and glycolysis-related genes. CCK-8 assay was applied in the determination of cell viability to assess the efficacy of DDP resistance. Extracellular acidification rate (ECAR), glucose consumption, lactate synthesis, Adenosine triphosphate (ATP) content, and oxygen consumption rate (OCR) were measured to evaluate glycolysis. RESULTS FOXD1 and KIFC1 were significantly upregulated in BC, with KIFC1 being significantly enriched in the glycolysis pathway. Overexpression of KIFC1 significantly enhanced the DDP resistance of BC cells, while promoting aerobic glycolysis. Mechanistically, FOXD1 was bound to the promoter of KIFC1 to activate its transcription. Its overexpression counteracted the inhibitory effect of KIFC1 knockdown on the DDP resistance of BC cells. CONCLUSION FOXD1 activates the glycolysis pathway by upregulating KIFC1, thereby facilitating BC cells' DDP resistance. Therefore, the FOXD1/KIFC1 axis linked the glycolysis pathway to DDP resistance and may be a promising new target for reinforcing DDP resistance in BC.
Collapse
Affiliation(s)
- Haitao Gao
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Jing Wang
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Jiacai Liu
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Huihua Wang
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Tiantian Wang
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Sha Li
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Lili Niu
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China
| | - Ya Wei
- General Surgery Department, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China.
| |
Collapse
|
|
2
|
Li H, Sun J, Hu H, Wang Y. Transcription Factor E2F8 Activates PDK1-Mediated DNA Damage Repair to Enhance Cisplatin Resistance in Lung Adenocarcinoma. Pharmacology 2024; 109:341-356. [PMID: 38810606 DOI: 10.1159/000537819] [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: 08/10/2023] [Accepted: 02/12/2024] [Indexed: 05/31/2024]
Abstract
INTRODUCTION Cisplatin (DDP) is the commonest chemo drug in lung adenocarcinoma (LUAD) treatment, and DDP resistance is a significant barrier to therapeutic therapy. This study attempted to elucidate the impact of PDK1 on DDP resistance in LUAD and its mechanism. METHODS Bioinformatics analysis was used to determine the expression and enriched pathways of PDK1 in LUAD tissue. Subsequently, E2F8, the upstream transcription factor of PDK1, was predicted, and the binding relationship between the two was analyzed using dual-luciferase and ChIP experiments. PDK1 and E2F8 levels in LUAD tissues and cells were detected via qRT-PCR. Cell viability, proliferation, and apoptosis levels were assayed by CCK-8, EdU, and flow cytometry experiments, respectively. Comet assay was used to assess DNA damage, and immunofluorescence was used to assess the expression of γ-H2AX. NHEJ reporter assay was to assess DNA repair efficiency. Western blot tested levels of DNA damage repair (DDR)-related proteins. Immunohistochemistry assessed the expression of relevant genes. Finally, an animal model was constructed to investigate the influence of PDK1 expression on LUAD growth. RESULTS PDK1 was found to be upregulated in LUAD and enhanced DDP resistance by mediating DDR. E2F8 was identified as an upstream transcription factor of PDK1 and was highly expressed in LUAD. Rescue experiments presented that knocking down E2F8 could weaken the promotion of PDK1 overexpression on DDR-mediated DDP resistance in LUAD. In vivo experiments showed that knocking down PDK1 plus DDP significantly reduced the growth of xenograft tumors. CONCLUSION Our results indicated that the E2F8/PDK1 axis mediated DDR to promote DDP resistance in LUAD. Our findings lead to an improved treatment strategy after drug resistance.
Collapse
Affiliation(s)
- Hongliang Li
- Department of Radiotherapy, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, China
| | - Junxia Sun
- Department of Radiotherapy, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, China
| | - Haibo Hu
- Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, China
| | - Yi Wang
- Department of Cardiothoracic Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, China
| |
Collapse
|
|
3
|
Sheikhshabani SH, Modarres P, Ghafouri‐Fard S, Amini‐Farsani Z, Khodaee L, Shaygan N, Amini‐Farsani Z, Omrani MD. Meta-analysis of microarray data to determine gene indicators involved in cisplatin resistance in non-small cell lung cancer. Cancer Rep (Hoboken) 2024; 7:e1970. [PMID: 38351531 PMCID: PMC10864718 DOI: 10.1002/cnr2.1970] [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: 07/14/2023] [Revised: 12/02/2023] [Accepted: 12/28/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Lung cancer is a major cause of cancer-related mortality worldwide, with a 5-year survival rate of approximately 22%. Cisplatin is one of the standard first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC), but its efficacy is often limited by the development of resistance. Despite extensive research on the molecular mechanisms of chemoresistance, the underlying causes remain elusive and complex. AIMS We analyzed three microarray datasets to find the gene signature and key pathways related to cisplatin resistance in NSCLC. METHODS AND RESULTS We compared the gene expression of sensitive and resistant NSCLC cell lines treated with cisplatin. We found 274 DEGs, including 111 upregulated and 163 downregulated genes, in the resistant group. Gene set enrichment analysis showed the potential roles of several DEGs, such as TUBB2B, MAPK7, TUBAL3, MAP2K5, SMUG1, NTHL1, PARP3, NTRK1, G6PD, PDK1, HEY1, YTHDF2, CD274, and MAGEA1, in cisplatin resistance. Functional analysis revealed the involvement of pathways, such as gap junction, base excision repair, central carbon metabolism, and Notch signaling in the resistant cell lines. CONCLUSION We identified several molecular factors that contribute to cisplatin resistance in NSCLC cell lines, involving genes and pathways that regulate gap junction communication, DNA damage repair, ROS balance, EMT induction, and stemness maintenance. These genes and pathways could be targets for future studies to overcome cisplatin resistance in NSCLC.
Collapse
Affiliation(s)
| | - Paratoo Modarres
- Department of Cell and Molecular Biology and Microbiology, Faculty of Science and TechnologyUniversity of IsfahanIsfahanIran
| | - Soudeh Ghafouri‐Fard
- Department of Medical GeneticsShahid Beheshti University of Medical SciencesTehranIran
| | - Zeinab Amini‐Farsani
- Department of Medical GeneticsShahid Beheshti University of Medical SciencesTehranIran
| | - Lavin Khodaee
- Department of Biotechnology and Plant BreedingIslamic Azad University Science and Research BranchTehranIran
| | - Nasibeh Shaygan
- Department of Medical GeneticsShahid Beheshti University of Medical SciencesTehranIran
| | - Zahra Amini‐Farsani
- Bayesian Imaging and Spatial Statistics Group, Institute of StatisticsLudwig‐Maximilian‐Universität MünchenMunichGermany
- Department of StatisticsLorestan UniversityKhorramabadIran
| | - Mir Davood Omrani
- Urogenital Stem Cell Research CenterShahid Beheshti University of Medical SciencesTehranIran
| |
Collapse
|
|
4
|
Gupta J, Ahmed AT, Tayyib NA, Zabibah RS, Shomurodov Q, Kadheim MN, Alsaikhan F, Ramaiah P, Chinnasamy L, Samarghandian S. A state-of-art of underlying molecular mechanisms and pharmacological interventions/nanotherapeutics for cisplatin resistance in gastric cancer. Biomed Pharmacother 2023; 166:115337. [PMID: 37659203 DOI: 10.1016/j.biopha.2023.115337] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 09/04/2023] Open
Abstract
The fourth common reason of death among patients is gastric cancer (GC) and it is a dominant tumor type in Ease Asia. One of the problems in GC therapy is chemoresistance. Cisplatin (CP) is a platinum compound that causes DNA damage in reducing tumor progression and viability of cancer cells. However, due to hyperactivation of drug efflux pumps, dysregulation of genes and interactions in tumor microenvironment, tumor cells can develop resistance to CP chemotherapy. The current review focuses on the CP resistance emergence in GC cells with emphasizing on molecular pathways, pharmacological compounds for reversing chemoresistance and the role of nanostructures. Changes in cell death mechanisms such as upregulation of pro-survival autophagy can prevent CP-mediated apoptosis that results in drug resistance. Moreover, increase in metastasis via EMT induction induces CP resistance. Dysregulation of molecular pathways such as PTEN, PI3K/Akt, Nrf2 and others result in changes in CP response of GC cells. Non-coding RNAs determine CP response of GC cells and application of pharmacological compounds with activity distinct of CP can result in sensitivity in tumor cells. Due to efficacy of exosomes in transferring bioactive molecules such as RNA and DNA molecules among GC cells, exosomes can also result in CP resistance. One of the newest progresses in overcoming CP resistance in GC is application of nanoplatforms for delivery of CP in GC therapy that they can increase accumulation of CP at tumor site and by suppressing carcinogenic factors and overcoming biological barriers, they increase CP toxicity on cancer cells.
Collapse
Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U.P., India
| | | | - Nahla A Tayyib
- Faculty of Nursing, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Qakhramon Shomurodov
- Department of Maxillofacial Surgery, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Scientific Affairs, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Mostafai N Kadheim
- Department of Dentistry, Kut University College, Kut, Wasit 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad 10022 Iraq
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | | | | | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, the Islamic Republic of Iran.
| |
Collapse
|
|
5
|
Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
Collapse
|
|
6
|
Guo Y, Zhou Y, Wu P, Ran M, Xu N, Shan W, Sha O, Tam KY. Dichloroacetophenone biphenylsulfone ethers as anticancer pyruvate dehydrogenase kinase inhibitors in non-small cell lung cancer models. Chem Biol Interact 2023; 378:110467. [PMID: 37004952 DOI: 10.1016/j.cbi.2023.110467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 03/16/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Pyruvate dehydrogenase kinase 1 (PDK1) is an important metabolic enzyme which is often overexpressed in many types of cancers, including non-small-cell lung cancers (NSCLC). Targeting PDK1 appears to be an attractive anticancer strategy. Based on a previously reported moderate potent anticancer PDK1 inhibitor, 64, we developed three dichloroacetophenone biphenylsulfone ethers, 30, 31 and 32, which showed strong PDK1 inhibitions of 74%, 83% and 72% at 10 μM, respectively. Then we investigated the anticancer effects of 31 in two NSCLC cell lines, namely, NCI-H1299 and NCI-H1975. It was found that 31 exhibited sub-micromolar cancer cell IC50s, suppressed colony formation, induced mitochondrial membrane potential depolarization, triggered apoptosis, altered cellular glucose metabolism, with concomitant reductions in extracellular lactate levels and enhanced the generation of reactive oxygen species in NSCLC cells. Moreover, 31 significantly suppressed the tumor growth in an NCI-H1975 mouse xenograft model, outperforming the anticancer effects of 64. Taken together our results suggested that inhibition of PDK1 via dichloroacetophenone biphenylsulfone ethers may provide a novel direction leading to an alternative treatment option in NSCLC therapy.
Collapse
|
|
7
|
Zhao Y, Li P. Strategies of LncRNA DLX6-AS1 on Study and Therapeutics. Front Genet 2022; 13:871988. [PMID: 35719380 PMCID: PMC9198352 DOI: 10.3389/fgene.2022.871988] [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: 02/09/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulating evidence has revealed the vital regulatory roles of lncRNA DLX6-AS1 in various tumors at pre-transcriptional, transcriptional, and post-transcriptional levels, which makes it a potential prognosis factor and therapeutic target. In addition, the presence of lncRNA DLX6-AS1 in the exosomes of peripheral blood of patients with tumors may also contribute to it being a possible cancer-related biomarker. However, most literature studies are devoted to studying the effect of lncRNA DLX6-AS1 as a sponging molecule of miRNAs, the research of which is likely to get stuck into a dilemma. Literature studies published already have demonstrated an exciting cell malignant phenotype inhibition with the knockdown of lncRNA DLX6-AS1 in various tumor cell lines. With the comprehensive development of delivery systems, high-throughput sequencing, and aptamers, the problems of finding novel research methods and exploring the therapeutic options which are based on lncRNA DLX6-AS1 in vivo could come into a period to deal with. This review aims to summarize the research statuses of lncRNA DLX6-AS1, discuss other study methodologies and therapeutic strategies on it, which might be of help to the deep learning of lncRNA DLX6-AS1 and its application from basic to clinical research.
Collapse
Affiliation(s)
- Yanyan Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
8
|
Niu ZS, Wang WH. Circular RNAs in hepatocellular carcinoma: Recent advances. World J Gastrointest Oncol 2022; 14:1067-1085. [PMID: 35949213 PMCID: PMC9244981 DOI: 10.4251/wjgo.v14.i6.1067] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) have covalently closed loop structures at both ends, exhibiting characteristics dissimilar to those of linear RNAs. Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma (HCC) by affecting the proliferation, apoptosis and invasive capacity of HCC cells. Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC. Therefore, circRNAs are expected to become novel biomarkers and therapeutic targets for HCC. Herein, we briefly review the characteristics and biological functions of circRNAs, focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.
Collapse
Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| |
Collapse
|
|
9
|
Wu S, Chen J, Liang Y, Luo Q, Tong Y, Xie L. Long Non-Coding RNA ZEB2-AS1 Promotes Hepatocellular Carcinoma Progression by Regulating The miR-582-5p/FOXC1 Axis. CELL JOURNAL 2022; 24:285-293. [PMID: 35892230 PMCID: PMC9315215 DOI: 10.22074/cellj.2022.7963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/26/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Long non-coding RNAs (lncRNAs) feature prominently in tumors. Reportedly, lncRNA zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) is aberrantly expressed in a variety of tumors. The present study was aimed to explore ZEB2-AS1 functions and determine mechanism in hepatocellular carcinoma (HCC) progression. MATERIALS AND METHODS In this experimental study, expressions of ZEB2-AS1, microRNA (miR)-582-5p and forkhead box C1 (FOXC1) mRNA in HCC tissues and cell lines were detected via quantitative reveres transcription polymerase chain reaction (qRT-PCR). After establishing gain- and loss-of-functions models, cell counting kit-8, 5-bromo-2'-deoxyuridine (BrdU), Transwell assays and flow cytometry analysis were conducted to examine HCC cell multiplication, migration, invasion and apoptosis, respectively. The targeted relationship between miR-582- 5p and ZEB2-AS1 was verified via dual-luciferase reporter gene assay. Western blot was utilized for detecting FOXC1 expression in HCC cells after selectively regulating ZEB2-AS1 and miR-582-5p. RESULTS In HCC tissues and cells, ZEB2-AS1 expression was increased. High ZEB2-AS1 expression was related to relatively large tumor volume, increased tumor-node-metastasis (TNM) stage and positive lymph node metastasis of the patients. ZEB2-AS1 overexpression facilitated HCC cell multiplication, migration, invasion and suppressed apoptosis, while ZEB2-AS1 knock-down caused the opposite effects. It was also confirmed that ZEB2-AS1 could competitively bind with miR-582-5p to repress its expression, and indirectly up-regulate FOXC1 expression level in HCC cells. CONCLUSION The current study revealed that ZEB2-AS1 was over-expressed in HCC tissues and cells. It also upregulated (FOXC1), through sponging miR-582-5p, to promote HCC progression. This provides new perspectives for elucidating the pathogenesis of HCC.
Collapse
Affiliation(s)
- Shimin Wu
- Center for Clinical LaboratoryGeneral Hospital of The Yangtze River ShippingWuhan Brain HospitalWuhanHubeiChina
| | | | | | | | | | | |
Collapse
|
|
10
|
Liu X, Yin Z, Wu Y, Zhan Q, Huang H, Fan J. Circular RNA lysophosphatidic acid receptor 3 (circ-LPAR3) enhances the cisplatin resistance of ovarian cancer. Bioengineered 2022; 13:3739-3750. [PMID: 35081867 PMCID: PMC8974081 DOI: 10.1080/21655979.2022.2029109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Circular RNA (circRNA) is considered to be an important regulator that mediates cancer chemoresistance. But whether circ-LPAR3 is involved in ovarian cancer (OC) cisplatin (DDP) resistance is unclear. The circ-LPAR3, miR-634 and pyruvate dehydrogenase kinase 1 (PDK1) expression was measured by quantitative real-time PCR (qRT-PCR). Cell cisplatin resistance and viability were measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. In addition, cell colony number, apoptosis, and metastasis were assessed by colony formation assay, flow cytometry and transwell assay. Furthermore, in vivo experiments were performed by constructing mice xenograft models. RNA interaction was confirmed by dual-luciferase reporter assay, and PDK1 protein expression was examined by Western blot analysis. Our results showed that circ-LPAR3 was markedly upregulated in DDP-resistant OC tissues and cells. Silencing of circ-LPAR3 enhanced the DDP sensitivity of OC cells and tumors. MiR-634 could interact with circ-LPAR3, and its inhibitor overturned the regulation of si-circ-LPAR3 on cell DDP resistance. Additionally, PDK1 was targeted by miR-634, and its overexpression inverted the effect of miR-634 on cell DDP resistance. To sum up, circ-LPAR3 might contribute to the DDP resistance of OC via the miR-634/PDK1 axis.
Collapse
Affiliation(s)
- Xuemei Liu
- Department of Gynaecology and Obstetrics, Jinan City People's Hospital, Jinan, China
| | - Zhiping Yin
- Department of Laboratory Medicine, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Yanjun Wu
- Department of Gynaecology and Obstetrics, Liaocheng People's Hospital, Liaocheng, China
| | - Qian Zhan
- Department of Laboratory Medicine, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, China
| | - Honghong Huang
- Department of Pharmacy, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jiangtao Fan
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
11
|
Yue Y, Lin X, Qiu X, Yang L, Wang R. The Molecular Roles and Clinical Implications of Non-Coding RNAs in Gastric Cancer. Front Cell Dev Biol 2021; 9:802745. [PMID: 34966746 PMCID: PMC8711095 DOI: 10.3389/fcell.2021.802745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world. It is also the fifth most common cancer in China. In recent years, a large number of studies have proved that non-coding RNAs (ncRNAs) can regulate cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. NcRNAs also influence the therapeutic resistance of gastric cancer. NcRNAs mainly consist of miRNAs, lncRNAs and circRNAs. In this paper, we summarized ncRNAs as biomarkers and therapeutic targets for gastric cancer, and also reviewed their role in clinical trials and diagnosis. We sum up different ncRNAs and related moleculars and signaling pathway in gastric cancer, like Bcl-2, PTEN, Wnt signaling. In addition, the potential clinical application of ncRNAs in overcoming chemotherapy and radiotherapy resistance in GC in the future were also focused on.
Collapse
Affiliation(s)
- Yanping Yue
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xinyue Qiu
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Lei Yang
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| |
Collapse
|
|
12
|
Ma Q, Yang T. E2F transcription factor 1/small nucleolar RNA host gene 18/microRNA-338-5p/forkhead box D1: an important regulatory axis in glioma progression. Bioengineered 2021; 13:418-430. [PMID: 34937497 PMCID: PMC8805867 DOI: 10.1080/21655979.2021.2005990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
This study aims to probe the biological functions of long non-coding RNA small nucleolar RNA host gene 18 (SNHG18) on glioma cells and its underlying mechanism. In this study, SNHG18 expression in glioma tissues was quantified employing GEPIA database; quantitative real-time PCR was adopted to examine the expressions of SNHG18, microRNA-338-5p (miR-338-5p) and forkhead box D1 (FOXD1) mRNA in glioma tissues and cell lines; cell proliferation, migration and invasion were detected utilizing cell counting kit-8, EdU and Transwell assays; Western blot was utilized to quantify the protein expressions of E-cadherin, N-cadherin, Vimentin and FOXD1; dual-luciferase reporter gene and RNA immunoprecipitation experiments were utilized to validate the targeting relationships between SNHG18 and miR-338-5p, as well as miR-338-5p and FOXD1 mRNA 3ʹUTR; dual-luciferase reporter gene and chromatin immunoprecipitation assays were utilized to verify the binding of E2F transcription factor 1 (E2F1) to the SNHG18 promoter region. It was revealed that, SNHG18 expression in glioma was up-regulated and associated with unfavorable prognosis of the patients; knockdown of SNHG18 repressed the malignant biological behaviors of glioma cells, enhanced E-cadherin expression and repressed N-cadherin and Vimentin expressions. MiR-338-5p was a target of SNHG18, and SNHG18 promoted the expression of FOXD1 by decoying miR-338-5p. Additionally, E2F1 could bind to the promoter of SNHG18 to elevate its expression. In conclusion, SNHG18 accelerates glioma progression via regulating the miR-338-5p/FOXD1 axis.
Collapse
Affiliation(s)
- Quanfeng Ma
- Department of Neurosurg, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurg Institution, Tianjin China
| | - Tianhao Yang
- Department of Radiology, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin China
| |
Collapse
|
|
13
|
Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
Collapse
Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| |
Collapse
|
|
14
|
Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
Collapse
Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| |
Collapse
|
|
15
|
Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ 2021; 43:21. [PMID: 34099061 PMCID: PMC8182944 DOI: 10.1186/s41021-021-00192-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.
Collapse
Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
16
|
Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis? Cancer Lett 2021; 509:63-80. [PMID: 33838282 DOI: 10.1016/j.canlet.2021.03.025] [Citation(s) in RCA: 176] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/18/2021] [Accepted: 03/24/2021] [Indexed: 12/12/2022]
Abstract
The nuclear factor-kappaB (NF-κB) signaling pathway is considered as a potential therapeutic target in cancer therapy. It has been well established that transcription factor NF-κB is involved in regulating physiological and pathological events including inflammation, immune response and differentiation. Increasing evidences suggest that deregulated NF-κB signaling can enhance cancer cell proliferation, metastasis and also mediate radio-as well as chemo-resistance. On the contrary, non-coding RNAs (ncRNAs) have been found to modulate NF-κB signaling pathway under different settings. MicroRNAs (miRNAs) can dually inhibit/induce NF-κB signaling thereby affecting the growth and migration of cancer cells. Furthermore, the response of cancer cells to radiotherapy and chemotherapy may also be regulated by miRNAs. Regulation of NF-κB by miRNAs may be mediated via binding to 3/-UTR region. Interestingly, anti-tumor compounds can increase the expression of tumor-suppressor miRNAs in inhibiting NF-κB activation and the progression of cancers. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can also effectively modulate NF-κB signaling thus affecting tumorigenesis. It is noteworthy that several studies have demonstrated that lncRNAs and circRNAs can affect miRNAs in targeting NF-κB activation. They can act as competing endogenous RNA (ceRNA) thereby reducing miRNA expression to induce NF-κB activation that can in turn promote cancer progression and malignancy.
Collapse
|
|
17
|
Kang J, Huang X, Dong W, Zhu X, Li M, Cui N. MicroRNA-1269b inhibits gastric cancer development through regulating methyltransferase-like 3 (METTL3). Bioengineered 2021; 12:1150-1160. [PMID: 33818282 PMCID: PMC8806277 DOI: 10.1080/21655979.2021.1909951] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The dysregulation of microRNAs (miRNAs) expression is relevant to the progression of many tumors. As reported, the abnormal expression of miR-1269b is pivotal in certain cancers’ progression. This work was designed to study the role and hidden mechanism of miR-1269b in gastric cancer (GC) progression. In this work, we proved that miR-1269b was lowly expressed in GC tissues and cell lines, which was associated with larger tumor size and lymph node metastasis. MiR-1269b overexpression repressed the multiplication, migration and invasion of GC cells while miR-1269b inhibition had the opposite effects. Methyltransferase-like 3 (METTL3) was identified as the direct target of miR-1269b in GC cells, and its overexpression reversed the inhibitory effect of transfection of miR-1269b mimics on GC cell viability, migration and invasion. On all accounts, these data indicated that miR-1269b inhibits GC progression via targeting METTL3.
Collapse
Affiliation(s)
- Jian Kang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| | - Xu Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| | - Xueying Zhu
- Department of General Practice, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| | - Ming Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| | - Ning Cui
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan Hubei Province, China
| |
Collapse
|
|
18
|
Taefehshokr S, Taefehshokr N, Hemmat N, Hajazimian S, Isazadeh A, Dadebighlu P, Baradaran B. The pivotal role of MicroRNAs in glucose metabolism in cancer. Pathol Res Pract 2020; 217:153314. [PMID: 33341548 DOI: 10.1016/j.prp.2020.153314] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/17/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.
Collapse
Affiliation(s)
- Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Hajazimian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Isazadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pourya Dadebighlu
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
19
|
Atas E, Oberhuber M, Kenner L. The Implications of PDK1-4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance. Front Oncol 2020; 10:583217. [PMID: 33384955 PMCID: PMC7771695 DOI: 10.3389/fonc.2020.583217] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/13/2020] [Indexed: 12/17/2022] Open
Abstract
A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis-known as the Warburg effect-is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1-3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.
Collapse
Affiliation(s)
- Emine Atas
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Monika Oberhuber
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Area ‘Data & Technologies’, CBmed—Center for Biomarker Research in Medicine GmbH, Graz, Austria
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Area ‘Data & Technologies’, CBmed—Center for Biomarker Research in Medicine GmbH, Graz, Austria
- Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics (CDL AM), Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
20
|
Yang X, Zhang Q, Guan B. Circ_0110805 Knockdown Enhances Cisplatin Sensitivity and Inhibits Gastric Cancer Progression by miR-299-3p/ENDOPDI Axis. Onco Targets Ther 2020; 13:11445-11457. [PMID: 33192077 PMCID: PMC7654533 DOI: 10.2147/ott.s279563] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/22/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer is a prevalent primary stomach tumor. Cisplatin is frequently used to treat gastric cancer. However, the resistance of cisplatin in gastric cancer often occurs, which brings a heavy burden to gastric cancer treatment. Methods In this study, we revealed a novel underlying mechanism about cisplatin-resistant effect in gastric cancer. A Cell Counting Kit-8 (CCK-8) cell viability assay and a xenograft model were performed to evaluate the function of circRNA in the cisplatin resistance of gastric cancer. Results Compared with control groups, we observed that circ_0110805 was highly expressed, the mRNA and protein expression levels of ENDOPDI were dramatically upregulated, and the expression of miR-299-3p was significantly downregulated in gastric cancer cells, cisplatin-resistant gastric cancer tissues or cells. Functionally, circ_0110805 knockdown improved cisplatin sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in AGS/DDP and HGC-27/DDP cells, which was reversed by miR-299-3p inhibitor. Additionally, ENDOPDI overexpression hindered the effects of miR-299-3p on cisplatin sensitivity and gastric cancer progression. Circ_0110805 knockdown enhanced cisplatin sensitivity in vivo. Mechanistically, circ_0110805 acted as a sponge of miR-299-3p and its targeted ENDOPDI. Conclusion We showed that circ_0110805 knockdown increased the sensitivity of gastric cancer to cisplatin, which also repressed gastric cancer progression by sponging miR-299-3p to downregulate ENDOPDI expression. It might provide a new insight for future studying cisplatin-resistant gastric cancer.
Collapse
Affiliation(s)
- Xi Yang
- Digestive Department, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, People's Republic of China
| | - Qunxiong Zhang
- Digestive Department, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, People's Republic of China
| | - Bugao Guan
- Department of General Surgery, People's Hospital of Jinhu, Huaian, Jiangsu, People's Republic of China
| |
Collapse
|
|
21
|
Li J, Xue H, Xiang Z, Song S, Yan R, Ji J, Zhu Z, Wei C, Yu Y. Genetic Profiles Affect the Biological Effects of Serine on Gastric Cancer Cells. Front Pharmacol 2020; 11:1183. [PMID: 32848786 PMCID: PMC7411129 DOI: 10.3389/fphar.2020.01183] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/20/2020] [Indexed: 12/18/2022] Open
Abstract
A high serine content in body fluid was identified in a portion of patients with gastric cancer, but its biological significance was not clear. Here, we investigated the biological effect of serine on gastric cancer cells. Serine was added into the culture medium of MGC803 and HGC27 cancer cells, and its influence on multiple biological functions, such as cell growth, migration and invasion, and drug resistance was analyzed. We examined the global transcriptomic profiles in these cultured cells with high serine content. Both MGC803 and HGC27 cell lines were originated from male patients, however, their basal gene expression patterns were very different. The finding of cell differentiation-associated genes, ALPI, KRT18, TM4SF1, KRT81, A2M, MT1E, MUC16, BASP1, TUSC3, and PRSS21 in MGC803 cells suggested that this cell line was more poorly differentiated, compared to HGC27 cell line. When the serine concentration was increased to 150mg/ml in medium, the response of these two gastric cancer cell lines was different, particularly on cell growth, cell migration, and invasion and 5-FU resistance. In animal experiment, administration of high concentration of serine promoted cancer cell metastasis to local lymph node. Taken together, we characterized the basal gene expressing profiles of MGC803 and HGC27. The HGC27 cells were more differentiated than MGC803 cells. MGC803 cells were more sensitive to the change of serine content. Our results suggested that the responsiveness of cancer cells to microenvironmental change is associated with their genetic background.
Collapse
Affiliation(s)
- Jun Li
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongzhang Xue
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Xiang
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuzheng Song
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ranlin Yan
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Ji
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaochun Wei
- Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, China
| | - Yingyan Yu
- Department of Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
22
|
Lin Z, Pan J, Chen L, Wang X, Chen Y. MiR-140 Resensitizes Cisplatin-Resistant NSCLC Cells to Cisplatin Treatment Through the SIRT1/ROS/JNK Pathway. Onco Targets Ther 2020; 13:8149-8160. [PMID: 32884297 PMCID: PMC7443038 DOI: 10.2147/ott.s261799] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/07/2020] [Indexed: 12/22/2022] Open
Abstract
Background Although cisplatin is an effective chemotherapeutic drug that is commonly used for non-small-cell lung cancer (NSCLC) treatment, the drug resistance usually occurs during the long-term use of it. It is urgent to develop strategies to reduce the resistance of NSCLC cells to cisplatin. Methods Cisplatin-resistant NSCLC cell lines (PC9/R and A549/R) were acquired through long-term exposure of PC9 and A549 cells to cisplatin. QRT-PCR analysis was performed to compare the expression of miR-140 between routine NSCLC cells and cisplatin-resistant NSCLC cells. CCK-8 assay was used to evaluate the effect of miR-140 on the sensitivity of PC9/R and A549/R to cisplatin. Western blot assay and luciferase reporter assay were used to confirm the regulation of miR-140 on SIRT1. Western blot and flow cytometry analysis were performed to evaluate the effect of miR-140 on the apoptosis pathway induced by cisplatin. Results PC9/R and A549/R exhibited obviously lower sensitivity compared to their parental PC9 and A549 cells, respectively. Furthermore, PC9/R and A549/R cells expressed significantly lower levels of miR-140 compared to their parental PC9 and A549 cells, respectively. However, transfection with miR-140 mimics significantly resensitized the PC9/R and A549/R to cisplatin-induced cytotoxicity. In the mechanism research, we confirmed that SIRT1 was overexpressed and was targeted by miR-140 in PC9/R and A549/R. Furthermore, overexpression of SIRT1 was responsible for the resistance to cisplatin in PC9/R and A549/R cells. Transfection with miR-140 was able to inhibit the expression of SIRT1 and thus inhibited the SIRT1/ROS/JNK pathway. As a result, the PC9/R and A549/R cells restored the sensitivity to cisplatin-induced apoptosis. Conclusion MiR-140 resensitizes cisplatin-resistant NSCLC cells to cisplatin treatment through the SIRT1/ROS/JNK pathway.
Collapse
Affiliation(s)
- Zhilai Lin
- Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People's Republic of China
| | - Jianguang Pan
- Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People's Republic of China
| | - Lei Chen
- Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People's Republic of China
| | - Xinhang Wang
- Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People's Republic of China
| | - Yuhua Chen
- Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People's Republic of China
| |
Collapse
|
|
23
|
Atas E, Oberhuber M, Kenner L. The Implications of PDK1-4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance. Front Oncol 2020. [PMID: 33384955 DOI: 10.3389/fonc.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis-known as the Warburg effect-is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1-3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.
Collapse
Affiliation(s)
- Emine Atas
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Monika Oberhuber
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Area 'Data & Technologies', CBmed-Center for Biomarker Research in Medicine GmbH, Graz, Austria
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Area 'Data & Technologies', CBmed-Center for Biomarker Research in Medicine GmbH, Graz, Austria
- Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics (CDL AM), Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| |
Collapse
|