Skip to main content

Advertisement

SpringerLink
Log in

DNA repair/recombination protein 54L promotes the progression of lung adenocarcinoma by activating mTORC1 pathway

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Lung adenocarcinoma (LUAD) is the most prevalent form of lung cancer and has a poor prognosis. RAD54L is a DNA repair protein upregulated in several cancer types, but its role in LUAD progression remains unclear. The objective of this study was to characterise the molecular pathways that oncogenic RAD54L modulates to drive LUAD progression. The Cancer Genome Atlas (TCGA)‒LUAD dataset was analysed to compare the RAD54L mRNA expression in LUAD tumours to that in normal lung tissue. RAD54L and E2F7 mRNA expression was confirmed in human cancer cell lines using RT-qPCR. Bioinformatics tools were used to predict the target genes and downstream signalling pathways of RAD54L. Proteins related to RAD54L, apoptosis, migration, and the mTORC1 pathway were assessed by Western blotting. Using the TCGA‒LUAD dataset, we found that RAD54L was higher in LUAD tumours compared to that in non-cancerous lung tissue, and RAD54L levels were significantly correlated with pathological TNM stage and unfavourable prognosis in patients with LUAD. RAD54L was ubiquitously upregulated in LUAD cells (NCI-H1975, H1299, H23 and A549). Furthermore, RAD54L silencing decreased cell proliferation, invasion, and migration, and induced cell apoptosis and G1 cell cycle phase arrest in H1299 and H23 human lung cancer cell lines. E2F7 was predicted as a target gene of RAD54L. E2F7 overexpression restored malignant cell behaviour in si-RAD54L-treated H1299 cells. Bioinformatic analysis suggested that the mTORC1 signalling pathway is downstream of RAD54L. Rapamycin treatment impaired RAD54L-mediated malignant cell behaviour in H1299 cells. Additionally, RAD54L promoted the progression of xenograft tumours and metastasis in vivo. In conclusion, the E2F7-RAD54L axis promotes the progression of LUAD through the mTORC1 signalling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

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

Code availability

Not applicable.

References

  1. Siegel RL, Miller KD. Jemal A (2020) cancer statistics. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  2. Xie X, Li X, Tang W, Xie P, Tan X. Primary tumor location in lung cancer: the evaluation and administration. Chin Med J (Engl). 2021;135(2):127–36.

    Article  Google Scholar 

  3. Wang M, Zhang G, Zhang Y, Cui X, Wang S, Gao S, Wang Y, Liu Y, Bae JH, Yang WH, Qi LS, Wang L, Liu R. Fibrinogen alpha chain knockout promotes tumor growth and metastasis through integrin-AKT signaling pathway in lung cancer. Mol Cancer Res. 2020;18(7):943–54.

    Article  CAS  Google Scholar 

  4. Chen X, Zhang Z, Hou X, Zhang Y, Zhou T, Liu J, Lin Z, Fang W, Yang Y, Ma Y, Huang Y, Zhao H, Zhang L. Immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer: a network meta-analysis. J Immunother Cancer. 2020;8(2):e001170.

  5. Poirier A, Gagne A, Laflamme P, Marcoux M, Orain M, Plante S, Joubert D, Joubert P, Laplante M. ZNF768 expression associates with high proliferative clinicopathological features in lung adenocarcinoma. Cancers (Basel). 2021;13(16):4136. Accessed 17 Aug 2021.

    Article  CAS  Google Scholar 

  6. Li Q, Xie W, Wang N, Li C, Wang M. CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma. Transl Oncol. 2018;11(2):300–6.

    Article  Google Scholar 

  7. Selemenakis P, Sharma N, Uhrig ME, Katz J, Kwon Y, Sung P, Wiese C. RAD51AP1 and RAD54L can underpin two distinct RAD51-dependent routes of DNA damage repair via homologous recombination. Front Cell Dev Biol. 2022;10:866601.

    Article  Google Scholar 

  8. Mun JY, Baek SW, Park WY, Kim WT, Kim SK, Roh YG, Jeong MS, Yang GE, Lee JH, Chung JW, Choi YH, Chu IS, Leem SH. E2F1 promotes progression of bladder cancer by modulating RAD54L Involved in homologous recombination repair. Int J Mol Sci. 2020;21(23):9025. Accessed 27 Nov 2020.

    Article  CAS  Google Scholar 

  9. Zheng S, Yao L, Li F, Huang L, Yu Y, Lin Z, Li H, Xia J, Lanuti M, Zhou H. Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma. PeerJ. 2021;9:e10680.

    Article  Google Scholar 

  10. Emanuele MJ, Enrico TP, Mouery RD, Wasserman D, Nachum S, Tzur A. Complex cartography: regulation of E2F transcription factors by cyclin F and ubiquitin. Trends Cell Biol. 2020;30(8):640–52.

    Article  CAS  Google Scholar 

  11. Yuan R, Liu Q, Segeren HA, Yuniati L, Guardavaccaro D, Lebbink RJ, Westendorp B, de Bruin A. Cyclin F-dependent degradation of E2F7 is critical for DNA repair and G2-phase progression. EMBO J. 2019;38(20):e101430.

    Article  CAS  Google Scholar 

  12. Yang R, Wang M, Zhang G, Bao Y, Wu Y, Li X, Yang W, Cui H. E2F7-EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression. Br J Cancer. 2020;123(9):1445–55.

    Article  CAS  Google Scholar 

  13. Wang Y, Pei X, Xu P, Tan Z, Zhu Z, Zhang G, Jiang Z, Deng Z. E2F7, regulated by miR30c, inhibits apoptosis and promotes cell cycle of prostate cancer cells. Oncol Rep. 2020;44(3):849–62.

    Article  CAS  Google Scholar 

  14. Teng F, Zhang JX, Chang QM, Wu XB, Tang WG, Wang JF, Feng JF, Zhang ZP, Hu ZQ. LncRNA MYLK-AS1 facilitates tumor progression and angiogenesis by targeting miR-424-5p/E2F7 axis and activating VEGFR-2 signaling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39(1):235.

    Article  CAS  Google Scholar 

  15. Wang Y, Wo Y, Lu T, Sun X, Liu A, Dong Y, Du W, Su W, Huang Z, Jiao W. Circ-AASDH functions as the progression of early stage lung adenocarcinoma by targeting miR-140-3p to activate E2F7 expression. Transl Lung Cancer Res. 2021;10(1):57–70.

    Article  CAS  Google Scholar 

  16. Liang R, Xiao G, Wang M, Li X, Li Y, Hui Z, Sun X, Qin S, Zhang B, Du N, Liu D, Ren H. SNHG6 functions as a competing endogenous RNA to regulate E2F7 expression by sponging miR-26a-5p in lung adenocarcinoma. Biomed Pharmacother. 2018;107:1434–46.

    Article  CAS  Google Scholar 

  17. Nooreldeen R, Bach H. Current and future development in lung cancer diagnosis. Int J Mol Sci. 2021;22(16):8661. Accessed 12 Aug 2021.

    Article  CAS  Google Scholar 

  18. Chang ET, Lau EC, Moolgavkar SH. Smoking, air pollution, and lung cancer risk in the nurses’ health study cohort: time-dependent confounding and effect modification. Crit Rev Toxicol. 2020;50(3):189–200.

    Article  CAS  Google Scholar 

  19. Sanchez N, Gallagher M, Lao N, Gallagher C, Clarke C, Doolan P, Aherne S, Blanco A, Meleady P, Clynes M, Barron N. MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3. PLoS ONE. 2013;8(6):e65671.

    Article  CAS  Google Scholar 

  20. Wang Q, Liu J, Cheang I, Li J, Chen T, Li Y, Yu B. Comprehensive analysis of the E2F transcription factor family in human lung adenocarcinoma. Int J Gen Med. 2022;15:5973–84.

    Article  Google Scholar 

  21. Guo H, Zhang L. MicroRNA-30a suppresses papillary thyroid cancer cell proliferation, migration and invasion by directly targeting E2F7. Exp Ther Med. 2019;18(1):209–15.

    CAS  Google Scholar 

  22. Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: epigenetics and beyond. Life Sci. 2020;262:118513.

    Article  CAS  Google Scholar 

  23. Guo M, Li N, Zheng J, Wang W, Wu Y, Han X, Guo J, Chen W, Bai Z, Bai W, Wu J. Epigenetic regulation of hepatocellular carcinoma progression through the mTOR signaling pathway. Can J Gastroenterol Hepatol. 2021;2021:5596712.

    Article  Google Scholar 

  24. Lu ZN, Song J, Sun TH, Sun G. UBE2C affects breast cancer proliferation through the AKT/mTOR signaling pathway. Chin Med J (Engl). 2021;134(20):2465–74.

    Article  CAS  Google Scholar 

  25. Ekman S, Wynes MW, Hirsch FR. The mTOR pathway in lung cancer and implications for therapy and biomarker analysis. J Thorac Oncol. 2012;7(6):947–53.

    Article  CAS  Google Scholar 

  26. Liu T, Ye P, Ye Y, Han B. MicroRNA-216b targets HK2 to potentiate autophagy and apoptosis of breast cancer cells via the mTOR signaling pathway. Int J Biol Sci. 2021;17(11):2970–83.

    Article  CAS  Google Scholar 

  27. Yu J, Wu C, Wu Q, Huang J, Fu W, Xie X, Li W, Tang W, Xu C, Jin G. PCYT1A suppresses proliferation and migration via inhibiting mTORC1 pathway in lung adenocarcinoma. Biochem Biophys Res Commun. 2020;529(2):353–61.

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Author notes

  1. Changjiang Liu, Wei Ren, these authors contributed equally to this work and should be considered as co-first author.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, 970 Hospital of PLA, Weihai, 264200, Shandong, People’s Republic of China

    Changjiang Liu, Wei Ren & Zhixin Zhang

  2. Department of Ophthalmology, 970 Hospital of PLA, No.8, Baoquan Road, Weihai, 264200, Shandong, People’s Republic of China

    Juanjuan Guan

Authors
  1. Changjiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhixin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juanjuan Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Contributions:(I) conception and design: CL and WR; (II) administrative support: CL and WR; (III) provision of study materials or patients: CL and WR; (IV) collection and assembly of data: ZZ, JJG; (V) data analysis and interpretation: ZZ, JJG; (VI) manuscript writing: all authors; (VII) final approval of manuscript: all authors.

Corresponding authors

Correspondence to Zhixin Zhang or Juanjuan Guan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of the 970 Hospital of PLA (No: 2021-08-15). Animal experiments were performed in accordance with guidelines set by the ethics board of the 970 Hospital of PLA (No: 2021-11-25).

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2671 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, C., Ren, W., Zhang, Z. et al. DNA repair/recombination protein 54L promotes the progression of lung adenocarcinoma by activating mTORC1 pathway. Human Cell 36, 421–433 (2023). https://doi.org/10.1007/s13577-022-00832-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-022-00832-z

Keywords

Search

Navigation