Download PDF
CC BY 4.0 · Glob Med Genet 2024; 11(04): 241-250
DOI: 10.1055/s-0044-1789199
Original Article

AQP4-AS1 Can Regulate the Expression of Ferroptosis-Related Regulator ALOX15 through Competitive Binding with miR-4476 in Lung Adenocarcinoma

Lin Du
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Geng Xu
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Xiuqiang Zhang
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Zhiwei Zhang
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Yang Yang
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Hongsheng Teng
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
,
Tao Yang
1   Department of Thoracic Surgery, Tianjin Fifth Center Hospital, Tianjin, China
› Author Affiliations Funding This study was supported by the Tianjin Key Medical Discipline (Specialty) Construction Project (number: TJKMDCP2021).
› Further Information
Also available at
   Permissions and Reprints

Abstract

Background The AQP4-AS1/miR-4476-ALOX15 regulatory axis was discovered in previous studies. We aimed to investigate the regulatory mechanism of the ferroptosis-related regulator ALOX15 by AQP4-AS1 and miR-4476 in lung adenocarcinoma (LUAD) and find new targets for clinical treatment.

Methods After bioinformatics analysis, we contained one ferroptosis-related gene (FRG), namely ALOX15. MicroRNAs (miRNAs) and long noncoding RNAs were predicted by miRWalk. Furthermore, we constructed overexpressed LUAD cell lines. Real-time quantitative polymerase chain reaction and western blot were used to determine the expression of mRNA and protein, respectively. Cell Counting Kit-8 (CCK-8) and EdU assay were used to detect the cell proliferation. Double luciferase assay was used to detect the binding relationship between AQP4-AS1 and miR-4464.

Results ALOX15 was the most significantly downregulated FRG compared with normal tissues. Furthermore, protein-protein interaction network analysis indicated that the AQP4-AS1-miR-4476-ALOX15 regulatory axis might be involved in the occurrence and development of LUAD and there might be direct interaction between AQP4-AS1 and miR-4476, and miR-4476 and ALOX15. Furthermore, AQP4-AS1 and ALOX15 were significantly downregulated in the LUAD tissue and cell lines, whereas miR-4476 showed the opposite results (p < 0.001). AQP4-AS1 overexpression improved the ALOX15 expression in LUAD cell lines. CCK-8 and EdU assay revealed that overexpression of AQP4-AS1 and ALOX15 inhibited the LUAD cell proliferation. Double luciferase assay results indicated that there was a combination between AQP4-AS1 and miRNA-4476. In addition, we found that overexpressed AQP4-AS1 activates the ferroptosis in LUAD cell lines.

Conclusions AQP4-AS1 can regulate the expression of ALOX15 through competitive binding with miR-4476, further activate ferroptosis and inhibit the proliferation of LUAD cells.

Keywords

lung adenocarcinoma - ALOX15 - ferroptosis - AQP4-AS1 - miRNA-4476

Ethics Statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


Author Contributions

All authors certify that they have participated in this work. The manuscript was conceptualized and supervised by L.D., with original draft writing, and review and editing by X.Z., Z.Z. contributed to formal analysis. Y.Y. and H.T. assisted with data curation. T.Y. participated in review and editing.


Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


Supplementary Material



Publication History

Article published online:
16 August 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Spella M, Stathopoulos GT. Immune resistance in lung adenocarcinoma. Cancers (Basel) 2021; 13 (03) 384
    CrossrefPubMedSearch in Google Scholar
  • 2 Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis 2018; 9 (02) 117
    PubMedSearch in Google Scholar
  • 3 Cheng WC, Chang CY, Lo CC. et al. Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma. Theranostics 2021; 11 (08) 3661-3675
    CrossrefPubMedSearch in Google Scholar
  • 4 Orcutt ST, Anaya DA. Liver resection and surgical strategies for management of primary liver cancer. Cancer Control 2018; 25 (01) 1073274817744621
    CrossrefPubMedSearch in Google Scholar
  • 5 Inamura K. Clinicopathological characteristics and mutations driving development of early lung adenocarcinoma: tumor initiation and progression. Int J Mol Sci 2018; 19 (04) 1259
    CrossrefPubMedSearch in Google Scholar
  • 6 Zhang T, Zhang SW, Li Y. Identifying driver genes for individual patients through inductive matrix completion. Bioinformatics 2021; 37 (23) 4477-4484
    CrossrefPubMedSearch in Google Scholar
  • 7 Larsen TV, Hussmann D, Nielsen AL. PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer. Cancer Commun (Lond) 2019; 39 (01) 30
    PubMedSearch in Google Scholar
  • 8 Geng W, Lv Z, Fan J. et al. Identification of the prognostic significance of somatic mutation-derived LncRNA signatures of genomic instability in lung adenocarcinoma. Front Cell Dev Biol 2021; 9: 657667
    CrossrefPubMedSearch in Google Scholar
  • 9 Halladay JR, Lenhart KC, Robasky K. et al. Applicability of precision medicine approaches to managing hypertension in rural populations. J Pers Med 2018; 8 (02) 16
    CrossrefPubMedSearch in Google Scholar
  • 10 Huang GZ, Wu QQ, Zheng ZN, Shao TR, Lv XZ. Identification of candidate biomarkers and analysis of prognostic values in oral squamous cell carcinoma. Front Oncol 2019; 9: 1054
    CrossrefPubMedSearch in Google Scholar
  • 11 Xing C, Cai Z, Gong J, Zhou J, Xu J, Guo F. Identification of potential biomarkers involved in gastric cancer through integrated analysis of non-coding RNA associated competing endogenous RNAs network. Clin Lab 2018; 64 (10) 1661-1669
    PubMedSearch in Google Scholar
  • 12 Li M, Zhang Y, Fan M, Ren H, Chen M, Shi P. Identification of the ferroptosis-related long non-coding RNAs signature to improve the prognosis prediction and immunotherapy response in patients with NSCLC. BMC Med Genomics 2021; 14 (01) 286
    CrossrefPubMedSearch in Google Scholar
  • 13 Petri BJ, Klinge CM. Regulation of breast cancer metastasis signaling by miRNAs. Cancer Metastasis Rev 2020; 39 (03) 837-886
    CrossrefPubMedSearch in Google Scholar
  • 14 Wang SS, Fang YY, Huang JC. et al. Clinical value of microRNA-198-5p downregulation in lung adenocarcinoma and its potential pathways. Oncol Lett 2019; 18 (03) 2939-2954
    PubMedSearch in Google Scholar
  • 15 Jiang X, Yuan Y, Tang L. et al. Identification and validation prognostic impact of MiRNA-30a-5p in lung adenocarcinoma. Front Oncol 2022; 12: 831997
    CrossrefPubMedSearch in Google Scholar
  • 16 Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22 (04) 266-282
    CrossrefPubMedSearch in Google Scholar
  • 17 Li J, Cao F, Yin HL. et al. Ferroptosis: past, present and future. Cell Death Dis 2020; 11 (02) 88
    CrossrefPubMedSearch in Google Scholar
  • 18 Zhang X, Yu K, Ma L. et al. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. Theranostics 2021; 11 (12) 5650-5674
    CrossrefPubMedSearch in Google Scholar
  • 19 Gao X, Tang M, Tian S, Li J, Liu W. A ferroptosis-related gene signature predicts overall survival in patients with lung adenocarcinoma. Future Oncol 2021; 17 (12) 1533-1544
    CrossrefPubMedSearch in Google Scholar
  • 20 Li N, Feng XB, Tan Q. et al. Identification of circulating long noncoding RNA Linc00152 as a novel biomarker for diagnosis and monitoring of non-small-cell lung cancer. Dis Markers 2017; 2017: 7439698
    PubMedSearch in Google Scholar
  • 21 Menon T, Gopal S, Rastogi Verma S. Targeted therapies in non-small cell lung cancer and the potential role of AI interventions in cancer treatment. Biotechnol Appl Biochem 2023; 70 (01) 344-356
    CrossrefPubMedSearch in Google Scholar
  • 22 Singh NK, Rao GN. Emerging role of 12/15-lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res 2019; 73: 28-45
    CrossrefPubMedSearch in Google Scholar
  • 23 Tian R, Zuo X, Jaoude J, Mao F, Colby J, Shureiqi I. ALOX15 as a suppressor of inflammation and cancer: lost in the link. Prostaglandins Other Lipid Mediat 2017; 132: 77-83
    CrossrefPubMedSearch in Google Scholar
  • 24 Ren Z, Hu M, Wang Z. et al. Ferroptosis-related genes in lung adenocarcinoma: prognostic signature and immune, drug resistance, mutation analysis. Front Genet 2021; 12: 672904
    CrossrefPubMedSearch in Google Scholar
  • 25 Wang Z, Zhang X, Tian X. et al. CREB stimulates GPX4 transcription to inhibit ferroptosis in lung adenocarcinoma. Oncol Rep 2021; 45 (06) 88
    CrossrefPubMedSearch in Google Scholar
  • 26 Yang WS, SriRamaratnam R, Welsch ME. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156 (1-2): 317-331
    CrossrefPubMedSearch in Google Scholar
  • 27 Hu K, Li K, Lv J. et al. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest 2020; 130 (04) 1752-1766
    CrossrefPubMedSearch in Google Scholar
  • 28 Li N, Wang W, Zhou H. et al. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic Biol Med 2020; 160: 303-318
    CrossrefPubMedSearch in Google Scholar
  • 29 Chen F, Fan Y, Hou J. et al. Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer. Aging (Albany NY) 2021; 13 (17) 21671-21699
    CrossrefPubMedSearch in Google Scholar
  • 30 Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater 2019; 31 (51) e1904197
    CrossrefPubMedSearch in Google Scholar
  • 31 Tang Q, Bai L, Zou Z. et al. Ferroptosis is newly characterized form of neuronal cell death in response to arsenite exposure. Neurotoxicology 2018; 67: 27-36
    CrossrefPubMedSearch in Google Scholar