Loss of FGL1 induces epithelial‑mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma

  • Authors:
    • Fenglong Bie
    • Guanghui Wang
    • Xiao Qu
    • Yadong Wang
    • Cuicui Huang
    • Yu Wang
    • Jiajun Du
  • View Affiliations

  • Published online on: July 15, 2019     https://doi.org/10.3892/ijo.2019.4838
  • Pages: 697-707
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Abstract

Liver kinase b1 (LKB1) is a tumor suppressor, and the inactivated mutation frequency of LKB1 in lung adenocarcinoma is ~20%. The present study aimed to explore potential novel biomarkers in LKB1 mutant lung adenocarcinoma. Gene expression data from lung adenocarcinoma patients were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. R software was used to analyze the gene expression profiles. Reverse transcription‑quantitative PCR (RT‑qPCR), western blot and immunohistochemistry (IHC) analyses were used to examine gene expression and function. Gene function was further explored via gene set enrichment analysis. A colony formation assay was used to evaluate cell proliferation. A wound‑healing assay and immunofluorescence analysis were used to evaluate cell migration and epithelial‑mesenchymal transition (EMT), respectively. Wound healing assay, immunofluorescence, western blot, RT‑qPCR and IHC results for EMT‑associated markers demonstrated that a loss of fibrinogen‑like 1 (FGL1) induced EMT in LKB1 mutant lung adenocarcinoma. RT‑qPCR and IHC analyses of angiogenesis‑related markers revealed that loss of FGL1 promoted angiogenesis in LKB1 mutant lung adenocarcinoma. Overall, the present results demonstrated that loss of FGL1 induced EMT and angiogenesis in LKB1 mutant lung adenocarcinoma. FGL1 may be a novel biomarker to indicate EMT and angiogenesis in patients with LKB1 mutant lung adenocarcinoma.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI

3 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 378:113–125. 2018. View Article : Google Scholar

5 

Dai C, Shen J, Ren Y, Zhong S, Zheng H, He J, Xie D, Fei K, Liang W, Jiang G, et al: Choice of surgical procedure for patients eith mon-dmall-vell lung vancer ≤1 cm or >1 to 2 cm smong lobectomy, segmentectomy, and wedge resection: A Population-based study. J Clin Oncol. 34:3175–3182. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Höglund P, et al: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 391:184–187. 1998. View Article : Google Scholar : PubMed/NCBI

7 

Cancer Genome Atlas Research Network: Comprehensive molecular profiling of lung adenocarcinoma. Nature. 511:543–550. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Mihaylova MM and Shaw RJ: The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 13:1016–1023. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Wodarz A and Näthke I: Cell polarity in development and cancer. Nat Cell Biol. 9:1016–1024. 2007. View Article : Google Scholar : PubMed/NCBI

10 

Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, Buttarazzi MS, Sanofsky BA, McNamara KL, Brandstetter KA, et al: Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell. 17:547–559. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Contreras CM, Akbay EA, Gallardo TD, Haynie JM, Sharma S, Tagao O, Bardeesy N, Takahashi M, Settleman J, Wong KK, et al: Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor mono-therapy. Dis Model Mech. 3:181–193. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Yamamoto T, Gotoh M, Sasaki H, Terada M, Kitajima M and Hirohashi S: Molecular cloning and initial characterization of a novel fibrinogen-related gene, HFREP-1. Biochem Biophys Res Commun. 193:681–687. 1993. View Article : Google Scholar : PubMed/NCBI

13 

Rijken DC, Dirkx SP, Luider TM and Leebeek FW: Hepatocyte-derived fibrinogen-related protein-1 is associated with the fibrin matrix of a plasma clot. Biochem Biophys Res Commun. 350:191–194. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Nayeb-Hashemi H, Desai A, Demchev V, Bronson RT, Hornick JL, Cohen DE and Ukomadu C: Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. Biochem Biophys Res Commun. 465:167–173. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C and Stuart JM; Cancer Genome Atlas Research Network: The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 45:1113–1120. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, et al: NCBI GEO: Archive for functional genomics data sets - update. Nucleic Acids Res. 41:D991–D995. 2013. View Article : Google Scholar

17 

Schabath MB, Welsh EA, Fulp WJ, Chen L, Teer JK, Thompson ZJ, Engel BE, Xie M, Berglund AE, Creelan BC, et al: Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene. 35:3209–3216. 2016. View Article : Google Scholar :

18 

Girard L, Rodriguez-Canales J, Behrens C, Thompson DM, Botros IW, Tang H, Xie Y, Rekhtman N, Travis WD, Wistuba II, et al: An expression signature as an aid to the histologic classification of non-small cell lung cancer. Clin Cancer Res. 22:4880–4889. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

20 

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 102:15545–15550. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, et al: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 34:267–273. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Yan TD, Black D, Bannon PG and McCaughan BC: Systematic review and meta-analysis of randomized and nonrandomized trials on safety and efficacy of video-assisted thoracic surgery lobectomy for early-stage non-small-cell lung cancer. J Clin Oncol. 27:2553–2562. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Na F, Wang J, Li C, Deng L, Xue J and Lu Y: Primary tumor standardized uptake value measured on F18-Fluorodeoxyglucose positron emission tomography is of prediction value for survival and local control in non-small-cell lung cancer receiving radiotherapy: meta-analysis. J Thorac Oncol. 9:834–842. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Rossi A, Chiodini P, Sun JM, O'Brien ME, von Plessen C, Barata F, Park K, Popat S, Bergman B, Parente B, et al: Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data. Lancet Oncol. 15:1254–1262. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Blumenthal GM, Zhang L, Zhang H, Kazandjian D, Khozin S, Tang S, Goldberg K, Sridhara R, Keegan P and Pazdur R: Milestone analyses of immune checkpoint inhibitors, targeted therapy, and conventional therapy in metastatic non-small cell lung cancer trials: A Meta-analysis. JAMA Oncol. 3:e1710292017. View Article : Google Scholar : PubMed/NCBI

26 

Kulkarni S, Vella E, Coakley N, Cheng S, Gregg R, Ung Y and Ellis PM: The use of systemic treatment in the maintenance of patients with non-small cell lung cancer: A systematic review. J Thorac Oncol. 11:989–1002. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Zer A, Ding K, Lee S, Goss G, Seymour L, Ellis P, Hackshaw A, Bradbury PA, Han L, O'Callaghan CJ, et al: Pooled analysis of the prognostic and predictive value of KRAS mutation status and mutation subtype in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol. 11:312–323. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Qiu F, Yang L, Ling X, Yang R, Yang X, Zhang L, Fang W, Xie C, Huang D, Zhou Y, et al: Sequence variation in mature MicroRNA-499 confers unfavorable prognosis of lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 21:1602–1613. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Tang H, Wang S, Xiao G, Schiller J, Papadimitrakopoulou V, Minna J, Wistuba II and Xie Y: Comprehensive evaluation of published gene expression prognostic signatures for biomarker-based lung cancer clinical studies. Ann Oncol. 28:733–740. 2017. View Article : Google Scholar : PubMed/NCBI

30 

Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: Metabolism and growth control in tumour suppression. Nat Rev Cancer. 9:563–575. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, Westra WH, Herman JG and Sidransky D: Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62:3659–3662. 2002.PubMed/NCBI

32 

Fang R, Zheng C, Sun Y, Han X, Gao B, Li C, Liu H, Wong KK, Liu XY, Chen H, et al: Integrative genomic analysis reveals a high frequency of LKB1 genetic alteration in Chinese lung adenocarcinomas. J Thorac Oncol. 9:254–258. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Calles A, Sholl LM, Rodig SJ, Pelton AK, Hornick JL, Butaney M, Lydon C, Dahlberg SE, Oxnard GR, Jackman DM, et al: Immunohistochemical loss of LKB1 is a biomarker for more aggressive biology in KRAS-mutant lung adenocarcinoma. Clin Cancer Res. 21:2851–2860. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Gao B, Sun Y, Zhang J, Ren Y, Fang R, Han X, Shen L, Liu XY, Pao W, Chen H, et al: Spectrum of LKB1, EGFR, and KRAS mutations in chinese lung adenocarcinomas. J Thorac Oncol. 5:1130–1135. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, et al: LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 23:143–158. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Demchev V, Malana G, Vangala D, Stoll J, Desai A, Kang HW, Li Y, Nayeb-Hashemi H, Niepel M, Cohen DE, et al: Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. PLoS One. 8:e580842013. View Article : Google Scholar : PubMed/NCBI

37 

Zou Z, Cai Y and Chen Y, Chen S, Liu L, Shen Z, Zhang S, Xu L and Chen Y: Bone marrow-derived mesenchymal stem cells attenuate acute liver injury and regulate the expression of fibrinogen-like-protein 1 and signal transducer and activator of transcription 3. Mol Med Rep. 12:2089–2097. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Wang H, Meyer CA, Fei T, Wang G, Zhang F and Liu XS: A systematic approach identifies FOXA1 as a key factor in the loss of epithelial traits during the epithelial-to-mesenchymal transition in lung cancer. BMC Genomics. 14:6802013. View Article : Google Scholar : PubMed/NCBI

39 

Çeliktas M, Tanaka I, Tripathi SC, Fahrmann JF, Aguilar-Bonavides C, Villalobos P, Delgado O, Dhillon D, Dennison JB, Ostrin EJ, et al: Role of CPS1 in cell growth, metabolism and prognosis in LKB1-inactivated lung adenocarcinoma. J Natl Cancer Inst. 109:1–9. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Okon IS, Coughlan KA, Zhang C, Moriasi C, Ding Y, Song P, Zhang W, Li G and Zou MH: Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J Clin Invest. 124:4590–4602. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Roy BC, Kohno T, Iwakawa R, Moriguchi T, Kiyono T, Morishita K, Sanchez-Cespedes M, Akiyama T and Yokota J: Involvement of LKB1 in epithelial-mesenchymal transition (EMT) of human lung cancer cells. Lung Cancer. 70:136–145. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA and Cantley LC: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 101:3329–3335. 2004. View Article : Google Scholar : PubMed/NCBI

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September 2019
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Copy and paste a formatted citation
APA
Bie, F., Wang, G., Qu, X., Wang, Y., Huang, C., Wang, Y., & Du, J. (2019). Loss of FGL1 induces epithelial‑mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma. International Journal of Oncology, 55, 697-707. https://doi.org/10.3892/ijo.2019.4838
MLA
Bie, F., Wang, G., Qu, X., Wang, Y., Huang, C., Wang, Y., Du, J."Loss of FGL1 induces epithelial‑mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma". International Journal of Oncology 55.3 (2019): 697-707.
Chicago
Bie, F., Wang, G., Qu, X., Wang, Y., Huang, C., Wang, Y., Du, J."Loss of FGL1 induces epithelial‑mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma". International Journal of Oncology 55, no. 3 (2019): 697-707. https://doi.org/10.3892/ijo.2019.4838