FRK plays an oncogenic role in non‐small cell lung cancer by enhancing the stemness phenotype via induction of metabolic reprogramming
Open accessAbstract
The role of Fyn‐related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK‐KO‐H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial–mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK‐KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U‐13C flux assay revealed that FRK‐KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.
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H460, A549, and H1299 cell lines are frequently used as widely accepted cell models in the context of the metabolic rewiring of NSCLC.
“H460, A549, and H1299 cell lines are frequently used as widely accepted cell models in the context of the metabolic rewiring of NSCLC [41,42,43].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [43]
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Cites
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology
Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Chirieac, L. R., D’Amico, T. A., DeCamp, M. M., Dilling, T. J., Dobelbower, M. C., et al. (2017) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.0050 · Cited by 1,305 · see citing works
Src family kinases in tumor progression and metastasis
Summy, J. M., & Gallick, G. E. (2003) · Cancer and Metastasis Reviews · doi:10.1023/a:1023772912750 · Cited by 827 · see citing works
Metabolic Reprogramming: the Emerging Concept and Associated Therapeutic Strategies
Yoshida, G. J. (2015) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-015-0221-y · Cited by 716 · see citing works
Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells
Li, J., Condello, S., Pepin, J. T., Ma, X., Xia, Y., Hurley, T. D., Matei, D. E., & Cheng, J. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.11.004 · Cited by 579 · see citing works
Metabolic reprogramming and epithelial‐to‐mesenchymal transition in cancer
Sciacovelli, M., & Frezza, C. (2017) · FEBS Journal · doi:10.1111/febs.14090 · Cited by 324 · see citing works
Mitochondria and cancer chemoresistance
Guerra, F., Arbini, A., & Moro, L. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.01.012 · Cited by 321 · see citing works
Yu, L., Lu, M., Jia, D., Ma, J., Ben‐Jacob, E., Levine, H., Kaipparettu, B. A., & Onuchic, J. N. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2074 · Cited by 272 · see citing works
Singh, S., Trevino, J. G., Bora-Singhal, N., Coppola, D., Haura, E. B., Altiok, S., & Chellappan, S. (2012) · Molecular Cancer · doi:10.1186/1476-4598-11-73 · Cited by 250 · see citing works
The role of EMT and MET in cancer dissemination
Banyard, J., & Bielenberg, D. R. (2015) · Connective Tissue Research · doi:10.3109/03008207.2015.1060970 · Cited by 248 · see citing works
VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
Fantozzi, A., Gruber, D. C., Pisarsky, L., Heck, C., Kunita, A., Yilmaz, M., Meyer‐Schaller, N., Cornille, K., Hopfer, U., Bentires‐Alj, M., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1641 · Cited by 233 · see citing works
Colon cancer: Cancer stem cells markers, drug resistance and treatment
Kozovská, Z., Gabrisova, V., & Kučerová, L. (2014) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2014.10.019 · Cited by 228 · see citing works
Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition
Jiang, L., Xiao, L., Sugiura, H., Huang, X., Ali, A., Kuro‐o, M., DeBerardinis, R. J., & Boothman, D. A. (2014) · Oncogene · doi:10.1038/onc.2014.321 · Cited by 221 · see citing works
Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function
Yim, E.-K., Peng, G., Dai, H., Hu, R., Li, K., Lu, Y., Mills, G. B., Meric‐Bernstam, F., Hennessy, B. T., Craven, R. J., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.02.012 · Cited by 209 · see citing works
Cancer Stem Cells and Tumor Metastasis: First Steps into Uncharted Territory
Dalerba, P. D., & Clarke, M. F. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.08.012 · Cited by 182 · see citing works
The Warburg effect version 2.0: Metabolic reprogramming of cancer stem cells
Menéndez, J. A., Joven, J., Cufí, S., Corominas-Faja, B., Oliveras‐Ferraros, C., Cuyàs, E., Martı́n-Castillo, B., López‐Bonet, E., Alarcón, T., & Vázquez‐Martín, A. (2013) · Cell Cycle · doi:10.4161/cc.24479 · Cited by 158 · see citing works
Molecular Prognostic Markers in Pancreatic Cancer
Coppola, D. (2000) · Cancer Control · doi:10.1177/107327480000700504 · Cited by 153 · see citing works
CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer
Zhao, H., Wang, J., Kong, X., Li, E., Liu, Y., Du, X., Kang, Z., Tang, Y. C., Kuang, Y., Yang, Z., et al. (2016) · Scientific Reports · doi:10.1038/srep29719 · Cited by 152 · see citing works
Activated pp60c-Src Leads to Elevated Hypoxia-inducible Factor (HIF)-1α Expression under Normoxia
Karni, R., Dor, Y., Keshet, E., Meyuhas, O., & Levitzki, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206141200 · Cited by 116 · see citing works
In silico identification of oncogenic potential of fyn-related kinase in hepatocellular carcinoma
Chen, J., Hung, W.-S., Chan, H.-H., Tsai, S., & Sun, H. S. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts715 · Cited by 116 · see citing works
Vázquez‐Martín, A., Vellón, L., Quirós, P. M., Cufí, S., de Galarreta, E. R., Oliveras‐Ferraros, C., Martín, Á. G., Martı́n-Castillo, B., López-Otı́n, C., & Menéndez, J. A. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19450 · Cited by 98 · see citing works
Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer
Rajeshkumar, N. V., Tan, A. C., Oliveira, E. D., Womack, C., Wombwell, H., Morgan, S. R., Warren, M. V., Walker, J., Green, T. P., Jimeno, A., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-3021 · Cited by 90 · see citing works
In vivo genetic dissection of tumor growth and the Warburg effect
Wang, C., Purkayastha, A., Jones, K. T., Thaker, S. K., & Banerjee, U. K. (2016) · eLife · doi:10.7554/elife.18126 · Cited by 90 · see citing works
Epithelial–mesenchymal transition and cancer stemness: the Twist1–Bmi1 connection
Wu, K.-J., & Yang, M. (2011) · Bioscience Reports · doi:10.1042/bsr20100114 · Cited by 84 · see citing works
Saito, S., Lin, Y., Tsai, M., Lin, C., Murayama, Y., Sato, R., & Yokoyama, K. K. (2015) · The Kaohsiung Journal of Medical Sciences · doi:10.1016/j.kjms.2015.03.002 · Cited by 74 · see citing works
Je, D. W., Young Moon, O., Ji, Y. G., Cho, Y., & Lee, D. H. (2014) · Pancreas · doi:10.1097/mpa.0000000000000103 · Cited by 71 · see citing works
Hébert-Chatelain, É., José, C., Cortés, N. G., Dupuy, J., Rocher, C., Dachary-Prigent, J., & Letellier, T. (2012) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.01.014 · Cited by 63 · see citing works
FRK controls migration and invasion of human glioma cells by regulating JNK/c-Jun signaling
Zhou, X., Hua, L., Zhang, W., Zhu, M., Shi, Q., Li, F., Zhang, L., Song, C., & Yu, R. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-012-0933-1 · Cited by 62 · see citing works
Self-citationUnderstanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology
Goel, R. K., & Lukong, K. E. (2016) · Cancer and Metastasis Reviews · doi:10.1007/s10555-016-9623-3 · Cited by 60 · see citing works
Cloning of FRK, a novel human intracellular SRC-like tyrosine kinaseencoding gene
Lee, J., Wang, Z., Luoh, S.-M., Wood, W. I., & Scadden, D. T. (1994) · Gene · doi:10.1016/0378-1119(94)90817-6 · Cited by 59 · see citing works
Characterization of Mice Deficient in the Src Family Nonreceptor Tyrosine Kinase Frk/rak
Chandrasekharan, S., Qiu, T. H., Alkharouf, N. W., Brantley, K., Mitchell, J. B., & Liu, E. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5235-5247.2002 · Cited by 41 · see citing works
Sebastián, C. (2014) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2014011844 · Cited by 34 · see citing works
Hosoya, N., Qiao, Y., Hangaishi, A., Wang, L., Nannya, Y., Sanada, M., Kurokawa, M., Chiba, S., Hirai, H., & Ogawa, S. (2004) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20147 · Cited by 31 · see citing works
Okamoto, K., Ninomiya, I., Ohbatake, Y., Hirose, A., Tsukada, T., Nakanuma, S., Sakai, S., Kinoshita, J., Makino, I., Nakamura, K., et al. (2016) · Oncology Reports · doi:10.3892/or.2016.5133 · Cited by 26 · see citing works
Role of Pericellular Matrix in the Regulation of Cancer Stemness
Avnet, S., & Cortini, M. (2016) · Stem Cell Reviews and Reports · doi:10.1007/s12015-016-9660-x · Cited by 23 · see citing works
Exploring Rak tyrosine kinase function in breast cancer
Yim, E.-K., Siwko, S. K., & Lin, S. (2009) · Cell Cycle · doi:10.4161/cc.8.15.9264 · Cited by 22 · see citing works
The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor
Jin, L., & Craven, R. J. (2013) · Oncogene · doi:10.1038/onc.2012.589 · Cited by 17 · see citing works
Lee, D., & Lee, S. E. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.3.047 · Cited by 17 · see citing works
Patel, R. M., & Folpe, A. L. (2009) · Pathology · doi:10.1080/00313020903121614 · Cited by 13 · see citing works
Mutation analysis of the FRK gene in non-small cell lung cancers
Jin, G., Jeon, H., Yang, E., & Park, J. Y. (2010) · Lung Cancer · doi:10.1016/j.lungcan.2010.10.002 · Cited by 5 · see citing works
Flagged first, then by citations
1 of the 41 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Sciacovelli M, Frezza C. Metabolic repro- gramming and epithelial-to-mesenchymal transi- tion in cancer. FEBS J 2017;284:3132-44.
Cited by
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Fedele, M., Sgarra, R., Battista, S., Cerchia, L., & Manfioletti, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020800 · Cited by 169 · see citing works
Chen, Y., Bei, J., Liu, M., Huang, J., Xie, L., Huang, W., Cai, M., Guo, Y., Lin, L., & Zhu, K. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.06.001 · Cited by 65 · see citing works
Xie, C., Liang, C., Wang, R., Yi, K., Zhou, X., Li, X., Chen, Y., Miao, D., Zhong, C., & Zhu, J. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109211 · Cited by 57 · see citing works
Silencing PFKP restrains the stemness of hepatocellular carcinoma cells
Sha, X., Wang, K., Wang, F., Zhang, C., Yang, L., & Zhu, X. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112789 · Cited by 50 · see citing works
CRISPR/Cas9 in Cancer Immunotherapy: Animal Models and Human Clinical Trials
Khalaf, K., Janowicz, K., Dyszkiewicz-Konwińska, M., Hutchings, G., Dompé, C., Moncrieff, L., Jankowski, M., Machnik, M., Oleksiewicz, U., Kocherova, I., et al. (2020) · Genes · doi:10.3390/genes11080921 · Cited by 52 · see citing works
CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool
Baghini, S. S., Gardanova, Z. R., Abadi, S. A. H., Zaman, B. A., İlhan, A., Shomali, N., Adili, A., Moghaddar, R., & Yaseri, A. F. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00336-6 · Cited by 46 · see citing works
EMT signaling: potential contribution of CRISPR/Cas gene editing
Mohammadinejad, R., Biagioni, A., Arunkumar, G., Shapiro, R. S., Chang, K., Sedeeq, M., Taiyab, A., Hashemabadi, M., Pardakhty, A., Mandegary, A., et al. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03449-3 · Cited by 30 · see citing works
Creeden, J. F., Alganem, K., Imami, A. S., Henkel, N., Brunicardi, F. C., Liu, S., Shukla, R., Tomar, T., Naji, F., & McCullumsmith, R. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228823 · Cited by 22 · see citing works
Shuvalov, O., Kirdeeva, Y., Fefilova, E., Netsvetay, S., Zorin, M., Vlasova, Y., Fedorova, O., Daks, A., Parfenyev, S., & Barlev, N. (2023) · Metabolites · doi:10.3390/metabo13050656 · Cited by 21 · see citing works
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Roda, N., Gambino, V., & Giorgio, M. (2020) · Cells · doi:10.3390/cells9092081 · Cited by 21 · see citing works
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Patra, S. K., Sahoo, R. K., Biswal, S., Panda, S. S., & Biswal, B. K. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102177 · Cited by 15 · see citing works
Siva, N., Gupta, S., Gupta, A., Shukla, J. N., Malik, B., & Shukla, N. (2021) · 3 Biotech · doi:10.1007/s13205-021-02680-4 · Cited by 14 · see citing works
Yu, W., Ling, J., Yu, H., Du, J., & Liu, T. (2020) · General Physiology and Biophysics · doi:10.4149/gpb_2019061 · Cited by 12 · see citing works
CRISPR-Cas9-mediated gene therapy in lung cancer
Kazemizadeh, H., & Kashefizadeh, A. (2022) · Clinical & Translational Oncology · doi:10.1007/s12094-022-03039-8 · Cited by 10 · see citing works
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Meng, J., & Luo, M. (2021) · Acta Biochimica Polonica · doi:10.18388/abp.2020_5543 · Cited by 7 · see citing works
Yang, X., Li, C., Cheng, Y., Qin, S., Zhang, L., Zhou, L., Zhou, J., Xiao, H., Bai, Y., & Wang, J. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217936 · Cited by 6 · see citing works
Self-citationHuang, Y., Zhu, H., Liang, Z., Wei, W., Yang, H., Wang, Q., Huang, H., He, H., Mo, R., Ye, J., et al. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167722 · Cited by 6 · see citing works
Self-citationKim, T., Park, B.-S., Heo, S., Jeon, H., Kim, J., Kim, D., Lee, S. K., Jung, S., Kong, S., & Lu, T. K. (2024) · eLife · doi:10.7554/elife.93921.3 · Cited by 9 · see citing works
Huang, H., Wang, Y., Gan, J., Bu, H., Li, C., Li, Y., Yang, Y., & Liu, D. (2024) · The FASEB Journal · doi:10.1096/fj.202400951r · Cited by 4 · see citing works
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Deng, M., Zhang, Z., Liu, B., Lv, Q., Hou, K., Che, X., Qu, X., Liu, Y., Zhang, Y., & Hu, X. (2020) · Cancer Biomarkers · doi:10.3233/cbm-191268 · Cited by 4 · see citing works
Wang, B., Zhang, N., Dai, L., Zhang, Y., Yin, S., & Yang, X. (2025) · Discover Oncology · doi:10.1007/s12672-025-01805-y · Cited by 2 · see citing works
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Jiang, K., Lin, X., Wu, J., Ying, Y., Yan, B., Wang, J., & Zou, J. (2024) · Research Square · doi:10.21203/rs.3.rs-3689329/v1
Kim, T., Park, B.-S., Heo, S., Jeon, H., Kim, J., Kim, D., Lee, S. K., Jung, S., Kong, S., & Lu, T. K. (2025) · eLife · doi:10.7554/elife.93921.2
Lin, X., Wu, J., Ying, Y., Yan, B., Wang, J., Zou, J., & Jiang, K. (2026) · Autism Research · doi:10.1002/aur.70310
Natanzi, A. S., Ahmadi, E., Shahraki, S., Koupaei, A. E., & Kashani, H. H. (2026) · Advanced Composites and Hybrid Materials · doi:10.1007/s42114-026-02049-2
- Authors
- Zhang, L., Yang, Y., Chai, L., Bu, H., Yang, Y., Huang, H., Ran, J., Zhu, Y., Li, L., Chen, F., & Li, W.
- Affiliations
- Sichuan University (CN)
- Corresponding author
- Li, Weimin
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2019-07-26
- Volume
- 146
- Issue
- 1
- Pages
- 208-222
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2953717774
- Cited by
- 29
- References
- 41
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 1 · 2022: 6 · 2021: 4 · 2020: 6
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81772478, 81871890)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- non-small cell lung cancer, cancer stemness, metabolic reprogramming, Warburg effect, epithelial-mesenchymal transition, CD44, CD133, oncogenic kinase, epidermal growth factor, metastasis, prognostic factors, therapeutic target
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Proteins, Oncogenes, Prognosis, Protein-Tyrosine Kinases, Neoplastic Stem Cells, Cell Line, Tumor, Gene Knockdown Techniques, Epithelial-Mesenchymal Transition, CRISPR-Cas Systems
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