Hypoxia-induced circ_0017521 enhances glycolysis and promotes NSCLC progression via upregulating the PFKFB3/PI3K-AKT pathway
Abstract
The hypoxic microenvironment is a critical feature of malignant progression in non-small cell lung cancer (NSCLC). However, the regulatory role of circular RNAs (circRNAs) in this context remains incompletely understood. Hypoxia-related circRNAs were screened by integrating GEO datasets, and the expression of circ_0017521 in hypoxia-treated cells was validated using qRT-PCR. RNase R digestion and actinomycin D assays were employed to assess its stability. Biological functions were evaluated through CCK-8, colony formation, Transwell, flow cytometry, and glycolytic metabolism assays. Dual-luciferase reporter, RNA pull-down, and rescue experiments were conducted to elucidate the circ_0017521/miR-532-3p/PFKFB3 axis. A nude mouse xenograft model was constructed. circ_0017521 was specifically upregulated in NSCLC tissues and hypoxia-treated cells, exhibiting remarkable stability compared to linear AKR1E2 and primarily localizing in the cytoplasm. Under hypoxic conditions, knockdown of circ_0017521 noticeably inhibited NSCLC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and glycolysis, while promoting apoptosis. Mechanistically, circ_0017521 competitively bound to miR-532-3p, relieving its suppression of PFKFB3 and thereby activating the PI3K/AKT signaling pathway. Upregulation of PFKFB3 drove the expression of glycolytic enzymes (GLUT1, LDHA, HK2) and synergistically activated EMT. Animal experiments confirmed that silencing circ_0017521 suppressed tumor growth and glycolysis. This study revealed that hypoxia-induced circ_0017521 activated the PI3K/AKT pathway through the miR-532-3p/PFKFB3 axis, synergistically driving EMT and glycolysis, thereby promoting NSCLC progression.
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Persistent activation of glycolytic pathways has been associated with malignant progression and poor clinical outcomes in NSCLC.
“Persistent activation of glycolytic pathways has also been associated with malignant progression and poor clinical outcomes in NSCLC (28, 29).”
From Bioinformatics-based identification of glycolysis-related signatures associated with drug resistance and prognosis in lung adenocarcinoma (2026) · cites this paper as [29]
Cites
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612 · see citing works
Reactive Oxygen Species in Cancer: Current Findings and Future Directions
Nakamura, H., & Takada, K. (2021) · Cancer Science · doi:10.1111/cas.15068 · Cited by 1,027 · see citing works
Non‐small cell lung cancer in China
Chen, P., Liu, Y., Wen, Y., & Zhou, C. (2022) · 癌症：英文版 · doi:10.1002/cac2.12359 · Cited by 673 · see citing works
Cantelmo, A. R., Conradi, L.-C., Brajic, A., Goveia, J., Kalucka, J., Pircher, A., Chaturvedi, P., Hol, J., Thienpont, B., Teuwen, L.-A., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.10.006 · Cited by 659 · see citing works
An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
Palazon, A., Tyrakis, P. A., Macias, D., Veliça, P., Rundqvist, H., Fitzpatrick, S., Vojnovic, N., Phan, A. T., Loman, N., Hedenfalk, I., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.10.003 · Cited by 521 · cited 4× · see citing works
“For instance, miR-532-3pattenuates the growth and metastatic potential of neoplastic cells through modulation of the GPNMB/HIF-1α/HK2 signaling cascade”
InfluentialPI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review)
Xie, Y., Shi, X., Sheng, K., Han, G., Li, W., Zhao, Q., Jiang, B., Feng, J., Li, J., & Gu, Y. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9713 · Cited by 505 · see citing works
Therapeutic targeting of the hypoxic tumour microenvironment
Singleton, D. C., Macann, A., & Wilson, W. R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00539-4 · Cited by 493 · see citing works
Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment
Alduais, Y., Zhang, H., Fan, F., Chen, J., & Chen, B. (2023) · Medicine · doi:10.1097/md.0000000000032899 · Cited by 371 · see citing works
Shi, L., Pan, H., Liu, Z., Xie, J., & Han, W. (2017) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2017.44 · Cited by 287 · see citing works
Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00848-6 · Cited by 245 · see citing works
Li, F., Liu, J., Bao, R., Yan, G., Feng, X., Xu, Y., Sun, Y., Yan, W., Ling, Z., Xiong, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-02950-5 · Cited by 197 · see citing works
Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter
Hompland, T., Fjeldbo, C. S., & Lyng, H. (2021) · Cancers · doi:10.3390/cancers13030499 · Cited by 179 · see citing works
Lin, J., Wang, X., Zhai, S., Shi, M., Peng, C., Deng, X., Fu, D., Wang, J., & Shen, B. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01348-7 · Cited by 166 · see citing works
The potential utility of PFKFB3 as a therapeutic target
Bartrons, R., Rodríguez‐García, A., Simon‐Molas, H., Castaño, E., Manzano, À., & Navarro‐Sabaté, À. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1498082 · Cited by 90 · see citing works
Hypoxia-associated circDENND2A promotes glioma aggressiveness by sponging miR-625-5p
Su, H. C., Zou, D., Sun, Y., & Dai, Y. (2019) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-019-0149-x · Cited by 68 · see citing works
Role of PFKFB3-driven glycolysis in sepsis
Xiao, M., Liu, D., Xu, Y., Mao, W., & Li, W. (2023) · Annals of Medicine · doi:10.1080/07853890.2023.2191217 · Cited by 64 · see citing works
CircRNA: Functions, Applications and Prospects
Xu, F., Xiao, Q., Du, W. W., Wang, S., & Yang, B. B. (2024) · Biomolecules · doi:10.3390/biom14121503 · Cited by 49 · see citing works
AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
Chen, T., Xie, S., Cheng, J., Zhao, Q. L., Wu, H., Jiang, P., & Du, W. (2024) · Nature Communications · doi:10.1038/s41467-024-44772-8 · Cited by 42 · see citing works
Yalçın, A., Altunok, T. H., Özcan, S. C., Güzel, S., Peker, S., Çelikler, S., Balaban, B. D., Demirdöğen, E., Gurpinar, Y., & Chesney, J. A. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.01.178 · Cited by 41 · see citing works
Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy
Li, X., Liu, J., Li, Q., Ke, H., Yao, C., Tian, W., Liu, Y., & Zhang, J. (2018) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-017-3258-8 · Cited by 37 · see citing works
Hypoxia-induced circRNF13 promotes the progression and glycolysis of pancreatic cancer
Zhao, Q., Zhu, Z., Xiao, W., Zong, G., Wang, C., Jiang, W., Li, K., Shen, J., Guo, X., Cui, J., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00877-y · Cited by 35 · see citing works
Cheng, X., Qiu, J., Wang, S., Yang, Y., Guo, M., Wang, D., Luo, Q., & Xu, L. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.08.79 · Cited by 33 · see citing works
Wu, D., Chen, T., Zhao, X., Huang, D., Huang, J., Huang, Y., Huang, Q., Liang, Z., Chen, C., Chen, M., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02336-y · Cited by 31 · see citing works
Zhang, W., Cai, S., Qin, L., Feng, Y., Ding, M., Luo, Z., Shan, J., & Di, L. (2024) · Communications Biology · doi:10.1038/s42003-024-06801-6 · Cited by 28 · see citing works
Li, L., Liu, D., Chen, T., Wei, C., Qiao, Y., Liu, W., Liang, Y., Liang, Z., Chen, C., Li, D., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03116-6 · Cited by 24 · see citing works
miR-532–3p suppresses proliferation and invasion of ovarian cancer cells via GPNMB/HIF-1α/HK2 axis
Tuo, X., Zhou, Y., Yang, X., Ma, S., Liu, D., Zhang, X., Hou, H., Wang, R., Li, X., & Zhao, L. (2022) · Pathology - Research and Practice · doi:10.1016/j.prp.2022.154032 · Cited by 24 · see citing works
Emerging role of circular RNAs in the pathobiology of lung cancer
Ghafouri‐Fard, S., Dinger, M. E., Maleki, P., Taheri, M. N., & Hajiesmaeili, M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111805 · Cited by 17 · see citing works
hsa_circ_0020378 regulating miR-339-3p/COL1A1 promotes osteosarcoma progression
Liu, L., & Huang, W. (2023) · Cancer Biology & Therapy · doi:10.1080/15384047.2023.2274120 · Cited by 10 · see citing works
MiR-532-3pinhibited the methylation ofSOCS2to suppress the progression of PC by targetingDNMT3A
Wang, K., Gong, D., Qiao, X. J., & Zheng, J. (2023) · Life Science Alliance · doi:10.26508/lsa.202201703 · Cited by 8 · see citing works
Circ_0007386 Promotes the Progression of Hepatocellular Carcinoma Through the miR-507/ CCNT2 Axis
Feng, Y., Liang, L., Jia, W., Wang, J., Xu, C., Deming, Z., Xu, B., Zhao, W., Ling, X., Zhou, Y., et al. (2024) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s459633 · Cited by 7 · see citing works
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Zheng, Q., Liu, Y., Li, T., Zhang, X., Geng, Y., Chen, Z., Zhou, J., Fan, W., Wang, Y., Zhang, L., et al. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1871582
Lin, C., Qin, A., Li, Y., & Yang, Y. (2026) · Current Genomics · doi:10.1016/j.curgen.2026.09.006
Castillejos-López, M. D. J., Barrera-Elizalde, U., Flores‐Soto, E., Colín-Godínez, L. A., Espíndola, L. M. T., Romero-Martínez, B. S., Guzmán-Castillo, J., González-Ávila, G., Luis‐García, E. R., Rojas-Durán, F., et al. (2026) · Antioxidants · doi:10.3390/antiox15101364
- Authors
- Zhu, J., Yan, J., Zhang, Y., Zhu, X., & Chen, G.
- Affiliations
- Zhongda Hospital Southeast University (CN)
- Corresponding author
- Chen, Guoping
- Venue
- Mammalian Genome
- Published
- 2026-02-16
- Volume
- 37
- Issue
- 1
- Pages
- 37-37
- ISSN
- 0938-8990 (ISSN-L)
- 1432-1777
- OpenAlex
- W7129051596
- Cited by
- 3
- References
- 30
- Citations by year
- 2026: 3
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Mammalian Genome (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- circular RNA, non-small cell lung cancer, tumor hypoxia, miR-532-3p, PFKFB3, PI3K/Akt signaling, glycolysis, epithelial-mesenchymal transition, tumor progression, tumor microenvironment
- MeSH terms
- RNA, Circular, Animals, Carcinoma, Non-Small-Cell Lung, Cell Movement, Glycolysis, Humans, Lung Neoplasms, Mice, Nude, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Disease Progression, Phosphatidylinositol 3-Kinases, Phosphofructokinase-2, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Epithelial-Mesenchymal Transition
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