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Huang D, Xu F, Xu L, Tang Z, Hu Y, Li J, Yu J. Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167814. [PMID: 40168755 DOI: 10.1016/j.bbadis.2025.167814] [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: 01/20/2025] [Revised: 03/15/2025] [Accepted: 03/21/2025] [Indexed: 04/03/2025]
Abstract
Thyroid hormones not only are crucial for normal growth, development, and metabolism but also influence the development and progression of various malignancies. The effects of thyroid hormones on cholangiocarcinoma remain unclear. Here, we examined the effects of triiodothyronine (T3), a major thyroid hormone, on the behavior of cultured human cholangiocarcinoma cells after short-term (1 week) or long-term (6 months) T3 treatment. Whereas short-term T3 treatment did not influence the growth or behavior of cholangiocarcinoma cells, long-term T3 treatment had several significant effects. Cell proliferation, colony-forming and spheroid formation assays indicated the long-term T3 treatment increased cholangiocarcinoma cell growth in vitro and in mouse xenografts, and increased resistance to gemcitabine and cisplatin. Cells exposed to T3 long-term also exhibited increased glycolysis in a manner dependent on the glucose transporter 1 (Glut1). Expression of both Glut1 and hypoxia-inducible transcription factor 1α (HIF-1α) was upregulated in long-term T3-treated cholangiocarcinoma cells. Either pharmacological inhibition of Glut1 activity or siRNA-mediated knockdown of HIF-1α expression suppressed the increase in proliferation and chemoresistance induced by long-term T3 treatment. Notably, HIF-1α knockdown also reversed the effects of T3 exposure on Glut1 expression and glycolytic rate. Moreover, inhibition of lactate dehydrogenase suppressed upregulated expression of HIF-1α in long-term T3-treated cells. Finally, we found that elevated T3 levels activated the HIF-1α/Glut1 axis in ICC tissues and was associated with a worse prognosis of ICC patients. These results demonstrate that chronic exposure to T3 can promote the proliferation and chemoresistance of cholangiocarcinoma cells through a pathway involving HIF-1α, Glut1, and glycolysis.
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Affiliation(s)
- Dihua Huang
- Department of Endocrinology, Shaoxing People's Hospital, China; School of Medicine, Shaoxing University, China
| | - Feng Xu
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, China; School of Medicine, Shaoxing University, China
| | - Luohang Xu
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, China; School of Medicine, Shaoxing University, China
| | - Zekai Tang
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, China
| | - Yanxin Hu
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, China; School of Medicine, Shaoxing University, China
| | - Jiandong Li
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, China
| | - Jianhua Yu
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, China; School of Medicine, Shaoxing University, China.
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2
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Shi P, Ma Y, Zhang S. Non-histone lactylation: unveiling its functional significance. Front Cell Dev Biol 2025; 13:1535611. [PMID: 39925738 PMCID: PMC11802821 DOI: 10.3389/fcell.2025.1535611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/09/2025] [Indexed: 02/11/2025] Open
Abstract
Lactylation, a newly discovered protein posttranslational modification (PTM) in 2019, primarily occurs on lysine residues. Lactylation of histones was initially identified, and subsequent studies have increasingly demonstrated its widespread presence on non-histone proteins. Recently, high-throughput proteomics studies have identified a large number of lactylated proteins and sites, revealing their global regulatory role in disease development. Notably, this modification is catalyzed by lactyltransferase and reversed by delactylase, with numerous new enzymes, such as AARS1/2, reported to be involved. Specifically, these studies have revealed how lactylation exerts its influence through alterations in protein spatial conformation, molecular interactions, enzyme activity and subcellular localization. Indeed, lactylation is implicated in various physiological and pathological processes, including tumor development, cardiovascular and cerebrovascular diseases, immune cell activation and psychiatric disorders. This review provides the latest advancements in research on the regulatory roles of non-histone protein lactylation, highlighting its crucial scientific importance for future studies.
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Affiliation(s)
- Pusong Shi
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yongjie Ma
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, China
| | - Shaolu Zhang
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, China
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3
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Pei J, Liao Y, Bai X, Li M, Wang J, Li X, Zhang H, Sui L, Kong Y. Dysregulated GLUT1 results in the pathogenesis of preeclampsia by impairing the function of trophoblast cells. Sci Rep 2024; 14:23761. [PMID: 39390043 PMCID: PMC11467397 DOI: 10.1038/s41598-024-74489-z] [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: 05/24/2024] [Accepted: 09/26/2024] [Indexed: 10/12/2024] Open
Abstract
Preeclampsia (PE) is a common placental-origin complication of pregnancy and a major cause of morbidity and mortality among pregnant women and fetuses. However, its pathogenesis has not been elucidated. Effective strategies for prevention, screening, and treatment are still lacking. Studies have indicated that dysfunction of placental trophoblast cells, such as impaired syncytialization, proliferation, and epithelial-mesenchymal transition processes, plays a crucial role in the development of PE. Glucose transporter 1 (GLUT1) is a key protein regulating glucose transport in placental tissues. However, the effect of GLUT1 on the function of trophoblast cells in PE is not well understood. In this study, we found that GLUT1 expression is reduced in PE placental tissues. GLUT1 promotes the syncytialization process by increasing the glucose uptake ability of BeWo cells. Additionally, GLUT1 promotes the proliferation, migration, and invasion capabilities of HTR-8/SVneo cells by regulating MAPK and PI3K/AKT signaling pathways. Overall, these findings provide a new insight into understanding the biological functions of GLUT1, clarifying the pathogenesis of PE, and identifying diagnostic and therapeutic targets for PE.
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Affiliation(s)
- Jingyuan Pei
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Yangyou Liao
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Xiaoxian Bai
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Min Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Jing Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Xiaotong Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China
| | - Hongshuo Zhang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Linlin Sui
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China.
| | - Ying Kong
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, Liaoning Province, China.
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Yuan X, Wen Y, Shi Q, Zhao Y, Ding J. MicroRNA-148a-3p suppresses the glycolysis and Cell proliferation by targeting transmembrane protein 54 in liver cancer. Biochem Biophys Res Commun 2024; 695:149424. [PMID: 38169186 DOI: 10.1016/j.bbrc.2023.149424] [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: 10/21/2023] [Revised: 12/08/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024]
Abstract
Liver cancer is the fourth most lethal cancer, but the treatment options for liver cancer are usually limited. Metabolic reprogramming is a hallmark of malignancy, ensuring activated cell glycolysis and increased macromolecular precursors required for the proliferation and migration of exuberant cancer cells. MicroRNAs (miRNAs) have been reported to participate in cancer metabolic shifts mainly by directly silencing the expression of specific genes. Here, we identified miR-148a-3p as a negative regulator for glycometabolism and cell proliferation in liver cancer. miR-148a-3p directly targets the 3'UTR of transmembrane protein 54 (TMEM54), leading to the significant inhibition of lactate production, glucose consumption, intracellular ATP level and extracellular acidification rate (ECAR), as well as the repression of the proliferation and colony formation ability of liver cancer cells. miR-148a-3p expression is often down-regulated in liver cancer tissues. In addition, there was a negative correlation between the expression levels of miR-148a-3p and TMEM54 in liver cancer tissues. Moreover, the low miR-148a-3p expression levels or high TMEM54 expression levels were associated with poorer prognosis in hepatocellular carcinoma (HCC) patients. Together, these findings support that the miR-148a-3p/TMEM54 regulatory pathway regulates the glycometabolism and cell proliferation in liver cancer, which is a possible target for the diagnosis and treatment of liver cancer.
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Affiliation(s)
- Xu Yuan
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yifan Wen
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qili Shi
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yingjun Zhao
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jie Ding
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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5
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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6
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Ding DY, Gan XJ, Zhang JN, Hou GJ, Tao QF, Sun DP, Li W, Yang Y, Ding WB, Yu J, Liu L, Yang F, Zhou WP, Yuan SX. Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma. Br J Cancer 2023; 128:907-917. [PMID: 36526676 PMCID: PMC9977883 DOI: 10.1038/s41416-022-02101-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/21/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.
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Affiliation(s)
- Dong-Yang Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Xiao-Jie Gan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Jia-Ning Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Guo-Jun Hou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Qi-Fei Tao
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Da-Peng Sun
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Wen Li
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Wen-Bin Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Jian Yu
- Department of General Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China
| | - Lei Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China.
| | - Fu Yang
- The Department of Medical Genetics, Naval Medical University, 200438, Shanghai, China.
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China.
| | - Sheng-Xian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China.
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7
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Sae-fung A, Mutirangura A, Jitkaew S. Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma. Front Immunol 2023; 13:1051273. [PMID: 36733386 PMCID: PMC9887182 DOI: 10.3389/fimmu.2022.1051273] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous and aggressive malignancy of the bile ducts with a poor prognosis and high mortality rate. Effective targeted therapy and accurate prognostic biomarkers are still lacking. Ferroptosis is a form of regulated cell death implicated in cancer progression and has emerged as a potential therapeutic target in various cancers. However, a comprehensive analysis of ferroptosis-related genes (FRGs) for predicting CCA prognosis and therapeutic targets and determining the role of ferroptosis in CCA remain to be performed. Here, we developed a prognostic FRG signature using a least absolute shrinkage and selection operator Cox regression analysis in a training cohort. We then validated it using four independent public datasets. The six-FRG signature was developed to predict CCA patient survival, stratifying them into low-risk and high-risk groups based on survival time. Significantly, the high-risk CCA patients had shorter overall survival. A receiver operating characteristic curve analysis further confirmed the prognostic FRG signature's strong predictive ability, indicating that it was an independent prognostic indicator for CCA patients. Furthermore, the high-risk group was associated with fluke infection and high clinical stages. Cancer-associated fibroblast (CAF) score and CAF markers were significantly higher in the high-risk group than the low-risk group. Moreover, our FRG signature could predict immune checkpoint markers for immunotherapy and drug sensitivity. The mRNA expression levels of the six-FRG signature was validated in 10 CCA cell lines and dividing them into low-risk and high-risk groups using the FRG signature. We further showed that high-risk CCA cell lines were more resistant to ferroptosis inducers, including erastin and RSL3, than the low-risk CCA cell lines. Our study constructed a novel FRG signature model to predict CCA prognoses which might provide prognostic biomarkers and potential therapeutic targets for CCA patients. Ferroptosis sensitivity in high-risk and low-risk CCA cell lines suggests that ferroptosis resistance is associated with high-risk group CCA. Therefore, ferroptosis could be a promising therapeutic target for precision therapy in CCA patients.
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Affiliation(s)
- Apiwit Sae-fung
- Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Faculty of Medicine, Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Siriporn Jitkaew
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,*Correspondence: Siriporn Jitkaew,
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8
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Ghafouri-Fard S, Safarzadeh A, Hussen BM, Taheri M, Samsami M. A review on the role of ncRNAs in the pathogenesis of cholangiocarcinoma. Int J Biol Macromol 2023; 225:809-821. [PMID: 36400211 DOI: 10.1016/j.ijbiomac.2022.11.144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022]
Abstract
Cholangiocarcinoma is a rare tumor but a challenging cancer in terms of pathological changes, clinical manifestations and therapeutic options. Recent studies have provided evidence for participation of non-coding RNAs in the carcinogenic process of cholangiocarcinoma. We demonstrate the role of long non-coding RNAs, microRNAs and circular RNAs in the pathogenesis of cholangiocarcinoma and highlight their significant position as therapeutic targets and biomarkers for this type of cancer. We also list a number of molecular axes comprising these non-coding RNAs that represent potential targets for therapeutic options in cholangiocarcinoma, based on their significant roles in the regulation of cell proliferation, differentiation and apoptosis of these cells.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Safarzadeh
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq; Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Majid Samsami
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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9
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Dong P, Wang F, Taheri M, Xiong Y, Ihira K, Kobayashi N, Konno Y, Yue J, Watari H. Long Non-Coding RNA TMPO-AS1 Promotes GLUT1-Mediated Glycolysis and Paclitaxel Resistance in Endometrial Cancer Cells by Interacting With miR-140 and miR-143. Front Oncol 2022; 12:912935. [PMID: 35712514 PMCID: PMC9195630 DOI: 10.3389/fonc.2022.912935] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/29/2022] [Indexed: 01/05/2023] Open
Abstract
Increased glycolysis in tumor cells is frequently associated with drug resistance. Overexpression of glucose transporter-1 (GLUT1) promotes the Warburg effect and mediates chemoresistance in various cancers. Aberrant GLUT1 expression is considered as an essential early step in the development of endometrial cancer (EC). However, its role in EC glycolysis and chemoresistance and the upstream mechanisms underlying GLUT1 overexpression, remain undefined. Here, we demonstrated that GLUT1 was highly expressed in EC tissues and cell lines and that high GLUT1 expression was associated with poor prognosis in EC patients. Both gain-of-function and loss-of-function studies showed that GLUT1 increased EC cell proliferation, invasion, and glycolysis, while also making them resistant to paclitaxel. The long non-coding RNA TMPO-AS1 was found to be overexpressed in EC tissues and to be negatively associated with EC patient outcomes. RNA-immunoprecipitation and luciferase reporter assays confirmed that TMPO-AS1 elevated GLUT1 expression by directly binding to two critical tumor suppressor microRNAs (miR-140 and miR-143). Downregulation of TMPO-AS1 remarkably reduced EC cell proliferation, invasion, glycolysis, and paclitaxel resistance in EC cells. This study established that dysregulation of the TMPO-AS1-miR-140/miR-143 axis contributes to glycolysis and drug resistance in EC cells by up-regulating GLUT1 expression. Thus, inhibiting TMPO-AS1 and GLUT1 may prove beneficial in overcoming glycolysis-induced paclitaxel resistance in patients with EC.
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Affiliation(s)
- Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Feng Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Ying Xiong
- Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kei Ihira
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Noriko Kobayashi
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yosuke Konno
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.,Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Hidemichi Watari
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
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10
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Ko S, Kim M, Molina L, Sirica AE, Monga SP. YAP1 activation and Hippo pathway signaling in the pathogenesis and treatment of intrahepatic cholangiocarcinoma. Adv Cancer Res 2022; 156:283-317. [PMID: 35961703 PMCID: PMC9972177 DOI: 10.1016/bs.acr.2022.02.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, is a highly lethal epithelial cell malignancy exhibiting features of cholangiocyte differentiation. iCCAs can potentially develop from multiple cell types of origin within liver, including immature or mature cholangiocytes, hepatic stem cells/progenitor cells, and from transdifferentiation of hepatocytes. Understanding the molecular mechanisms and genetic drivers that diversely drive specific cell lineage pathways leading to iCCA has important biological and clinical implications. In this context, activation of the YAP1-TEAD dependent transcription, driven by Hippo-dependent or -independent diverse mechanisms that lead to the stabilization of YAP1 is crucially important to biliary fate commitment in hepatobiliary cancer. In preclinical models, YAP1 activation in hepatocytes or cholangiocytes is sufficient to drive their malignant transformation into iCCA. Moreover, nuclear YAP1/TAZ is highly prevalent in human iCCA irrespective of the varied etiology, and significantly correlates with poor prognosis in iCCA patients. Based on the ubiquitous expression and diverse physiologic roles for YAP1/TAZ in the liver, recent studies have further revealed distinct functions of active YAP1/TAZ in regulating tumor metabolism, as well as the tumor immune microenvironment. In the current review, we discuss our current understanding of the various roles of the Hippo-YAP1 signaling in iCCA pathogenesis, with a specific focus on the roles played by the Hippo-YAP1 pathway in modulating biliary commitment and oncogenicity, iCCA metabolism, and immune microenvironment. We also discuss the therapeutic potential of targeting the YAP1/TAZ-TEAD transcriptional machinery in iCCA, its current limitations, and what future studies are needed to facilitate clinical translation.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Pittsburgh Liver Research Center, Pittsburgh, PA, United States.
| | - Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Laura Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Pittsburgh Liver Research Center, Pittsburgh, PA, United States
| | - Alphonse E Sirica
- Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Pittsburgh Liver Research Center, Pittsburgh, PA, United States; Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, PA, United States.
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11
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Chen N, Zhou YS, Wang LC, Huang JB. Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review). Oncol Rep 2022; 47:55. [PMID: 35039878 PMCID: PMC8808708 DOI: 10.3892/or.2022.8266] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
Therapeutic approaches that target the metabolism of tumor cells have been a popular research topic in recent years. Previous studies have demonstrated that glycolysis inhibitors reduce the proliferation of non‑small cell lung cancer (NSCLC) cells by interfering with the aerobic glycolytic pathway. However, the mitochondrial oxidative phosphorylation (OXPHOS) pathway in tumor cells has also been implicated in lung cancer metabolism. Metformin, a known inhibitor of mitochondrial OXPHOS, has been indicated to reduce NSCLC morbidity and mortality in clinical studies. The present article reviewed the therapeutic effects of metformin against NSCLC, both as a single agent and combined with other anticancer treatments, in order to provide a theoretical basis for its clinical use in adjuvant therapy for NSCLC.
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Affiliation(s)
- Na Chen
- Department of Medical Imaging, Faculty of Medicine, Yangtze University, Yangtze University Research and Experimentation Centre, Jingzhou, Hubei 434000, P.R. China
| | - Yi-Shu Zhou
- Department of Medical Imaging, Faculty of Medicine, Yangtze University, Yangtze University Research and Experimentation Centre, Jingzhou, Hubei 434000, P.R. China
| | - Li-Cui Wang
- Department of Medical Imaging, Faculty of Medicine, Yangtze University, Yangtze University Research and Experimentation Centre, Jingzhou, Hubei 434000, P.R. China
| | - Jin-Bai Huang
- Department of Medical Imaging, Faculty of Medicine, Yangtze University, Yangtze University Research and Experimentation Centre, Jingzhou, Hubei 434000, P.R. China
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12
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Yang H, Hou H, Zhao H, Yu T, Hu Y, Hu Y, Guo J. HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells. Front Oncol 2021; 11:794015. [PMID: 34858863 PMCID: PMC8631922 DOI: 10.3389/fonc.2021.794015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 10/25/2021] [Indexed: 01/10/2023] Open
Abstract
The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including SOX2 and OCT4) and drug resistance-related gene MDR1. The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene HK2, providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.
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Affiliation(s)
- Hao Yang
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Hui Hou
- Department of Pediatric Hematology and Oncology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Haiping Zhao
- Department of Abdominal Tumor Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Tianwei Yu
- Department of Transfusion Medicine, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Yuchong Hu
- Department of Gynaecology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Yue Hu
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Junmei Guo
- Department of Radiation Oncology, Inner Mongolia Cancer Hospital and Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, China
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13
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Ren Y, Wang X, Ji T, Cai X. MicroRNA-146b-5p suppresses cholangiocarcinoma cells by targeting TRAF6 and modulating p53 translocation. Acta Histochem 2021; 123:151793. [PMID: 34610483 DOI: 10.1016/j.acthis.2021.151793] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/14/2021] [Accepted: 09/18/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND In view of the poor prognosis and high mortality of cholangiocarcinoma, there is a need for new therapeutic strategies. This study aims to reveal the biological function of miR-146b-5p in cholangiocarcinoma cell and its possible mechanism. METHODS The expression level and prognostic information on miR-146b-5p in cholangiocarcinoma were obtained in TCGA database. The biological function of miR-146b-5p on proliferation and vitality of cholangiocarcinoma cell HUCCT-1 was examined by EdU and MTT assay, and the apoptosis of HUCCT-1 cells transfected with miR-146b-5p mimic, mimic control, inhibitor, inhibitor control was detected by flow cytometry analysis. The western blot was done to evaluate the effect of miR-146b-5p targeting substrate and the expression of p53 in whole-cell protein and mitochondria fractions. RESULTS Our finding revealed that miR-146b-5p expression in patients with CHOL was lower than the normal group(p＜0.001). MiR-146b-5p expression was down-regulated in human cholangiocarcinoma HUCCT-1 and RBE cells compared to normal control HIBEC and other cancer cells. The miR-146b-5p mimic could inhibit HUCCT-1 cell proliferation (p＜0.05) and promote HUCCT-1 cell apoptosis significantly (p＜0.05). The results of western blot showed that miR-146b-5p mimic could directly target TRAF6 3'UTR region and up-regulate the expression of p53 in mitochondria and miR-146b-5p inhibitor could down-regulated the level of p53 in mitochondria. CONCLUSION MiR-146b-5p is a cholangiocarcinoma suppressor by inhibiting cell proliferation and promoting cell apoptosis with targeting TRAF6, possibly via modulating p53 translocation to mitochondria.
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Affiliation(s)
- Yiyue Ren
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Department of Medical Imaging, Bengbu Medical College, Bengbu, China
| | - Tong Ji
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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14
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Thamrongwaranggoon U, Sangkhamanon S, Seubwai W, Saranaruk P, Cha'on U, Wongkham S. Aberrant GLUT1 Expression Is Associated With Carcinogenesis and Progression of Liver Fluke-associated Cholangiocarcinoma. In Vivo 2021; 35:267-274. [PMID: 33402473 DOI: 10.21873/invivo.12255] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM Glucose transporter 1 (GLUT1) has been demonstrated to be overexpressed in various cancer tissues and play a significant role on growth, metastasis, and apoptosis in cancer cells. This study aimed to reveal the clinical relevance of glucose transporter 1 (GLUT1) in carcinogenesis and progression on liver fluke-associated cholangiocarcinoma (CCA). MATERIALS AND METHODS Expression of GLUT1 in CCA tissues from patients, as well as from a liver fluke-induced CCA hamster model, was determined using immunohistochemistry. CCA cell lines were transfected with GLUT1 siRNA and the roles of GLUT1 on cell growth as well as migration and invasion were investigated by using a clonogenic assay and Boyden chamber assays, respectively. RESULTS GLUT1 was aberrantly expressed in hyperplastic/dysplastic bile ducts and CCA, but not in the normal bile ducts. High GLUT1 expression was significantly associated with non-papillary type, large tumor size, and short survival of patients. GLUT1 was expressed during cholangio-carcinogenesis and gradually increased with progression of histopathologic bile ducts. Silencing of GLUT1 expression significantly suppressed growth, migration, and invasion of CCA cell lines. CONCLUSION GLUT1 plays important roles in carcinogenesis and progression of liver fluke-associated CCA. Targeting GLUT1 may be a strategy for treatment of metastasis in liver fluke-associated CCA.
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Affiliation(s)
- Ubonrat Thamrongwaranggoon
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Sakkarn Sangkhamanon
- Departmemt of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Wunchana Seubwai
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.,Department of Forensic Medicine, Faculty of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Paksiree Saranaruk
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Ubon Cha'on
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sopit Wongkham
- Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; .,Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
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15
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You J, Wang X. Circ_HIPK3 Knockdown Inhibits Cell Proliferation, Migration and Invasion of Cholangiocarcinoma Partly via Mediating the miR-148a-3p/ULK1 Pathway. Cancer Manag Res 2021; 13:3827-3839. [PMID: 34007215 PMCID: PMC8123961 DOI: 10.2147/cmar.s293823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
Background The incidence of cholangiocarcinoma (CCA) is on the rise in recent years, and its pathogenesis may be associated with the deregulation of circular RNAs (circRNAs). Hence, we aimed to investigate the role of circRNA homeodomain interacting protein kinase 3 (circ_HIPK3) in CCA. Methods The expression of circ_HIPK3, miR-148a-3p and unc-51 like kinase 3 (ULK1) mRNA was detected using quantitative real-time polymerase chain reaction (qPCR). The role of circ_HIPK3 in cell proliferation was detected by 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide (MTT) assay and colony formation assay. Cell apoptosis and cell cycle progression were investigated using flow cytometry assay. Cell migration and invasion were detected by transwell assay. The protein levels of ULK1 and migration/invasion-associated markers were measured using Western blot. The putative relationship between miR-148a-3p and circ_HIPK3 or ULK1 was validated by dual-luciferase reporter assay. The role of circ_HIPK3 was also investigated in vivo. Results Circ_HIPK3 was overexpressed in CCA tissues and cells. In function, circ_HIPK3 knockdown inhibited CCA cell proliferation, migration and invasion and induced apoptosis and cycle arrest. It was confirmed that miR-148a-3p was a target of circ_HIPK3, and ULK1 was a target of miR-148a-3p. Circ_HIPK3 regulated ULK1 expression by targeting miR-148a-3p. Rescue experiments showed that miR-148a-3p inhibition reversed the effects of circ_HIPK3 knockdown. Besides, miR-148a-3p enrichment-blocked cell proliferation, migration and invasion were recovered by ULK1 overexpression. In vivo, circ_HIPK3 knockdown inhibited solid tumor growth. Conclusion Circ_HIPK3 knockdown blocked CCA malignant development partly via regulating the miR-148a-3p/ULK1 pathway.
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Affiliation(s)
- Junning You
- Department of Emergency, Xianyang Hosptial, Yan'an University, XianYang, Shaanxi, People's Republic of China
| | - Xiaolin Wang
- Department of General Surgery, Yulin No.2 Hospital, Yulin, Shaanxi, People's Republic of China
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16
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Hayes C, Donohoe CL, Davern M, Donlon NE. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment. Cancer Lett 2021; 500:75-86. [PMID: 33347908 DOI: 10.1016/j.canlet.2020.12.021] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022]
Abstract
The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.
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Affiliation(s)
- Conall Hayes
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Claire L Donohoe
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Maria Davern
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Noel E Donlon
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland.
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17
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Ashrafizadeh M, Zarrabi A, Hushmandi K, Hashemi F, Moghadam ER, Owrang M, Hashemi F, Makvandi P, Goharrizi MASB, Najafi M, Khan H. Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: Role of microRNAs and upstream mediators. Cell Signal 2021; 78:109871. [PMID: 33279671 DOI: 10.1016/j.cellsig.2020.109871] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/24/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Cisplatin (CP) is a well-known chemotherapeutic agent with excellent clinical effects. The anti-tumor activity of CP has been demonstrated in different cancers such as breast, cervical, reproductive, lung, brain, and prostate cancers. However, resistance of cancer cells to CP chemotherapy has led to its failure in eradication of cancer cells, and subsequent death of patients with cancer. Fortunately, much effort has been put to identify molecular pathways and mechanisms involved in CP resistance/sensitivity. It seems that microRNAs (miRs) are promising candidates in mediating CP resistance/sensitivity, since they participate in different biological aspects of cells such as proliferation, migration, angiogenesis, and differentiation. In this review, we focus on miRs and their regulation in CP chemotherapy of lung cancer, as the most malignant tumor worldwide. Oncogenic miRs trigger CP resistance in lung cancer cells via targeting various pathways such as Wnt/β-catenin, Rab6, CASP2, PTEN, and Apaf-1. In contrast, onco-suppressor miRs inhibit oncogene pathways such as STAT3 to suppress CP resistance. These topics are discussed to determine the role of miRs in CP resistance/sensitivity. We also describe the upstream modulators of miRs such as lncRNAs, circRNAs, NF-κB, SOX2 and TRIM65 and their association with CP resistance/sensitivity in lung cancer cells. Finally, the effect of anti-tumor plant-derived natural compounds on miR expression during CP sensitivity of lung cancer cells is discussed.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Ebrahim Rahmani Moghadam
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Owrang
- Department of Anatomical Sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Pooyan Makvandi
- Istituto Italiano di Tecnologia, Centre for Micro-BioRobotics, viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa, Italy
| | | | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
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18
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Lang Q, Xiao P, Zhao M, Liang D, Meng Q, Pei T. COUP-TFII promotes metastasis and epithelial-to-mesenchymal transition through upregulating Snail in human intrahepatic cholangiocarcinoma. Acta Biochim Biophys Sin (Shanghai) 2020; 52:1247-1256. [PMID: 33166992 DOI: 10.1093/abbs/gmaa117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/02/2020] [Indexed: 11/15/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. The overexpression of COUP-TFII has been observed in several types of malignancies. However, its role in ICC progression remains unclear. In this study, we found that the protein level of COUP-TFII was increased, but the mRNA level was unchanged in ICC tissues. High protein expression was positively associated with tumor size, lymph node metastasis, and poor prognosis in ICC patients. Furthermore, the overexpression of COUP-TFII promoted the proliferation, migration, and invasion of ICC cells in vitro and enhanced tumor growth and metastasis in nude mouse models. Mechanistic studies revealed that COUP-TFII induced epithelial-to-mesenchymal transition in ICC cells by upregulating Snail expression. Moreover, the activation of PI3K/AKT signaling led to the upregulation of COUP-TFII protein expression in ICC. Together, these findings indicate that COUP-TFII promotes epithelial-to-mesenchymal transition and metastasis in ICC and suggest that this protein is a potential target for adjuvant therapy for these patients.
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Affiliation(s)
- Qingfu Lang
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Peng Xiao
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Ming Zhao
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Desen Liang
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Qinghui Meng
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Tiemin Pei
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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19
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Lixin S, Wei S, Haibin S, Qingfu L, Tiemin P. miR-885-5p inhibits proliferation and metastasis by targeting IGF2BP1 and GALNT3 in human intrahepatic cholangiocarcinoma. Mol Carcinog 2020; 59:1371-1381. [PMID: 33052627 DOI: 10.1002/mc.23262] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/22/2022]
Abstract
The incidence of intrahepatic cholangiocarcinoma (iCCA) continues to increase worldwide, however its molecular pathogenesis remains poorly understood. Recent studies have implicated microRNAs in iCCA progression. In this study, we demonstrated that miR-885-5p was significantly decreased in iCCA tissues. Downregulation of miR-885-5p was correlated with vascular invasion, lymph node metastasis, unfavorable overall survival, and shorter disease-free survival. Silencing or overexpressing miR-885-5p by lentiviral approaches significantly influenced iCCA cell proliferation and metastasis in vitro and in vivo. Mechanistically, overexpression of miR-885-5p inhibited iCCA metastasis and proliferation by directly inhibiting GALNT3 as well as by indirectly promoting the downregulation of insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1). Furthermore, miR-885-5p inhibited iCCA metastasis by downregulating the PI3K/AKT/MMPs signaling pathway via targeting GALNT3. Collectively, we demonstrated that miR-885-5p was an important mediator of iCCA proliferation and metastasis by regulating GALNT3 and IGF2BP1, thus offering a potential target for iCCA treatment.
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Affiliation(s)
- Sun Lixin
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Sun Wei
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Song Haibin
- Department of General Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lang Qingfu
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Pei Tiemin
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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20
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E Z, Li C, Xiang Y. LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells. Open Med (Wars) 2020; 15:1193-1201. [PMID: 33336076 PMCID: PMC7718651 DOI: 10.1515/med-2020-0177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/10/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023] Open
Abstract
This research aimed to illustrate the biological function and associated regulatory mechanism of lncRNA FOXD3-AS1 (FOXD3-AS1) in nasopharyngeal carcinoma (NPC). This research initially found that FOXD3-AS1 was obviously upregulated in NPC cell lines by quantitative reverse transcription polymerase chain reaction (qRT-PCR) detection. Next, the direct target of FOXD3-AS1 was predicted by bioinformatics and further verified by dual-luciferase reporter assay. MiroRNA-135a-5p (miR-135a-5p) was identified as the target gene of FOXD3-AS1 and down-expressed in C666-1 cells compared to NP69. In addition, function assays were conducted in C666-1 cells, including methyl tetrazolium assay, flow cytometry, Caspase3 activity detection, and western blot assay. Our results suggested that miR-135a-5p upregulation inhibited NPC cell growth, enhanced cell apoptosis, promoted Caspase3 activity, increased cleaved-Caspase3, and reduced pro-Caspase3 level. Moreover, we found that FOXD3-AS1 knockdown notably inhibited C666-1 cell proliferation, increased cell apoptosis, enhanced Caspase3 activity, enhanced cleaved-Caspase3 expression, and suppressed pro-Caspase3 level in C666-1 cells. However, these findings were reversed in C666-1 cells by miR-135a-5p mimic co-transfection. To sum up, our data showed that FOXD3-AS1 knockdown regulated cell growth and apoptosis in NCP cells via altering miR-135a-5p expression, suggesting that FOXD3-AS1 might be a therapeutic target for NPC diagnosis and treatment.
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Affiliation(s)
- Zhang E
- Department of Otorhinolaryngology, Wuhan No. 1 Hospital, No. 215 Zhongshan Road, Wuhan 430022, China
| | - Chunli Li
- Department of Otorhinolaryngology, Wuhan No. 1 Hospital, No. 215 Zhongshan Road, Wuhan 430022, China
| | - Yuandi Xiang
- Department of Otorhinolaryngology, Wuhan No. 1 Hospital, No. 215 Zhongshan Road, Wuhan 430022, China
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21
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Bekric D, Neureiter D, Ritter M, Jakab M, Gaisberger M, Pichler M, Kiesslich T, Mayr C. Long Non-Coding RNAs in Biliary Tract Cancer-An Up-to-Date Review. J Clin Med 2020; 9:jcm9041200. [PMID: 32331331 PMCID: PMC7231154 DOI: 10.3390/jcm9041200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
The term long non-coding RNA (lncRNA) describes non protein-coding transcripts with a length greater than 200 base pairs. The ongoing discovery, characterization and functional categorization of lncRNAs has led to a better understanding of the involvement of lncRNAs in diverse biological and pathological processes including cancer. Aberrant expression of specific lncRNA species was demonstrated in various cancer types and associated with unfavorable clinical characteristics. Recent studies suggest that lncRNAs are also involved in the development and progression of biliary tract cancer, a rare disease with high mortality and limited therapeutic options. In this review, we summarize current findings regarding the manifold roles of lncRNAs in biliary tract cancer and give an overview of the clinical and molecular consequences of aberrant lncRNA expression as well as of underlying regulatory functions of selected lncRNA species in the context of biliary tract cancer.
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Affiliation(s)
- Dino Bekric
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Markus Ritter
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Jakab
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Martin Gaisberger
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria;
| | - Tobias Kiesslich
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
| | - Christian Mayr
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Correspondence:
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