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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

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

Author(s): Long Chen, Demeng Yang, Fen Huang, Weicai Xu, Xiaopan Luo, Lili Mei* and Ying He*

Volume 27, Issue 2, 2024

Published on: 22 May, 2023

Page: [203 - 213] Pages: 11

DOI: 10.2174/1386207326666230419080531

Price: $65

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.

Keywords: NPM3, lung adenocarcinoma, oncogenic pathways, prognostic biomarker, MYC translational activation, carcinogenesis.

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[1]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1038/onc.2012.227] [PMID: 22665062]

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