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Transcriptional profiling revealed the anti-proliferative effect of MFN2 deficiency and identified risk factors in lung adenocarcinoma

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Tumor Biology

Abstract

Mitofusin-2 (MFN2) was initially identified as a hyperplasia suppressor in hyper-proliferative vascular smooth muscle cells (VSMCs) of hypertensive rat arteries, which has also been implicated in various cancers. There exists a controversy in whether it is an oncogene or exerting anti-proliferative effect on tumor cells. Our previous cell cycle analysis and MTT assay showed that cell proliferation was inhibited in MFN2 deficient A549 human lung adenocarcinoma cells, without investigating the changes in regulatory network or addressing the underlying mechanisms. Here, we performed expression profiling in MFN2 knockdown A549 cells and found that cancer-related pathways were among the most susceptible pathways to MFN2 deficiency. Through comparison with expression profiling of a cohort consisting of 61 pairs of tumor-normal matched samples from The Cancer Genome Atlas (TCGA), we teased out the specific pathways to address the impact that MFN2 ablation had on A549 cells, as well as identified a few genes whose expression level associated with clinicopathologic parameters. In addition, transcriptional factor target enrichment analysis identified E2F as a potential transcription factor that was deregulated in response to MFN2 deficiency. Although bioinformatics analysis usually entail further verification, our study provided considerable information for future scientific inquiries in related areas as well as a paradigm for characterizing perturbation in regulatory network.

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References

  1. Sakashita S, Sakashita M, Sound Tsao M. Genes and pathology of non-small cell lung carcinoma. Semin Oncol. 2014;41(1):28–39.

    Article  CAS  PubMed  Google Scholar 

  2. Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  3. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GRJ, Tsao A, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1):44–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hanahan D, R. a W. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  5. Sholl LM. Biomarkers in lung adenocarcinoma: a decade of progress. Arch Pathol Lab Med. 2015;139(4):469–80.

    Article  PubMed  Google Scholar 

  6. Chen K-H, Guo X, Ma D, Guo Y, Li Q, Yang D, et al. Dysregulation of HSG triggers vascular proliferative disorders. Nat Cell Biol. 2004;6(9):872–83.

    Article  CAS  PubMed  Google Scholar 

  7. Hall a R, Burke N, Dongworth RK, Hausenloy DJ. Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol. 2014;171(8):1890–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456(7222):605–10.

    Article  PubMed  Google Scholar 

  9. Wang R, He J, Li J-J, Ni W, Wu Z-Y, Chen W-J, et al. Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease. Clin Chim Acta. 2015;451(Pt B):263–70.

    Article  CAS  PubMed  Google Scholar 

  10. Lv H, Wang L, Zhang W, Wang Z, Zuo Y, Liu J, et al. A cohort study of Han Chinese MFN2-related Charcot-Marie-Tooth 2A. J Neurol Sci. 2015;358(1-2):153–7.

    Article  PubMed  Google Scholar 

  11. Stuppia G, Rizzo F, Riboldi G, Del Bo R, Nizzardo M, Simone C, et al. MFN2-related neuropathies: clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci. 2015;356(1–2):7–18.

    Article  CAS  PubMed  Google Scholar 

  12. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160(2):189–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang G-E, Jin H-L, Lin X-K, Chen C, Liu X-S, Zhang Q, et al. Anti-tumor effects of mfn2 in gastric cancer. Int J Mol Sci. 2013;14(7):13005–21.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen KH, Dasgupta A, Ding J, Indig FE, Ghosh P, Longo DL. Role of mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J. 2014;28(1):382–94.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang W, Lu J, Zhu F, Wei J, Jia C, Zhang Y, et al. Pro-apoptotic and anti-proliferative effects of mitofusin-2 via Bax signaling in hepatocellular carcinoma cells. Med Oncol. 2012;29(1):70–6.

    Article  PubMed  Google Scholar 

  16. Ding Y, Gao H, Zhao L, Wang X, Zheng M. Mitofusin 2-deficiency suppresses cell proliferation through disturbance of autophagy. PLoS One. 2015;10(3):e0121328.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lou Y, Li R, Liu J, Zhang Y, Zhang X, Jin B, et al. Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma. Med Oncol. 2015;32(4):132.

    Article  PubMed  Google Scholar 

  18. Wang L, Zhou G-B, Liu P, Song J-H, Liang Y, Yan X-J, et al. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci U S A. 2008;105(12):4826–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang B, Kirov S, Snoddy J. WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 2005;33(Web Server issue):W741–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walter W, Sanchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015;31(17):2912–4.

    Article  CAS  PubMed  Google Scholar 

  21. Kamburov A, Pentchev K, Galicka H, Wierling C, Lehrach H, Herwig R. ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. 2011;39 suppl 1:D712–7.

    Article  CAS  PubMed  Google Scholar 

  22. Kamburov A, Wierling C, Lehrach H, Herwig R. ConsensusPathDB—a database for integrating human functional interaction networks. Nucleic Acids Res. 2009;37(Database issue):D623–8.

    Article  CAS  PubMed  Google Scholar 

  23. Nishimura D. BioCarta. Biotech Softw Internet Rep Comput Softw J Sci. 2001;2(3):117–20.

    Article  Google Scholar 

  24. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Joshi-Tope G, Gillespie M, Vastrik I, D’Eustachio P, Schmidt E, de Bono B, et al. Reactome: a knowledgebase of biological pathways. Nucleic Acids Res. 2005;33 suppl 1:D428–32.

    CAS  PubMed  Google Scholar 

  26. Frolkis A, Knox C, Lim E, Jewison T, Law V, Hau DD, et al. SMPDB: the small molecule pathway database. Nucleic Acids Res. 2010;38 suppl 1:D480–7.

    Article  CAS  PubMed  Google Scholar 

  27. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010;11(1):R3.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pico AR, Kelder T, Van Iersel MP, Hanspers K, Conklin BR, Evelo C. WikiPathways: pathway editing for the people. PLoS Biol. 2008;6(7):e184.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12(8):564–71.

    Article  CAS  PubMed  Google Scholar 

  30. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008;68(5):1303–9.

    Article  CAS  PubMed  Google Scholar 

  31. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.

    Article  CAS  PubMed  Google Scholar 

  32. Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC, et al. Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene. 2004;23:3689–99. December 2003.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang C, Guo H, Li B, Sui C, Zhang Y, Xia X, et al. Effects of Slit3 silencing on the invasive ability of lung carcinoma A549 cells. Oncol Rep. 2015;34(2):952–60.

    CAS  PubMed  Google Scholar 

  34. Sharma J, Gray KP, Harshman LC, Evan C, Nakabayashi M, Fichorova R, et al. Elevated IL-8, TNF-α, and MCP-1 in men with metastatic prostate cancer starting androgen-deprivation therapy (ADT) are associated with shorter time to castration-resistance and overall survival. Prostate. 2014;74(8):820–8.

    Article  CAS  PubMed  Google Scholar 

  35. Wang H, Meyer CA, Fei T, Wang G, Zhang F, 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. 2013;14:680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sharma J, Gray KP, Evan C, Nakabayashi M, Fichorova R, Rider J, et al. Elevated insulin-like growth factor binding protein-1 (IGFBP-1) in men with metastatic prostate cancer starting androgen deprivation therapy (ADT) is associated with shorter time to castration resistance and overall survival. Prostate. 2014;74(3):225–34.

    Article  CAS  PubMed  Google Scholar 

  37. Ell B, Kang Y. Transcriptional control of cancer metastasis. Trends Cell Biol. 2013;23(12):603–11.

    Article  CAS  PubMed  Google Scholar 

  38. Lee H-J, Yun C-H, Lim SH, Kim B-C, Baik KG, Kim J-M, et al. SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling. Oncogene. 2007;26(2):173–85.

    Article  CAS  PubMed  Google Scholar 

  39. Khatri P, Sirota M, Butte AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS Comput Biol. 2012;8(2):e1002375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ozcan U. XMitofusins: mighty regulators of metabolism. Cell. 2013;155(1):17–8.

    Article  CAS  PubMed  Google Scholar 

  41. Rhodes DR, Chinnaiyan AM. Integrative analysis of the cancer transcriptome. Nat Genet. 2005;37:S31–7.

    Article  CAS  PubMed  Google Scholar 

  42. Murohashi M, Hinohara K, Kuroda M, Isagawa T, Tsuji S, Kobayashi S, et al. Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells. Br J Cancer. 2010;102(1):206–12.

    Article  CAS  PubMed  Google Scholar 

  43. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Furusawa Y, Uruno A, Yagishita Y, Higashi C, Yamamoto M. Nrf2 induces fibroblast growth factor 21 in diabetic mice. Genes to Cells. 2014;19(12):864–78.

    Article  CAS  PubMed  Google Scholar 

  45. Nasrallah CM, Horvath TL. Mitochondrial dynamics in the central regulation of metabolism. Nat Rev Endocrinol. 2014;10(11):650–8.

    Article  CAS  PubMed  Google Scholar 

  46. Kawalec M, Boratyńska-Jasińska A, Beręsewicz M, Dymkowska D, Zabłocki K, Zabłocka B. Mitofusin 2 deficiency affects energy metabolism and mitochondrial biogenesis in MEF cells. PLoS One. 2015;10(7):e0134162.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32(40):4814–24.

    Article  CAS  PubMed  Google Scholar 

  48. Takai D, Yagi Y, Wakazono K, Ohishi N, Morita Y, Sugimura T, et al. Silencing of HTR1B and reduced expression of EDN1 in human lung cancers, revealed by methylation-sensitive representational difference analysis. Oncogene. 2001;20(51):7505–13.

    Article  CAS  PubMed  Google Scholar 

  49. Lu J-W, Liao C-Y, Yang W-Y, Lin Y-M, Jin S-LC, Wang H-D, et al. Overexpression of endothelin 1 triggers hepatocarcinogenesis in Zebrafish and promotes cell proliferation and migration through the AKT Pathway. PLoS One. 2014;1:e85318.

    Article  Google Scholar 

  50. Younes M, Wu Z, Dupouy S, Lupo AM, Mourra N, Takahashi T, et al. Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib. Oncotarget. 2014;5(18):8252.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER, et al. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res. 2002;62(20):5874–80.

    CAS  PubMed  Google Scholar 

  52. Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F. Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene. 2003;22(29):4611–6.

    Article  CAS  PubMed  Google Scholar 

  53. Dickinson RE, Dallol A, Bieche I, Krex D, Morton D, Maher ER, et al. Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers. Br J Cancer. 2004;91(12):2071–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tseng R-C, Lee S-H, Hsu H-S, Chen B-H, Tsai W-C, Tzao C, et al. SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res. 2010;70(2):543–51.

    Article  CAS  PubMed  Google Scholar 

  55. Thakur A, Bollig A, Wu J, Liao DJ. Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice. Mol Cancer. 2008;7:11.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhang X, Yee D. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility. Cancer Res. 2002;62(15):4369–75.

    CAS  PubMed  Google Scholar 

  57. Chen H-Z, Tsai S-Y, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9(11):785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bertino JR, Banerjee D, Minko T, Garbuzenko OB, Xie X, Kerrigan JE, et al. E2F as a target of hormone refractory prostate cancer. Google Patents. 2014.

  59. Zhao X, He L, Li T, Lu Y, Miao Y, Liang S, et al. SRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer. Cell Death Differ. 2014;21(12):1900–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science foundation of China (81201839, 81572249, 81402378, and 81472642), the Research Project of Shanghai Municipal Commission of Health and Family Planning (20124Y108 and 201440032), the Excellent Young Teachers Program of Shanghai Jiaotong University School of Medicine, and Shanghai international cooperation project of science and technology (14430723300).

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    1. Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai, 200030, People’s Republic of China

      Yuqing Lou, Yanwei Zhang, Rong Li, Ping Gu, Liwen Xiong, Hua Zhong, Wei Zhang & Baohui Han

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    1. Yuqing Lou
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    2. Yanwei Zhang
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    Correspondence to Wei Zhang or Baohui Han.

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    Yuqing Lou and Yanwei Zhang contributed equally to this work.

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    Lou, Y., Zhang, Y., Li, R. et al. Transcriptional profiling revealed the anti-proliferative effect of MFN2 deficiency and identified risk factors in lung adenocarcinoma. Tumor Biol. 37, 8643–8655 (2016). https://doi.org/10.1007/s13277-015-4702-6

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