NPM3 as an Unfavorable Prognostic Biomarker Involved in Oncogenic Pathways of Lung Adenocarcinoma via MYC Translational Activation


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Abstract

Background:The nucleoplasmin/nucleophosmin (NPM) family was previously regarded as a critical regulator during disease development, and its mediation in carcinogenesis has achieved intensive attention recently. However, the clinical importance and functional mechanism of NPM3 in lung adenocarcinoma (LUAD) have not been reported yet.

Objective:This study aimed to investigate the role and clinical significance of NPM3 in the development and progression of LUAD, including the underlying mechanisms.

Methods:The expression of NPM3 in pan-cancer was analyzed via GEPIA. The effect of NPM3 on prognosis was analyzed by the Kaplan-Meier plotter and the PrognoScan database. In vitro, cell transfection, RT-qPCR, CCK-8 assay, and wound healing assay were employed to examine the role of NPM3 in A549 and H1299 cells. Gene set enrichment analysis (GSEA) was performed using the R software package to analyze the tumor hallmark pathway and KEGG pathway of NPM3. The transcription factors of NPM3 were predicted based on the ChIP-Atlas database. Dual-luciferase reporter assay was applied to verify the transcriptional regulatory factor of the NPM3 promoter region.

Results:The NPM3 expression was found to be markedly higher in the LUAD tumor group than the normal group and to be positively correlated with poor prognosis, tumor stages, and radiation therapy. In vitro, the knockdown of NPM3 greatly inhibited the proliferation and migration of A549 and H1299 cells. Mechanistically, GSEA predicted that NPM3 activated the oncogenic pathways. Further, the NPM3 expression was found to be positively correlated with cell cycle, DNA replication, G2M checkpoint, HYPOXIA, MTORC1 signaling, glycolysis, and MYC targets. Besides, MYC targeted the promoter region of NPM3 and contributed to the enhanced expression of NPM3 in LUAD.

Conclusion:The overexpression of NPM3 is an unfavorable prognostic biomarker participating in oncogenic pathways of LUAD via MYC translational activation and it contributes to tumor progression. Thus, NPM3 could be a novel target for LUAD therapy.

About the authors

Long Chen

Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)

Email: info@benthamscience.net

Demeng Yang

Faculty of College of Food and Pharmaceutical Sciences, Ningbo University

Email: info@benthamscience.net

Fen Huang

Department of Operating Room, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College),

Email: info@benthamscience.net

Weicai Xu

Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)

Email: info@benthamscience.net

Xiaopan Luo

Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)

Email: info@benthamscience.net

Lili Mei

, Kunming University of Science and Technology

Author for correspondence.
Email: info@benthamscience.net

Ying He

Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)

Author for correspondence.
Email: info@benthamscience.net

References

  1. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33. doi: 10.3322/caac.21654 PMID: 33433946
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  3. Succony, L.; Rassl, D.M.; Barker, A.P.; McCaughan, F.M.; Rintoul, R.C. Adenocarcinoma spectrum lesions of the lung: Detection, pathology and treatment strategies. Cancer Treat. Rev., 2021, 99, 102237. doi: 10.1016/j.ctrv.2021.102237 PMID: 34182217
  4. Denisenko, T.V.; Budkevich, I.N.; Zhivotovsky, B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis., 2018, 9(2), 117. doi: 10.1038/s41419-017-0063-y PMID: 29371589
  5. Ettinger, D.S.; Wood, D.E.; Aisner, D.L.; Akerley, W.; Bauman, J.; Chirieac, L.R.; D’Amico, T.A.; DeCamp, M.M.; Dilling, T.J.; Dobelbower, M.; Doebele, R.C.; Govindan, R.; Gubens, M.A.; Hennon, M.; Horn, L.; Komaki, R.; Lackner, R.P.; Lanuti, M.; Leal, T.A.; Leisch, L.J.; Lilenbaum, R.; Lin, J.; Loo, B.W., Jr; Martins, R.; Otterson, G.A.; Reckamp, K.; Riely, G.J.; Schild, S.E.; Shapiro, T.A.; Stevenson, J.; Swanson, S.J.; Tauer, K.; Yang, S.C.; Gregory, K.; Hughes, M. Non–small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw., 2017, 15(4), 504-535. doi: 10.6004/jnccn.2017.0050 PMID: 28404761
  6. Xing, P.; Wang, S.; Wang, Q.; Ma, D.; Hao, X.; Wang, M.; Wang, Y.; Shan, L.; Xin, T.; Liang, L.; Liang, H.; Du, Y.; Zhang, Z.; Li, J. Efficacy of crizotinib for advanced ALK-rearranged non-small-cell lung cancer patients with brain metastasis: A multicenter, retrospective study in china. Target. Oncol., 2019, 14(3), 325-333. doi: 10.1007/s11523-019-00637-5 PMID: 31025247
  7. Jonna, S.; Subramaniam, D.S. Molecular diagnostics and targeted therapies in non-small cell lung cancer (NSCLC): An update. Discov. Med., 2019, 27(148), 167-170. PMID: 31095926
  8. Darracq, A.; Pak, H.; Bourgoin, V.; Zmiri, F.; Dellaire, G.; Affar, E.B.; Milot, E. NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes. PLoS Genet., 2019, 15(11), e1008463. doi: 10.1371/journal.pgen.1008463 PMID: 31675375
  9. Martelli, M.P.; Rossi, R.; Venanzi, A.; Meggendorfer, M.; Perriello, V.M.; Martino, G.; Spinelli, O.; Ciurnelli, R.; Varasano, E.; Brunetti, L.; Ascani, S.; Quadalti, C.; Cardinali, V.; Mezzasoma, F.; Gionfriddo, I.; Milano, F.; Pacini, R.; Tabarrini, A.; Bigerna, B.; Albano, F.; Specchia, G.; Vetro, C.; Di Raimondo, F.; Annibali, O.; Avvisati, G.; Rambaldi, A.; Falzetti, F.; Tiacci, E.; Sportoletti, P.; Haferlach, T.; Haferlach, C.; Falini, B. Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML. Blood, 2021, 138(25), 2696-2701. doi: 10.1182/blood.2021012732 PMID: 34343258
  10. Liu, X.; Liu, D.; Qian, D.; Dai, J.; An, Y.; Jiang, S.; Stanley, B.; Yang, J.; Wang, B.; Liu, X.; Liu, D.X. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J. Biol. Chem., 2012, 287(23), 19599-19609. doi: 10.1074/jbc.M112.363622 PMID: 22528486
  11. Karimi Dermani, F.; Gholamzadeh Khoei, S.; Afshar, S.; Amini, R. The potential role of nucleophosmin (NPM1) in the development of cancer. J. Cell. Physiol., 2021, 236(11), 7832-7852. doi: 10.1002/jcp.30406 PMID: 33959979
  12. Liu, X.S.; Zhou, L.M.; Yuan, L.L.; Gao, Y.; Kui, X.Y.; Liu, X.Y.; Pei, Z.J. NPM1 is a prognostic biomarker involved in immune infiltration of lung adenocarcinoma and associated with m6a modification and glycolysis. Front. Immunol., 2021, 12, 724741. doi: 10.3389/fimmu.2021.724741 PMID: 34335635
  13. Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102. doi: 10.1093/nar/gkx247 PMID: 28407145
  14. Lánczky, A.; Nagy, Á.; Bottai, G.; Munkácsy, G.; Szabó, A.; Santarpia, L. Győrffy, B. miRpower: A web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res. Treat., 2016, 160(3), 439-446. doi: 10.1007/s10549-016-4013-7 PMID: 27744485
  15. Ghaffarnia, R.; Nasrollahzadeh, A.; Bashash, D.; Nasrollahzadeh, N.; Mousavi, S.A.; Ghaffari, S.H. Inhibition of c-Myc using 10058-F4 induces anti-tumor effects in ovarian cancer cells via regulation of FOXO target genes. Eur. J. Pharmacol., 2021, 908, 174345. doi: 10.1016/j.ejphar.2021.174345 PMID: 34270986
  16. Cao, W.; Chen, H.D.; Yu, Y.W.; Li, N.; Chen, W.Q. Changing profiles of cancer burden worldwide and in China: A secondary analysis of the global cancer statistics 2020. Chin. Med. J., 2021, 134(7), 783-791. doi: 10.1097/CM9.0000000000001474 PMID: 33734139
  17. Herbst, R.S.; Morgensztern, D.; Boshoff, C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689), 446-454. doi: 10.1038/nature25183 PMID: 29364287
  18. Chen, J.; Yang, H.; Teo, A.S.M.; Amer, L.B.; Sherbaf, F.G.; Tan, C.Q.; Alvarez, J.J.S.; Lu, B.; Lim, J.Q.; Takano, A.; Nahar, R.; Lee, Y.Y.; Phua, C.Z.J.; Chua, K.P.; Suteja, L.; Chen, P.J.; Chang, M.M.; Koh, T.P.T.; Ong, B.H.; Anantham, D.; Hsu, A.A.L.; Gogna, A.; Too, C.W.; Aung, Z.W.; Lee, Y.F.; Wang, L.; Lim, T.K.H.; Wilm, A.; Choi, P.S.; Ng, P.Y.; Toh, C.K.; Lim, W.T.; Ma, S.; Lim, B.; Liu, J.; Tam, W.L.; Skanderup, A.J.; Yeong, J.P.S.; Tan, E.H.; Creasy, C.L.; Tan, D.S.W.; Hillmer, A.M.; Zhai, W. Genomic landscape of lung adenocarcinoma in East Asians. Nat. Genet., 2020, 52(2), 177-186. doi: 10.1038/s41588-019-0569-6 PMID: 32015526
  19. Huang, N.; Negi, S.; Szebeni, A.; Olson, M.O.J. Protein NPM3 interacts with the multifunctional nucleolar protein B23/nucleophosmin and inhibits ribosome biogenesis. J. Biol. Chem., 2005, 280(7), 5496-5502. doi: 10.1074/jbc.M407856200 PMID: 15596447
  20. Murga-Zamalloa, C.A.; Mendoza-Reinoso, V.; Sahasrabuddhe, A.A.; Rolland, D.; Hwang, S.R.; McDonnell, S.R.P.; Sciallis, A.P.; Wilcox, R.A.; Bashur, V.; Elenitoba-Johnson, K.; Lim, M.S. NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma. Oncogene, 2017, 36(15), 2085-2094. doi: 10.1038/onc.2016.366 PMID: 27694894
  21. Ding, A.; Zhao, W.; Shi, X.; Yao, R.; Zhou, F.; Yue, L.; Liu, S.; Qiu, W. Impact of NPM, TFF3 and TACC1 on the prognosis of patients with primary gastric cancer. PLoS One, 2013, 8(12), e82136. doi: 10.1371/journal.pone.0082136 PMID: 24358147
  22. Lu, Y.C.; Wang, P.; Wang, J.; Ma, R.; Lee, S.C. PCNA and JNK1 Stat3 pathways respectively promotes and inhibits diabetes associated centrosome amplification by targeting at the ROCK1/14‐3‐3σ complex in human colon cancer HCT116 cells. J. Cell. Physiol., 2019, 234(7), 11511-11523. doi: 10.1002/jcp.27813 PMID: 30478982
  23. Dai, L.; Li, J.; Xing, M.; Sanchez, T.W.; Casiano, C.A.; Zhang, J.Y. Using serological proteome analysis to identify serum anti-nucleophosmin 1 autoantibody as a potential biomarker in european-american and african-american patients with prostate cancer. Prostate, 2016, 76(15), 1375-1386. doi: 10.1002/pros.23217 PMID: 27418398
  24. Masiuk, M.; Lewandowska, M.; Dobak, E.; Urasinska, E. Nucleolin and nucleophosmin expression in gleason 3 and gleason 4 prostate cancer with seminal vesicles invasion (pT3b). Anticancer Res., 2020, 40(4), 1973-1979. doi: 10.21873/anticanres.14152 PMID: 32234886
  25. Sawazaki, H.; Ito, K.; Asano, T.; Kuroda, K.; Horiguchi, A.; Tsuda, H.; Asano, T. Expressions of P-Glycoprotein, multidrug resistance protein 1 and annexin A2 as predictive factors for intravesical recurrence of bladder cancer after the initial transurethral resection and immediate single intravesical instillation of adriamycin. Asian Pac. J. Cancer Prev., 2021, 22(5), 1459-1466. doi: 10.31557/APJCP.2021.22.5.1459 PMID: 34048174
  26. Gerard, R.D.; Gluzman, Y. New host cell system for regulated simian virus 40 DNA replication. Mol. Cell. Biol., 1985, 5(11), 3231-3240. PMID: 3018509
  27. Qin, J.; Wang, S.; Shi, J.; Ma, Y.; Wang, K.; Ye, H.; Zhang, X.; Wang, P.; Wang, X.; Song, C.; Dai, L.; Wang, K.; Jiang, B.; Zhang, J. Using recursive partitioning approach to select tumor associated antigens in immunodiagnosis of gastric adenocarcinoma. Cancer Sci., 2019, 110(6), 1829-1841. doi: 10.1111/cas.14013 PMID: 30950146
  28. Wang, X.; Xiao, H.; Wu, D.; Zhang, D.; Zhang, Z. miR-335-5p regulates cell cycle and metastasis in lung adenocarcinoma by targeting CCNB2. OncoTargets Ther., 2020, 13, 6255-6263. doi: 10.2147/OTT.S245136 PMID: 32636645
  29. Ma, C.; Luo, H.; Cao, J.; Gao, C.; Fa, X.; Wang, G. Independent prognostic implications of RRM2 in lung adenocarcinoma. J. Cancer, 2020, 11(23), 7009-7022. doi: 10.7150/jca.47895 PMID: 33123291
  30. Shi, R.; Bao, X.; Unger, K.; Sun, J.; Lu, S.; Manapov, F.; Wang, X.; Belka, C.; Li, M. Identification and validation of hypoxia-derived gene signatures to predict clinical outcomes and therapeutic responses in stage I lung adenocarcinoma patients. Theranostics, 2021, 11(10), 5061-5076. doi: 10.7150/thno.56202 PMID: 33754044
  31. Kopeková, J.; Lenártová, P.; Mrázová, J.; Gaarová, M.; Higieny, K.J.J.R.P.Z. IThe relationship between seeds consumption, lipid profile and body mass index among patients with cardiovascular diseases. Rocz. Panstw. Zakl. Hig., 2021, 72(2), 145-145. doi: 10.32394/rpzh.2021.0159
  32. Zhang, L.; Zhang, Z.; Yu, Z. Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma. J. Transl. Med., 2019, 17(1), 423. doi: 10.1186/s12967-019-02173-2 PMID: 31847905
  33. Quintanal-Villalonga, A.; Taniguchi, H.; Zhan, Y.A.; Hasan, M.M.; Chavan, S.S.; Meng, F.; Uddin, F.; Allaj, V.; Manoj, P.; Shah, N.S.; Chan, J.M.; Ciampricotti, M.; Chow, A.; Offin, M.; Ray-Kirton, J.; Egger, J.D.; Bhanot, U.K.; Linkov, I.; Asher, M.; Roehrl, M.H.; Ventura, K.; Qiu, J.; de Stanchina, E.; Chang, J.C.; Rekhtman, N.; Houck-Loomis, B.; Koche, R.P.; Yu, H.A.; Sen, T.; Rudin, C.M. Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation. J. Hematol. Oncol., 2021, 14(1), 170. doi: 10.1186/s13045-021-01186-z PMID: 34656143
  34. Beer, S.; Zetterberg, A.; Ihrie, R.A.; McTaggart, R.A.; Yang, Q.; Bradon, N.; Arvanitis, C.; Attardi, L.D.; Feng, S.; Ruebner, B.; Cardiff, R.D.; Felsher, D.W. Developmental context determines latency of MYC-induced tumorigenesis. PLoS Biol., 2004, 2(11), e332. doi: 10.1371/journal.pbio.0020332 PMID: 15455033
  35. Wang, L.; Wang, H.; Wu, B.; Zhang, C.; Yu, H.; Li, X.; Wang, Q.; Shi, X.; Fan, C.; Wang, D.; Luo, J.; Yang, J. Long Noncoding RNA LINC00551 Suppresses Glycolysis and Tumor Progression by Regulating c-Myc-Mediated PKM2 Expression in Lung Adenocarcinoma. OncoTargets Ther., 2020, 13, 11459-11470. doi: 10.2147/OTT.S273797 PMID: 33204101
  36. Li, Z.; Hann, S.R. Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene 2013, 32(15), 1988-1994. doi: 10.1038/onc.2012.227 PMID: 22665062

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