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Ma Q, Jiang H, Tan S, You F, Zheng C, Wang Q, Ren Y. Emerging trends and hotspots in lung cancer-prediction models research. Ann Med Surg (Lond) 2024; 86:7178-7192. [PMID: 39649903 PMCID: PMC11623829 DOI: 10.1097/ms9.0000000000002648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 10/02/2024] [Indexed: 12/11/2024] Open
Abstract
Objective In recent years, lung cancer-prediction models have become popular. However, few bibliometric analyses have been performed in this field. Methods This study aimed to reveal the scientific output and trends in lung cancer-prediction models from a global perspective. In this study, publications were retrieved and extracted from the Web of Science Core Collection (WoSCC) database. CiteSpace 6.1.R3 and VOSviewer 1.6.18 were used to analyze hotspots and theme trends. Results A marked increase in the number of publications related to lung cancer-prediction models was observed. A total of 2711 institutions from in 64 countries/regions published 2139 documents in 566 academic journals. China and the United States were the leading country in the field of lung cancer-prediction models. The institutions represented by Fudan University had significant academic influence in the field. Analysis of keywords revealed that lncRNA, tumor microenvironment, immune, cancer statistics, The Cancer Genome Atlas, nomogram, and machine learning were the current focus of research in lung cancer-prediction models. Conclusions Over the last two decades, research on risk-prediction models for lung cancer has attracted increasing attention. Prognosis, machine learning, and multi-omics technologies are both current hotspots and future trends in this field. In the future, in-depth explorations using different omics should increase the sensitivity and accuracy of lung cancer-prediction models and reduce the global burden of lung cancer.
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Affiliation(s)
- Qiong Ma
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Hua Jiang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Shiyan Tan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Fengming You
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Chuan Zheng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qian Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Yifeng Ren
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
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Maqbool M, Hussain MS, Bisht AS, Kumari A, Kamran A, Sultana A, Kumar R, Khan Y, Gupta G. Connecting the dots: LncRNAs in the KRAS pathway and cancer. Pathol Res Pract 2024; 262:155570. [PMID: 39226802 DOI: 10.1016/j.prp.2024.155570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/17/2024] [Accepted: 08/28/2024] [Indexed: 09/05/2024]
Abstract
Long non-coding RNAs (lncRNAs) have been identified as important participants in several biological functions, particularly their complex interactions with the KRAS pathway, which provide insights into the significant roles lncRNAs play in cancer development. The KRAS pathway, a central signaling cascade crucial for cell proliferation, survival, and differentiation, stands out as a key therapeutic target due to its aberrant activation in many human cancers. Recent investigations have unveiled a myriad of lncRNAs, such as H19, ANRIL, and MEG3, intricately modulating the KRAS pathway, influencing both its activation and repression through various mechanisms, including epigenetic modifications, transcriptional regulation, and post-transcriptional control. These lncRNAs function as fine-tuners, delicately orchestrating the balance required for normal cellular function. Their dysregulation has been linked to the development and progression of multiple malignancies, including lung, pancreatic, and colorectal carcinomas, which frequently harbor KRAS mutations. This scrutiny delves into the functional diversity of specific lncRNAs within the KRAS pathway, elucidating their molecular mechanisms and downstream effects on cancer phenotypes. Additionally, it underscores the diagnostic and prognostic potential of these lncRNAs as indicators for cancer detection and assessment. The complex regulatory network that lncRNAs construct within the context of the KRAS pathway offers important insights for the creation of focused therapeutic approaches, opening new possibilities for precision medicine in oncology. However, challenges such as the dual roles of lncRNAs in different cancer types and the difficulty in therapeutically targeting these molecules highlight the ongoing debates and need for further research. As ongoing studies unveil the complexities of lncRNA-mediated KRAS pathway modulation, the potential for innovative cancer interventions becomes increasingly promising.
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Affiliation(s)
- Mudasir Maqbool
- Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Md Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India.
| | - Ajay Singh Bisht
- School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Patel Nagar, Dehradun, Uttarakhand 248001, India
| | - Alka Kumari
- University institute of pharmacy, Chandigarh University, Gharaun, Punjab 140413, India
| | - Almaz Kamran
- HIMT College of Pharmacy, Plot No. 08, Knowledge Park - 1, Greater Noida, Uttar Pradesh 201310, India
| | - Ayesha Sultana
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya University, Deralakatte, Mangalore, Karnataka, India
| | - Rajesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Yumna Khan
- Institute of Biotechnology and Genetic Engineering (Health Division), The University of Agriculture, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
| | - Gaurav Gupta
- Centre for Research Impact & Outcome-Chitkara College of Pharmacy, Chitkara University, Punjab, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
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Seyhan AA. Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges. Int J Mol Sci 2024; 25:7974. [PMID: 39063215 PMCID: PMC11277426 DOI: 10.3390/ijms25147974] [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: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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Suh YS, Lee J, George J, Seol D, Jeong K, Oh SY, Bang C, Jun Y, Kong SH, Lee HJ, Kim JI, Kim WH, Yang HK, Lee C. RNA expression of 6 genes from metastatic mucosal gastric cancer serves as the global prognostic marker for gastric cancer with functional validation. Br J Cancer 2024; 130:1571-1584. [PMID: 38467827 PMCID: PMC11059174 DOI: 10.1038/s41416-024-02642-6] [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: 08/16/2023] [Revised: 02/08/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Abstract
BACKGROUND Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg). METHODS Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets. RESULTS Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival. CONCLUSION The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Jieun Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Joshy George
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Donghyeok Seol
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Kyoungyun Jeong
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Young Oh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Chanmi Bang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Yukyung Jun
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
- Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, South Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
| | - Charles Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
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Patel RS, Krause-Hauch M, Kenney K, Miles S, Nakase-Richardson R, Patel NA. Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans. Int J Mol Sci 2024; 25:1473. [PMID: 38338752 PMCID: PMC10855201 DOI: 10.3390/ijms25031473] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741; p = 0.0012). The optimal cutoff for VLDLR-AS1 was ≤153.8 ng. A secondary analysis of clinical data from LIMBIC CENC was conducted to evaluate the psychological symptom burden, and the results show that lncRNAs VLDLR-AS1 and MALAT1 are correlated with symptoms of depression. In conclusion, lncRNA VLDLR-AS1 may serve as a blood biomarker for identifying chronic rmTBI and depression in patients.
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Affiliation(s)
- Rekha S. Patel
- Research Service, James A. Haley Veteran’s Hospital, 13000 Bruce B Downs Blvd., Tampa, FL 33612, USA; (R.S.P.); (S.M.)
| | - Meredith Krause-Hauch
- Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Kimbra Kenney
- Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA;
| | - Shannon Miles
- Research Service, James A. Haley Veteran’s Hospital, 13000 Bruce B Downs Blvd., Tampa, FL 33612, USA; (R.S.P.); (S.M.)
- Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA
| | - Risa Nakase-Richardson
- Chief of Staff Office, James A. Haley Veteran’s Hospital, Tampa, FL 33612, USA;
- Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine, University of South Florida, Tampa, FL 33620, USA
| | - Niketa A. Patel
- Research Service, James A. Haley Veteran’s Hospital, 13000 Bruce B Downs Blvd., Tampa, FL 33612, USA; (R.S.P.); (S.M.)
- Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA;
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Wang Y, Yao M, Li C, Yang K, Qin X, Xu L, Shi S, Yu C, Meng X, Xie C. Targeting ST8SIA6-AS1 counteracts KRAS G12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling. Exp Hematol Oncol 2023; 12:105. [PMID: 38104151 PMCID: PMC10724920 DOI: 10.1186/s40164-023-00466-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/03/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. METHODS By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. RESULTS KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. CONCLUSIONS Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
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Affiliation(s)
- Yafang Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
| | - Mingyue Yao
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Cheng Li
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Kexin Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiaolong Qin
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Lansong Xu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), University of Science and Technology of China, Hefei, Anhui, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
| | - Shangxuan Shi
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Chengcheng Yu
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, People's Republic of China
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China
| | - Xiangjun Meng
- Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
- China Center for Digestive Diseases Research and Clinical Translation of Shanghai Jiao Tong University, Shanghai, 200001, China
- China Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200001, China
| | - Chengying Xie
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, People's Republic of China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Lingang Laboratory, 319 Yueyang Road, Shanghai, 200031, China.
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Yang K, Xiao Y, Zhong L, Zhang W, Wang P, Ren Y, Shi L. p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy. Cancer Gene Ther 2023; 30:1456-1470. [PMID: 37679529 DOI: 10.1038/s41417-023-00662-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 08/19/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023]
Abstract
Long non-coding RNAs (lncRNAs) have been identified as master gene regulators through various mechanisms such as transcription, translation, protein modification and RNA-protein complexes. LncRNA dysregulation is frequently associated with a variety of biological functions and human diseases including cancer. The p53 network is a key tumor-suppressive mechanism that transcriptionally activates target genes to suppress cellular proliferation in human malignancies. Recent research indicates that lncRNAs play an important role in the p53 signaling pathway. In this review, we summarize the current knowledge of lncRNAs in p53-relevant functions and provide an overview of how these altered lncRNAs contribute to tumor initiation and progression. We also discuss the association between lncRNA and up- or downstream genes of p53. These findings imply that lncRNAs can help identify cellular vulnerabilities that may prove to be promising potential biomarkers and therapeutic targets for cancer treatment.
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Affiliation(s)
- Kaixin Yang
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Yinan Xiao
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Linghui Zhong
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Wenyang Zhang
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Peng Wang
- College of Animal Science and Technology, Hebei North University, Zhangjiakou, 075131, People's Republic of China
| | - Yaru Ren
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Lei Shi
- RNA Oncology Group, School of Public Health, Lanzhou University, Lanzhou, 730000, People's Republic of China.
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Miao X, Xi W, Bao Y. LncRNA RP11-58O9.2 predicts poor prognosis and promotes progression of non-small cell lung cancer. J Int Med Res 2023; 51:3000605231206295. [PMID: 37871619 PMCID: PMC10594974 DOI: 10.1177/03000605231206295] [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: 12/15/2022] [Accepted: 09/21/2023] [Indexed: 10/25/2023] Open
Abstract
OBJECTIVE Long non-coding RNAs (lncRNAs) play a crucial role in non-small cell lung cancer (NSCLC). This study aimed to investigate the novel biomarker, lncRNA RP11-58O9.2, in patients with NSCLC. METHODS RP11-58O9.2 expression in NSCLC cells and tissues was detected by reverse transcription-quantitative polymerase chain reaction. Patient survival was analyzed in relation to RP11-58O9.2 expression levels. RP11-58O9.2 expression was knocked down and endogenous expression was verified in two NSCLC cell lines. Cell proliferation was then assessed by Cell Counting Kit-8 and colony-formation assays, and cell invasion and migration were assessed by Transwell and wound-healing assays, respectively. In vivo experiments were performed in mice, and the combination of RP11-58O9.2 and miR-6749-3p was predicted by miRanda. RESULTS RP11-58O9.2 was highly expressed in NSCLC cell lines and tissues, and was associated with advanced stage, lymphatic metastasis, and differentiation group. High RP11-58O9.2 levels were also associated with shorter survival. RP11-58O9.2 knockdown inhibited the proliferation, invasion, and migration of lung cancer cells, and tumor growth in mouse xenografts in vivo. RP11-58O9.2 may target and regulate miR-6749-3p. CONCLUSIONS LncRNA RP11-58O9.2 is associated with NSCLC prognosis and promotes lung cancer progression. Further studies are needed to investigate the mechanisms and the regulatory association between RP11-58O9.2 and miR-6749-3p.
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Affiliation(s)
- Xuan Miao
- Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wen Xi
- Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongxia Bao
- Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Kong Y, Luo Y, Zheng S, Yang J, Zhang D, Zhao Y, Zheng H, An M, Lin Y, Ai L, Diao X, Lin Q, Chen C, Chen R. Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma. Cancer Res 2023; 83:3077-3094. [PMID: 37363990 PMCID: PMC10502454 DOI: 10.1158/0008-5472.can-22-3997] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/05/2023] [Accepted: 06/21/2023] [Indexed: 06/28/2023]
Abstract
Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis. SIGNIFICANCE Increased splicing-mediated biogenesis of circARFGEF2 in KRAS-mutant pancreatic ductal adenocarcinoma activates JAK2-STAT3 signaling and triggers lymph node metastasis, suggesting circARFGEF2 could be a therapeutic target to inhibit pancreatic cancer progression.
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Affiliation(s)
- Yao Kong
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
| | - Yuming Luo
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Shangyou Zheng
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Jiabin Yang
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Dingwen Zhang
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Yue Zhao
- Department of Tumor Intervention, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, P.R. China
| | - Hanhao Zheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China
| | - Mingjie An
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China
| | - Yan Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China
| | - Le Ai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xiayao Diao
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Qing Lin
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Changhao Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P.R. China
| | - Rufu Chen
- Department of Pancreas Center, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P.R. China
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, P.R. China
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10
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Igarashi T, Mazevet M, Yasuhara T, Yano K, Mochizuki A, Nishino M, Yoshida T, Yoshida Y, Takamatsu N, Yoshimi A, Shiraishi K, Horinouchi H, Kohno T, Hamamoto R, Adachi J, Zou L, Shiotani B. An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress. Nat Commun 2023; 14:4991. [PMID: 37591859 PMCID: PMC10435487 DOI: 10.1038/s41467-023-40578-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023] Open
Abstract
Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRASG12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRASG12V-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRASG12V-induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability.
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Affiliation(s)
- Taichi Igarashi
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Biosciences, School of Science, Kitasato University, Minami-ku, Sagamihara-city, Kanagawa, 252-0373, Japan
| | - Marianne Mazevet
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takaaki Yasuhara
- Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Kimiyoshi Yano
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akifumi Mochizuki
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Respiratory Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Makoto Nishino
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yukihiro Yoshida
- Department of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
| | - Nobuhiko Takamatsu
- Department of Biosciences, School of Science, Kitasato University, Minami-ku, Sagamihara-city, Kanagawa, 252-0373, Japan
| | - Akihide Yoshimi
- Department of Biosciences, School of Science, Kitasato University, Minami-ku, Sagamihara-city, Kanagawa, 252-0373, Japan
- Division of Cancer RNA Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Clinical Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Jun Adachi
- Laboratory of Proteomics for Drug Discovery, Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-city, Osaka, 567-0085, Japan
| | - Lee Zou
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27708, USA
| | - Bunsyo Shiotani
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan.
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11
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Tang P, Sun D, Xu W, Li H, Chen L. Long non‑coding RNAs as potential therapeutic targets in non‑small cell lung cancer (Review). Int J Mol Med 2023; 52:68. [PMID: 37350412 PMCID: PMC10413047 DOI: 10.3892/ijmm.2023.5271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 05/02/2023] [Indexed: 06/24/2023] Open
Abstract
Non‑small cell lung cancer (NSCLC) is one of the most common malignancies with a high morbidity and mortality rate. Long non‑coding RNAs (lncRNAs) have been reported to be closely associated with the occurrence and progression of NSCLC. In addition, lncRNAs have been documented to participate in the development of drug resistance and radiation sensitivity in patients with NSCLC. Due to their extensive functional characterization, high tissue specificity and sex specificity, lncRNAs have been proposed to be novel biomarkers and therapeutic targets for NSCLC. Therefore, in the current review, the functional classification of lncRNAs were presented, whilst the potential roles of lncRNAs in NSCLC were also summarized. Various physiological aspects, including proliferation, invasion and drug resistance, were all discussed. It is anticipated that the present review will provide a perspective on lncRNAs as potential diagnostic molecular biomarkers and therapeutic targets for NSCLC.
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Affiliation(s)
- Peiyu Tang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
| | - Wei Xu
- Institute of Structural Pharmacology and TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
- Institute of Structural Pharmacology and TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016
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12
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Yang K, Zhang W, Zhong L, Xiao Y, Sahoo S, Fassan M, Zeng K, Magee P, Garofalo M, Shi L. Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer. Cell Death Differ 2023; 30:1533-1549. [PMID: 37041291 PMCID: PMC10089381 DOI: 10.1038/s41418-023-01160-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 03/18/2023] [Accepted: 03/28/2023] [Indexed: 04/13/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.
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Affiliation(s)
- Kaixin Yang
- RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China
| | - Wenyang Zhang
- RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China
| | - Linghui Zhong
- RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China
| | - Yinan Xiao
- RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China
| | - Sudhakar Sahoo
- Computational Biology Support, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, 35100, Italy
| | - Kang Zeng
- Imaging & Cytometry Facility, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK
| | - Peter Magee
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK
| | - Michela Garofalo
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK
| | - Lei Shi
- RNA Oncology Group, School of Public Health, Lanzhou University, 730000, Lanzhou, People's Republic of China.
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK.
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13
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Bortoletto AS, Parchem RJ. KRAS Hijacks the miRNA Regulatory Pathway in Cancer. Cancer Res 2023; 83:1563-1572. [PMID: 36946612 PMCID: PMC10183808 DOI: 10.1158/0008-5472.can-23-0296] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/01/2023] [Accepted: 03/20/2023] [Indexed: 03/23/2023]
Abstract
Extensive studies have focused on the misregulation of individual miRNAs in cancer. More recently, mutations in the miRNA biogenesis and processing machinery have been implicated in several malignancies. Such mutations can lead to global miRNA misregulation, which may promote many of the well-known hallmarks of cancer. Interestingly, recent evidence also suggests that oncogenic Kristen rat sarcoma viral oncogene homolog (KRAS) mutations act in part by modulating the activity of members of the miRNA regulatory pathway. Here, we highlight the vital role mutations in the miRNA core machinery play in promoting malignant transformation. Furthermore, we discuss how mutant KRAS can simultaneously impact multiple steps of miRNA processing and function to promote tumorigenesis. Although the ability of KRAS to hijack the miRNA regulatory pathway adds a layer of complexity to its oncogenic nature, it also provides a potential therapeutic avenue that has yet to be exploited in the clinic. Moreover, concurrent targeting of mutant KRAS and members of the miRNA core machinery represents a potential strategy for treating cancer.
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Affiliation(s)
- Angelina S. Bortoletto
- Center for Cell and Gene Therapy, Stem Cell and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Department of Neuroscience, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas
| | - Ronald J. Parchem
- Center for Cell and Gene Therapy, Stem Cell and Regenerative Medicine Center, Department of Molecular and Cellular Biology, Department of Neuroscience, Translational Biology and Molecular Medicine Program, Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas
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14
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Zhang J, Sheng H, Zhang L, Li X, Guo Y, Wang Y, Guo H, Ding X. Bta-miR-206 and a Novel lncRNA-lncA2B1 Promote Myogenesis of Skeletal Muscle Satellite Cells via Common Binding Protein HNRNPA2B1. Cells 2023; 12:cells12071028. [PMID: 37048101 PMCID: PMC10093610 DOI: 10.3390/cells12071028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/05/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
Skeletal muscle satellite cells (MuSCs) can proliferate, differentiate, and self-renew, and can also participate in muscle formation and muscle injury repair. Long noncoding RNAs (lncRNAs) can play an important role with the RNA binding protein and microRNAs (miRNAs) to regulate the myogenesis of bovine MuSCs, however, its molecular mechanism is still being explored. In this study, differentially expressed 301 lncRNAs were identified during the myogenic differentiation of cells based on an in vitro model of induced differentiation of bovine MuSCs using RNA sequencing (RNA-seq). Based on the ability of miR-206 to regulate myogenic cell differentiation, a new kind of lncRNA-lncA2B1 without protein-coding ability was found, which is expressed in the nucleus and cytoplasm. Subsequently, lncA2B1 inhibited cell proliferation by downregulating the expression of the proliferation marker Pax7 and promoted myogenic differentiation by upregulating the expression of the differentiation marker MyHC, whose regulatory function is closely related to miR-206. By RNA pulldown/LC-MS experiments, heterogeneous ribonucleoprotein A2/B1 (HNRNPA2B1), and DExH-Box Helicase 9 (DHX9) were identified as common binding proteins of lncA2B1 and miR-206. Overexpression of lncA2B1 and miR-206 significantly upregulated the expression level of HNRNPA2B1. Downregulation of HNRNPA2B1 expression significantly decreased the expression level of the differentiation marker MyHC, which indicates that miR-206 and lncA2B1 regulate myogenic differentiation of bovine MuSCs by acting on HNRNPA2B1. This study screened and identified a novel lncRNA-lncA2B1, which functions with miR-206 to regulate myogenesis via the common binding proteins HNRNPA2B1. The results of this study provide a new way to explore the molecular mechanisms by which lncRNAs and miRNAs regulate muscle growth and development.
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Affiliation(s)
- Junxing Zhang
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Hui Sheng
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Linlin Zhang
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Xin Li
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Yiwen Guo
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Yimin Wang
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Hong Guo
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
| | - Xiangbin Ding
- Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, Tianjin 300384, China
- College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, China
- Correspondence:
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15
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Huo Y, Li Q, Yang L, Li X, Sun C, Liu Y, Liu H, Pan Z, Li Q, Du X. SDNOR, a Novel Antioxidative lncRNA, Is Essential for Maintaining the Normal State and Function of Porcine Follicular Granulosa Cells. Antioxidants (Basel) 2023; 12:antiox12040799. [PMID: 37107173 PMCID: PMC10135012 DOI: 10.3390/antiox12040799] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/15/2023] [Accepted: 03/22/2023] [Indexed: 04/29/2023] Open
Abstract
Increasing evidence shows that lncRNAs, an important kind of endogenous regulator, are involved in the regulation of follicular development and female fertility, but the mechanism remain largely unknown. In this study, we found that SDNOR, a recently identified antiapoptotic lncRNA, is a potential multifunctional regulator in porcine follicular granulosa cells (GCs) through RNA-seq and multi-dimension analyses. SDNOR-mediated regulatory networks were established and identified that SOX9, a transcription factor inhibited by SDNOR, mediates SDNOR's regulation of the transcription of downstream targets. Functional analyses showed that loss of SDNOR significantly impairs GC morphology, inhibits cell proliferation and viability, reduces E2/P4 index, and suppresses the expression of crucial markers, including PCNA, Ki67, CDK2, CYP11A1, CYP19A1, and StAR. Additionally, after the detection of ROS, SOD, GSH-Px, and MDA, we found that SDNOR elevates the resistance of GCs to oxidative stress (OS) and also inhibits OS-induced apoptosis. Notably, GCs with high SDNOR levels are insensitive to oxidative stress, leading to lower apoptosis rates and higher environmental adaptability. In summary, our findings reveal the regulation of porcine GCs in response to oxidative stress from the perspective of lncRNA and demonstrate that SDNOR is an essential antioxidative lncRNA for maintaining the normal state and function of GCs.
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Affiliation(s)
- Yangan Huo
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Qiqi Li
- College of Animal Husbandry and Veterinary Medicine, Jiangsu Vocational College Agriculture and Forestry, Jurong 215314, China
| | - Liu Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiaoxue Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Chen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yang Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Honglin Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zengxiang Pan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Qifa Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xing Du
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
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16
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Jacksi M, Schad E, Buday L, Tantos A. Absence of Scaffold Protein Tks4 Disrupts Several Signaling Pathways in Colon Cancer Cells. Int J Mol Sci 2023; 24:ijms24021310. [PMID: 36674824 PMCID: PMC9861885 DOI: 10.3390/ijms24021310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/12/2023] Open
Abstract
Tks4 is a large scaffold protein in the EGFR signal transduction pathway that is involved in several cellular processes, such as cellular motility, reactive oxygen species-dependent processes, and embryonic development. It is also implicated in a rare developmental disorder, Frank-ter Haar syndrome. Loss of Tks4 resulted in the induction of an EMT-like process, with increased motility and overexpression of EMT markers in colorectal carcinoma cells. In this work, we explored the broader effects of deletion of Tks4 on the gene expression pattern of HCT116 colorectal carcinoma cells by transcriptome sequencing of wild-type and Tks4 knockout (KO) cells. We identified several protein coding genes with altered mRNA levels in the Tks4 KO cell line, as well as a set of long non-coding RNAs, and confirmed these changes with quantitative PCR on a selected set of genes. Our results show a significant perturbation of gene expression upon the deletion of Tks4, suggesting the involvement of different signal transduction pathways over the well-known EGFR signaling.
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Affiliation(s)
- Mevan Jacksi
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
- Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, 1117 Budapest, Hungary
| | - Eva Schad
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - László Buday
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
- Department of Molecular Biology, Semmelweis University Medical School, 1094 Budapest, Hungary
| | - Agnes Tantos
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
- Correspondence:
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17
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Singh G, Thakur N, Kumar U. RAS: Circuitry and therapeutic targeting. Cell Signal 2023; 101:110505. [PMID: 36341985 DOI: 10.1016/j.cellsig.2022.110505] [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: 08/05/2022] [Revised: 10/05/2022] [Accepted: 10/21/2022] [Indexed: 11/26/2022]
Abstract
Cancer has affected the lives of millions worldwide and is truly regarded as a devastating disease process. Despite advanced understanding of the genomic underpinning of cancer development and progression, therapeutic challenges are still persistent. Among all the human cancers, around 33% are attributed to mutations in RAS oncogene, a crucial component of the signaling pathways. With time, our understanding of RAS circuitry has improved and now the fact that it activates several downstream effectors, depending on the type and grades of cancer has been established. The circuitry is controlled via post-transcriptional mechanisms and frequent distortions in these mechanisms lead to important metabolic as well as immunological states that favor cancer cells' growth, survival, plasticity and metastasis. Therefore, understanding RAS circuitry can help researchers/clinicians to develop novel and potent therapeutics that, in turn, can save the lives of patients suffering from RAS-mutant cancers. There are many challenges presented by resistance and the potential strategies with a particular focus on novel combinations for overcoming these, that could move beyond transitory responses in the direction of treatment. Here in this review, we will look at how understanding the circuitry of RAS can be put to use in making strategies for developing therapeutics against RAS- driven malignancies.
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Affiliation(s)
- Gagandeep Singh
- Department of Biosciences (UIBT), Chandigarh University, NH-05, Ludhiana - Chandigarh State Hwy, Sahibzada Ajit Singh Nagar, Punjab 140413, India
| | - Neelam Thakur
- Department of Biosciences (UIBT), Chandigarh University, NH-05, Ludhiana - Chandigarh State Hwy, Sahibzada Ajit Singh Nagar, Punjab 140413, India; Department of Zoology, Sardar Patel University, Vallabh Government College Campus, Paddal, Kartarpur, Mandi, Himachal Pradesh 175001, India.
| | - Umesh Kumar
- School of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), Adhyatmik Nagar, NH09, Ghaziabad, Uttar Pradesh 201015, India.
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18
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Zhu Q, Zhang C, Qu T, Lu X, He X, Li W, Yin D, Han L, Guo R, Zhang E. MNX1-AS1 Promotes Phase Separation of IGF2BP1 to Drive c-Myc-Mediated Cell-Cycle Progression and Proliferation in Lung Cancer. Cancer Res 2022; 82:4340-4358. [PMID: 36214649 DOI: 10.1158/0008-5472.can-22-1289] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/18/2022] [Accepted: 10/05/2022] [Indexed: 01/24/2023]
Abstract
c-Myc and E2F1 play critical roles in many human cancers. As long noncoding RNAs (lncRNA) are known to regulate various tumorigenic processes, elucidation of mechanisms of cross-talk between lncRNAs and c-Myc/E2F1-related signaling pathways could provide important insights into cancer biology. In this study, we used integrated bioinformatic analyses and found that the lncRNA MNX1-AS1 is upregulated in non-small cell lung cancer (NSCLC) via copy-number gain and c-Myc-mediated transcriptional activation. High levels of MNX1-AS1 were associated with poor clinical outcomes in patients with lung cancer. MNX1-AS1 promoted cell proliferation and colony formation in vitro and tumor growth in vivo. MNX1-AS1 bound and drove phase separation of IGF2BP1, which increased the interaction of IGF2BP1 with the 3'-UTR (untranslated region) of c-Myc and E2F1 mRNA to promote their stability. The c-Myc/MNX1-AS1/IGF2BP1 positive feedback loop accelerated cell-cycle progression and promoted continuous proliferation of lung cancer cells. In a lung cancer patient-derived xenograft model, inhibition of MNX1-AS1 suppressed cancer cell proliferation and tumor growth. These findings offer new insights into the regulation and function of c-Myc and E2F1 signaling in NSCLC tumorigenesis and suggest that the MNX1-AS1/IGF2BP1 axis may serve as a potential biomarker and therapeutic target in NSCLC. SIGNIFICANCE MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.
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Affiliation(s)
- Qingqing Zhu
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Chongguo Zhang
- Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Tianyu Qu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Xiyi Lu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Xuezhi He
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Wei Li
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Dandan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, P.R. China
| | - Liang Han
- Department of Oncology, Xuzhou Central Hospital, Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, P.R. China
| | - Renhua Guo
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Erbao Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, P.R. China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, P.R. China
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19
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Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine. Nat Commun 2022; 13:6016. [PMID: 36224201 PMCID: PMC9556435 DOI: 10.1038/s41467-022-33761-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 09/30/2022] [Indexed: 12/08/2022] Open
Abstract
KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a "quasi-triad plane" that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.
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20
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Yang K, Li C, Liu Y, Gu X, Jiang L, Shi L. Prognostic and Immunotherapeutic Roles of KRAS in Pan-Cancer. Cells 2022; 11:cells11091427. [PMID: 35563733 PMCID: PMC9105487 DOI: 10.3390/cells11091427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/17/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS is one well-established tumor-driver gene associated with cancer initiation, development, and progression. Nonetheless, comparative studies of the relevance of KRAS across diverse tumors remain sparse. We explored the KRAS expression and prognostic values in diverse cancer types via multiple web-based bioinformatics tools, including cBioPortal, Oncomine, PrognoScan, Kaplan–Meier Plotter, etc. We found that KRAS is highly expressed in various malignancies compared to normal cohorts (BRCA, CHOL, ESCA, HNSC, LIHC, LUAD, LUSC, and STAD) and less expressed in COAD, KIRC, READ, and THCA than in normal samples. We observed the dysregulation of the DNA methylation of KRAS in cancers and discovered that numerous oncogenic and tumor-suppressive transcription factors bind the KRAS promoter region. Pan-cancer analysis also showed that a high level of KRAS is associated with poor outcomes. Additionally, KRAS is remarkably correlated with the level of immune cell infiltration and tumorigenic gene signatures. In conclusion, our findings reveal novel insights into KRAS expression and its biological functions in diverse cancer types, indicating that KRAS could serve as a prognostic biomarker and is associated with immune infiltrates.
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Affiliation(s)
- Kaixin Yang
- School of Public Health, Lanzhou University, Lanzhou 730000, China; (K.Y.); (C.L.); (X.G.)
| | - Chengyun Li
- School of Public Health, Lanzhou University, Lanzhou 730000, China; (K.Y.); (C.L.); (X.G.)
| | - Yang Liu
- Gansu Provincial People’s Hospital, Lanzhou 730000, China;
| | - Xueyan Gu
- School of Public Health, Lanzhou University, Lanzhou 730000, China; (K.Y.); (C.L.); (X.G.)
| | - Longchang Jiang
- Department of Vascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Correspondence: (L.J.); (L.S.); Tel.: +86-21-3880-4518 (L.J.); +86-93-1891-3592(L.S.)
| | - Lei Shi
- School of Public Health, Lanzhou University, Lanzhou 730000, China; (K.Y.); (C.L.); (X.G.)
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester SK10 4TG, UK
- Correspondence: (L.J.); (L.S.); Tel.: +86-21-3880-4518 (L.J.); +86-93-1891-3592(L.S.)
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21
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Xue Y, Ning B, Liu H, Jia B. Construction of immune-related lncRNA signature to predict aggressiveness, immune landscape, and drug resistance of colon cancer. BMC Gastroenterol 2022; 22:127. [PMID: 35300596 PMCID: PMC8928673 DOI: 10.1186/s12876-022-02200-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 02/24/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Colon cancer remains one of the most common malignancies across the world. Thus far, a biomarker, which can comprehensively predict the survival outcomes, clinical characteristics, and therapeutic sensitivity, is still lacking. METHODS We leveraged transcriptomic data of colon cancer from the existing datasets and constructed immune-related lncRNA (irlncRNA) pairs. After integrating with clinical survival data, we performed differential analysis and identified 11 irlncRNAs signature using Lasso regression analysis. We next plotted the 1-, 5-, and 10-year curve lines of receiver operating characteristics, calculated the areas under the curve, and recognized the optimal cutoff point. Then, we validated the pair-risk model in terms of the survival outcomes of the patients involved. Moreover, we tested the reliability of the model for predicting tumor aggressiveness and therapeutic susceptibility of colon cancer. Additionally, we reemployed the 11 of irlncRNAs involved in the pair-risk model to construct an expression-risk model to predict the prognostic outcomes of the patients involved. RESULTS We recognized a total of 377 differentially expressed irlncRNAs (DEirlcRNAs), including 28 low-expressed and 349 high-expressed irlncRNAs in colon cancer patients. After performing a univariant Cox analysis, we identified 115 risk irlncRNAs that were significantly correlated with survival outcomes of patients involved. By taking the overlap of the DEirlcRNAs and the risk irlncRNAs, we ultimately recognized 55 irlncRNAs as core irlncRNAs. Then, we established a Cox HR model (pair-risk model) as well as an expression HR model (exp-risk model) based on 11 of the 55 core irlncRNAs. We found that both of the two models significantly outperformed the commonly used clinical characteristics, including age, T, N, and M stages when predicting survival outcomes. Moreover, we validated the pair-risk model as a potential tool for studying the tumor microenvironment of colon cancer and drug susceptibility. Additionally, we noticed that combinational use of the pair-risk model and the exp-risk model yielded a more robust approach for predicting the survival outcomes of patients with colon cancer. CONCLUSIONS We recognized 11 irlncRNAs and created a pair-risk model and an exp-risk model, which have the potential to predict clinical characteristics of colon cancer, either solely or conjointly.
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Affiliation(s)
- Yonggan Xue
- Department of General Surgery, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Bobin Ning
- Department of General Surgery, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Hongyi Liu
- Department of General Surgery, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Baoqing Jia
- Department of General Surgery, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.
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22
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Stavast CJ, van Zuijen I, Erkeland SJ. MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer. Cells 2022; 11:cells11050769. [PMID: 35269391 PMCID: PMC8909004 DOI: 10.3390/cells11050769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/17/2022] [Accepted: 02/19/2022] [Indexed: 11/25/2022] Open
Abstract
Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer.
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23
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Ghafouri-Fard S, Shirvani-Farsani Z, Hussen BM, Taheri M, Jalili Khoshnoud R. Emerging role of non-coding RNAs in the regulation of KRAS. Cancer Cell Int 2022; 22:68. [PMID: 35139853 PMCID: PMC8827276 DOI: 10.1186/s12935-022-02486-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/24/2022] [Indexed: 01/17/2023] Open
Abstract
The Kirsten ras oncogene KRAS is a member of the small GTPase superfamily participating in the RAS/MAPK pathway. A single amino acid substitution in KRAS gene has been shown to activate the encoded protein resulting in cell transformation. This oncogene is involved in the malignant transformation in several tissues. Notably, numerous non-coding RNAs have been found to interact with KRAS protein. Such interaction results in a wide array of human disorders, particularly cancers. Orilnc1, KIMAT1, SLCO4A1-AS1, LINC01420, KRAS1P, YWHAE, PART1, MALAT1, PCAT-1, lncRNA-NUTF2P3-001 and TP53TG1 are long non-coding RNAs (lncRNAs) whose interactions with KRAS have been verified in the context of cancer. miR-143, miR-96, miR-134 and miR-126 have also been shown to interact with KRAS in different tissues. Finally, circITGA7, circ_GLG1, circFNTA and circ-MEMO1 are examples of circular RNAs (circRNAs) that interact with KRAS. In this review, we describe the interaction between KRAS and lncRNAs, miRNAs and circRNAs, particularly in the context of cancer.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Shirvani-Farsani
- Department of Cellular and Molecular Biology, Faculty of Life Sciences and Technology, Shahid Beheshti University, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, 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.
| | - Reza Jalili Khoshnoud
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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24
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Jin L, Chen C, Huang L, Sun Q, Bu L. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4. Open Med (Wars) 2022; 17:87-95. [PMID: 34993348 PMCID: PMC8678621 DOI: 10.1515/med-2021-0403] [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: 07/13/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 11/23/2022] Open
Abstract
Long noncoding RNA (lncRNA), specifically the upregulation of lncRNA NR2F1 antisense RNA 1 (NR2F1-AS1), has been involved in the progression of non-small cell lung cancer (NSCLC), but the mechanisms that underlie this remain unclear. In this study, the expression of NR2F1-AS1, miR-363-3p, and SOX4 was assessed in NSCLC cells. A loss-of-function assay was used to measure the tumorigenicity of NSCLC cells. The glycolysis and glutamine metabolism of NSCLC cells was also measured via extracellular acidification rate, consumption of glucose and glutamine, and production of lactate and ATP. The relationships among NR2F1-AS1, miR-363-3p, and SOX4 were detected via dual-luciferase reporter assay. HK-2, GLS1, and SOX4 levels were also analyzed. We found that both NSCLC tissues and cells had higher levels of NR2F1-AS1. Silencing of NR2F1-AS1 inhibited the tumorigenicity of cells in vitro and reduced the glycolysis and glutamine metabolism of NSCLC cells. Regarding its mechanism, NR2F1-AS1 positively regulated the SOX4 level by sponging miR-363-3p. Furthermore, miR-363-3p inhibition or SOX4 overexpression reversed the repressing role of sh-NR2F1-AS1 in the tumorigenicity of NSCLC cells. In summary, NR2F1-AS1 promotes the tumorigenicity of NSCLC cells by regulating miR-363-3p/SOX4.
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Affiliation(s)
- Luming Jin
- Department of Thoracic Surgery, Xiamen University Institute of Chest and Lung Disease, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Chaoyang Chen
- Department of Thoracic Surgery, Xiamen University Institute of Chest and Lung Disease, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Lipeng Huang
- Department of Thoracic Surgery, Xiamen University Institute of Chest and Lung Disease, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Qingyu Sun
- Department of Thoracic Surgery, Xiamen University Institute of Chest and Lung Disease, Xiang'an Hospital of Xiamen University, Xiamen, China
| | - Liang Bu
- Department of Thoracic Surgery, Xiamen University Institute of Chest and Lung Disease, Xiang'an Hospital of Xiamen University, Xiamen, China
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25
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Shui B, La Rocca G, Ventura A, Haigis KM. Interplay between K-RAS and miRNAs. Trends Cancer 2022; 8:384-396. [PMID: 35093302 PMCID: PMC9035052 DOI: 10.1016/j.trecan.2022.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/25/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023]
Abstract
K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.
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26
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Xu Y, Li Y, Qiu Y, Sun F, Zhu G, Sun J, Cai G, Lin W, Fu Y, Wu H, Jiang S, Wen Z, Feng F, Luo J, Yang Y, Zhang Q. LncRNA NEAT1 Promotes Gastric Cancer Progression Through miR-17-5p/TGFβR2 Axis Up-Regulated Angiogenesis. Front Cell Dev Biol 2021; 9:705697. [PMID: 34552925 PMCID: PMC8452045 DOI: 10.3389/fcell.2021.705697] [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: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/13/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) have been indicated to play critical roles in gastric cancer (GC) tumorigenesis and progression. However, their roles in GC remain to be further elucidated. Methods RT-qPCR and fluorescence in situ hybridzation (FISH) were conducted to detect the expression of lncRNA NEAT1 in GC tissues and cell lines. Gene Set Enrichment Analysis (GSEA) was performed to screen out potential phenotypes and pathways that NEAT1 may participate in. NEAT1-silenced AGS and MGC803 cells were constructed and a series of functional experiments to investigate the roles of NEAT1 in GC angiogenesis both in vitro and in vivo. RNA pull down and luciferase reporter assays were utilized to illustrate the mechanisms underlying the functions of NEAT1 in GC. Results We observed that NEAT1 was upregulated in most GC specimens and cell lines. NEAT1 high was correlated with poor prognosis of GC patients. In vitro experiments showed that NEAT1 promoted GC angiogenesis by enhancing proliferation, migration, and tube formation ability of endothelial cells. Mechanism researches revealed that NEAT1 could competitively sponge miR-17-5p which targeted TGFβR2 directly. Subsequently, activate TGFβ/Smad pathway by following with upregulation of a series of classical proangiogenic factors especially VEGF. Conclusion The study unveiled that the LncRNA NEAT1/miR-17-5p/TGFβR2 axis is a novel mechanism in GC angiogenesis. Disrupting this axis may be a potential strategy for GC treatment.
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Affiliation(s)
- Yangwei Xu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanyan Li
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yue Qiu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fei Sun
- Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Guifang Zhu
- Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jingbo Sun
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guixing Cai
- Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Wanmei Lin
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Nanfang Hospital, First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Yun Fu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hongmei Wu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Shanshan Jiang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhihui Wen
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Feiyan Feng
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Junjie Luo
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yuqin Yang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Qingling Zhang
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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27
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La Montagna M, Shi L, Magee P, Sahoo S, Fassan M, Garofalo M. AMPKα loss promotes KRAS-mediated lung tumorigenesis. Cell Death Differ 2021; 28:2673-2689. [PMID: 34040167 PMCID: PMC8408205 DOI: 10.1038/s41418-021-00777-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 02/04/2023] Open
Abstract
AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRASG12D increased lung tumour burden and reduced survival in KrasLSLG12D/+/AMPKαfl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.
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Affiliation(s)
- Manuela La Montagna
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK
| | - Lei Shi
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK
| | - Peter Magee
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK
| | - Sudhakar Sahoo
- Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
| | - Michela Garofalo
- Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
- Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK.
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28
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Yuan W, Al-Hadid Q, Wang Z, Shen L, Cho H, Wu X, Yang Y. TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution. Nucleic Acids Res 2021; 49:8573-8591. [PMID: 34329467 PMCID: PMC8421139 DOI: 10.1093/nar/gkab642] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 06/14/2021] [Accepted: 07/19/2021] [Indexed: 11/12/2022] Open
Abstract
R-loops, which consist of a DNA/RNA hybrid and a displaced single-stranded DNA (ssDNA), are increasingly recognized as critical regulators of chromatin biology. R-loops are particularly enriched at gene promoters, where they play important roles in regulating gene expression. However, the molecular mechanisms that control promoter-associated R-loops remain unclear. The epigenetic ‘reader’ Tudor domain-containing protein 3 (TDRD3), which recognizes methylarginine marks on histones and on the C-terminal domain of RNA polymerase II, was previously shown to recruit DNA topoisomerase 3B (TOP3B) to relax negatively supercoiled DNA and prevent R-loop formation. Here, we further characterize the function of TDRD3 in R-loop metabolism and introduce the DExH-box helicase 9 (DHX9) as a novel interaction partner of the TDRD3/TOP3B complex. TDRD3 directly interacts with DHX9 via its Tudor domain. This interaction is important for recruiting DHX9 to target gene promoters, where it resolves R-loops in a helicase activity-dependent manner to facilitate gene expression. Additionally, TDRD3 also stimulates the helicase activity of DHX9. This stimulation relies on the OB-fold of TDRD3, which likely binds the ssDNA in the R-loop structure. Thus, DHX9 functions together with TOP3B to suppress promoter-associated R-loops. Collectively, these findings reveal new functions of TDRD3 and provide important mechanistic insights into the regulation of R-loop metabolism.
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Affiliation(s)
- Wei Yuan
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Qais Al-Hadid
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Zhihao Wang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Lei Shen
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Hyejin Cho
- Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Xiwei Wu
- Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
| | - Yanzhong Yang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, CA 91010, USA
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