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PIK3R2 predicts poor outcomes for patients with melanoma and contributes to the malignant progression via PI3K/AKT/NF-κB axis

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Abstract

Background

Melanoma is an aggressive form of skin cancer worldwide. Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) exerts carcinogenic roles in various tumors. So far, the function and mechanism of PIK3R2 in melanoma are not been fully clarified.

Objective

We aimed to clarify the role of PIK3R2 in melanoma.

Methods

PIK3R2 expressions in melanoma clinical tissues and melanoma cells were measured using quantitative real-time PCR and Western blot. In addition, PIK3R2 expressions in different tumor stages of melanoma were determined by immunohistochemistry assay. Meanwhile, PIK3R2 function was evaluated using loss or gain-of-function assays, Cell Counting Kit-8 assay, flow cytometry, and Transwell analysis. Furthermore, PIK3R2 mechanism in melanoma was assessed by a series of rescue experiments.

Results

PIK3R2 was highly expressed in melanoma tissues and cells, and PIK3R2 expressions were the highest in Stage IV. Functionally, PIK3R2 knockdown repressed melanoma cell proliferation, invasion, epithelial-mesenchymal transition, and facilitated cell apoptosis. Also, PIK3R2 overexpression produced an opposite trend. Mechanistically, PIK3R2 facilitated melanoma progression by activating PI3K/AKT/NF-κB pathway. Furthermore, PIK3R2 knockdown restrained the melanoma tumor growth in vivo.

Conclusions

PIK3R2 aggravated melanoma by activating PI3K/AKT/NF-κB pathway, prompting that PIK3R2 might be a therapeutic target for melanoma.

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Data availability

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

References

  1. Shellenberger R, Nabhan M, Kakaraparthi S. Melanoma screening: a plan for improving early detection. Ann Med. 2016;48(3):142–8.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang C, Song C, Liu T, Tang R, Chen M, Gao F, et al. KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway. Cell Death Dis. 2017;8(7): e2940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Boussios S, Rassy E, Samartzis E, Moschetta M, Sheriff M, Pérez-Fidalgo JA, et al. Melanoma of unknown primary: new perspectives for an old story. Crit Rev Oncol Hematol. 2021;158: 103208.

    Article  PubMed  Google Scholar 

  4. Lo JA, Fisher DE. The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. Science (New York, NY). 2014;346(6212):945–9.

    Article  CAS  Google Scholar 

  5. Liu W, Stachura P, Xu HC, Umesh Ganesh N, Cox F, Wang R, et al. Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications. J Exp Clin Cancer Res. 2020;39(1):38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell. 1989;57(1):167–75.

    Article  CAS  PubMed  Google Scholar 

  7. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–19.

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Peng J, Bai S, Yu H, He H, Fan C, et al. A PIK3R2 mutation in familial temporal lobe epilepsy as a possible pathogenic variant. Front Genet. 2021;12: 596709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fu R, Tong JS. miR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells. J Cell Mol Med. 2020;24(13):7600–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Song L, Xie X, Yu S, Peng F, Peng L. MicroRNA-126 inhibits proliferation and metastasis by targeting pik3r2 in prostate cancer. Mol Med Rep. 2016;13(2):1204–10.

    Article  CAS  PubMed  Google Scholar 

  11. Marsh Durban V, Deuker MM, Bosenberg MW, Phillips W, McMahon M. Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. J Clin Investig. 2013;123(12):5104–18.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhu L, Liu Z, Dong R, Wang X, Zhang M, Guo X, et al. MicroRNA-3662 targets ZEB1 and attenuates the invasion of the highly aggressive melanoma cell line A375. Cancer Manag Res. 2019;11:5845–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kappelmann M, Bosserhoff A, Kuphal S. AP-1/c-Jun transcription factors: regulation and function in malignant melanoma. Eur J Cell Biol. 2014;93(1–2):76–81.

    Article  CAS  PubMed  Google Scholar 

  14. Song L, Li D, Gu Y, Wen ZM, Jie J, Zhao D, et al. MicroRNA-126 targeting PIK3R2 inhibits NSCLC A549 cell proliferation, migration, and invasion by regulation of PTEN/PI3K/AKT pathway. Clin Lung Cancer. 2016;17(5):e65–75.

    Article  CAS  PubMed  Google Scholar 

  15. Xu HF, Huang TJ, Yang Q, Xu L, Lin F, Lang YH, et al. Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression. Cancer Manag Res. 2019;11:5557–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hao X, Wang S, Jiang C, Zhang J, Fan Y, Pang J, et al. The relation between plasma miR-126 levels and cerebral collateral circulation in patients with intracranial arterial stenosis. Neurol Neurochir Pol. 2021;55(3):281–8.

    Article  PubMed  Google Scholar 

  17. Gao J, Zhou XL, Kong RN, Ji LM, He LL, Zhao DB. microRNA-126 targeting PIK3R2 promotes rheumatoid arthritis synovial fibro-blasts proliferation and resistance to apoptosis by regulating PI3K/AKT pathway. Exp Mol Pathol. 2016;100(1):192–8.

    Article  CAS  PubMed  Google Scholar 

  18. Chen Y, Tang J, Lu T, Liu F. CAPN1 promotes malignant behavior and erlotinib resistance mediated by phosphorylation of c-Met and PIK3R2 via degrading PTPN1 in lung adenocarcinoma. Thorac Cancer. 2020;11(7):1848–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu N, Zhang D, Xie H, Zhou Z, Chen H, Hu T, et al. Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Mol Cell Biochem. 2011;351(1–2):157–64.

    Article  CAS  PubMed  Google Scholar 

  20. Meng F, Wang F, Wang L, Wong SC, Cho WC, Chan LW. MiR-30a-5p overexpression may overcome EGFR-inhibitor resistance through regulating PI3K/AKT signaling pathway in non-small cell lung cancer cell lines. Front Genet. 2016;7:197.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science (New York, NY). 2004;304(5670):554.

    Article  CAS  Google Scholar 

  22. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008;27(41):5486–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol (Baltimore, Md: 1950). 2017;198(3):1006–14.

    Article  CAS  Google Scholar 

  24. Li S, Jiang J, Yang Z, Li Z, Ma X, Li X. Cardiac progenitor cell-derived exosomes promote H9C2 cell growth via Akt/mTOR activation. Int J Mol Med. 2018;42(3):1517–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Barile E, De SK, Feng Y, Chen V, Yang L, Ronai Z, et al. Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma. Chem Biol Drug Des. 2013;82(5):520–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu M, Qi B, Xiaoxiang W, Xu J, Liu X. Baicalein increases cisplatin sensitivity of A549 lung adenocarcinoma cells via PI3K/Akt/NF-κB pathway. Biomed Pharmacother. 2017;90:677–85.

    Article  CAS  PubMed  Google Scholar 

  27. Chen H, Zhou L, Wu X, Li R, Wen J, Sha J, et al. The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci (Landmark edition). 2016;21:1084–91.

    Article  CAS  Google Scholar 

  28. Boussios S, Rassy E, Shah S, Ioannidou E, Sheriff M, Pavlidis N. Aberrations of DNA repair pathways in prostate cancer: a cornerstone of precision oncology. Expert Opin Ther Targets. 2021;25(5):329–33.

    Article  PubMed  Google Scholar 

  29. Revythis A, Shah S, Kutka M, Moschetta M, Ozturk MA, Pappas-Gogos G, et al. Unraveling the wide spectrum of melanoma biomarkers. Diagnostics (Basel, Switzerland). 2021;11(8):1341.

    CAS  PubMed  Google Scholar 

  30. Cao C, Su Y, Gao Y, Luo C, Yin L, Zhao Y, et al. Ginkgo biloba exocarp extract inhibits the metastasis of B16–F10 melanoma involving PI3K/Akt/NF-κB/MMP-9 signaling pathway. Evid Based Complement Altern Med. 2018;2018:4969028.

    Article  Google Scholar 

  31. Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR pathway in hormone-positive breast cancer. Drugs. 2020;80(16):1685–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pearlman RL, Montes de Oca MK, Pal HC, Afaq F. Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. Cancer lett. 2017;391:125–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Prasad P, Vasas A, Hohmann J, Bishayee A, Sinha D. Cirsiliol suppressed epithelial to mesenchymal transition in B16F10 malignant melanoma cells through alteration of the PI3K/Akt/NF-κB signaling pathway. Int J Mol Sci. 2019;20(3):608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was generously supported by the Natural Science Foundation of Jiangsu Province of China (Grant No.BK20191176 ), the Jiangsu Province Maternal and Child Health Research Project (Grant No. F202116), Gusu Health Talent Project of Suzhou City (Grant No.GSWS2020049), National Tutorial System Training Program for key Young Health Talents in Suzhou (Grant No. Qngg2021011), the Scientific Research Project of Jiangsu Health Commission (Grant No. M2022062), Suzhou Science and Technology Development Plan [People's Livelihood Science and Technology (Grant No. SYSD2019118, SYS2020151 and SYS2020161)], Suzhou Science and Technology Development Plan [Innovation in medical and health technology (Grant No. SKY2022055, SKY2022173, SKY2022174 and SKJYD2021093)] and Key Laboratory of Structural Deformities in Children of Suzhou (Grant No. SZS2022018. The funders had no role in the study design, data collection and analysis, decision to publish, or in the preparation of the manuscript.

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Author notes

  1. Jianguo Wang and Shizhong Cai contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Nanjing Pukou Central Hospital (Pukou Branch Hospital of Jiangsu Province Hospital), Nanjing, 211800, Jiangsu, People’s Republic of China

    Jianguo Wang & Deyu Weng

  2. Department of Child and Adolescent Healthcare, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, People’s Republic of China

    Shizhong Cai

  3. Department of Urology, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, People’s Republic of China

    Qianwei Xiong

  4. Department of Anesthesiology, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou, 215025, Jiangsu, People’s Republic of China

    Qian Wang

  5. Department of Burns and Plastic Surgery, Children’s Hospital of Soochow University, No. 92 Zhongnan Street, Suzhou, 215025, Jiangsu, People’s Republic of China

    Zhourui Ma

  6. Suzhou Key Laboratory of Structural Deformities in Children, No. 92 Zhongnan Street, Suzhou, 215025, Jiangsu, People’s Republic of China

    Shizhong Cai, Qianwei Xiong & Zhourui Ma

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  1. Jianguo Wang
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Correspondence to Qian Wang or Zhourui Ma.

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All animal research was conducted with the approval of the Ethics Committee of Nanjing Pukou Central Hospital (Pukou Branch Hospital of Jiangsu Province Hospital).

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All animal experiments were performed following the ARRIVE guidelines (https://arriveguidelines.org).

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Wang, J., Cai, S., Xiong, Q. et al. PIK3R2 predicts poor outcomes for patients with melanoma and contributes to the malignant progression via PI3K/AKT/NF-κB axis. Clin Transl Oncol 25, 1402–1412 (2023). https://doi.org/10.1007/s12094-022-03036-x

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  • DOI: https://doi.org/10.1007/s12094-022-03036-x

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