Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice

Oncogene volume 32, pages 2273–2281 (2013) Cite this article

Save article
View saved research

Abstract

Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses epidermal growth factor receptor (EGFR). However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 (30kDa HIV-1 Tat interacting protein) is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II (AT2) cells, and also increased expression of EGFR and its downstream signaling factors in the lung of Tip30−/− mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung, and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30-expression lung adenocarcinoma.

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news in related subjects.

Abbreviations

TIP30:

30kDa HIV-1 Tat interacting protein

EGFR:

epidermal growth factor receptor

References

  1. Jackson EL, Olive KP, Tuveson DA, Bronson R, Crowley D, Brown M et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res 2005; 65: 10280–10288.

    Article  CAS  Google Scholar 

  2. Tchou-Wong KM, Jiang Y, Yee H, LaRosa J, Lee TC, Pellicer A et al. Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer. Am J Respir Cell Mol Biol 2002; 27: 186–193.

    Article  CAS  Google Scholar 

  3. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001; 15: 3249–3262.

    Article  CAS  Google Scholar 

  4. Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 2001; 15: 3243–3248.

    Article  CAS  Google Scholar 

  5. Ehrhardt A, Bartels T, Geick A, Klocke R, Paul D, Halter R . Development of pulmonary bronchiolo-alveolar adenocarcinomas in transgenic mice overexpressing murine c-myc and epidermal growth factor in alveolar type II pneumocytes. Br J Cancer 2001; 84: 813–818.

    Article  CAS  Google Scholar 

  6. Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 2006; 9: 485–495.

    Article  CAS  Google Scholar 

  7. Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE . Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 2006; 20: 1496–1510.

    Article  CAS  Google Scholar 

  8. Berger AH, Niki M, Morotti A, Taylor BS, Socci ND, Viale A et al. Identification of DOK genes as lung tumor suppressors. Nat Genet 2010; 42: 216–223.

    Article  CAS  Google Scholar 

  9. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–144.

    Article  CAS  Google Scholar 

  10. Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Zaman M, Hoda S et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993; 53: 2379–2385.

    CAS  Google Scholar 

  11. Gazdar AF, Minna JD . Deregulated EGFR signaling during lung cancer progression: mutations, amplicons, and autocrine loops. Cancer Prev Res (Phila) 2008; 1: 156–160.

    Article  CAS  Google Scholar 

  12. Shtivelman E . A link between metastasis and resistance to apoptosis of variant small cell lung carcinoma. Oncogene 1997; 14: 2167–2173.

    Article  CAS  Google Scholar 

  13. Xiao H, Tao Y, Greenblatt J, Roeder RG . A cofactor, TIP30, specifically enhances HIV-1 Tat-activated transcription. Proc Natl Acad Sci USA 1998; 95: 2146–2151.

    Article  CAS  Google Scholar 

  14. Ito M, Jiang C, Krumm K, Zhang X, Pecha J, Zhao J et al. TIP30 deficiency increases susceptibility to tumorigenesis. Cancer Res 2003; 63: 8763–8767.

    CAS  PubMed  Google Scholar 

  15. Zhao J, Ni H, Ma Y, Dong L, Dai J, Zhao F et al. TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. Hu Pathol 2007; 38: 293–298.

    Article  CAS  Google Scholar 

  16. Chen X, Cao X, Dong W, Luo S, Suo Z, Jin Y . Expression of TIP30 tumor suppressor gene is down-regulated in human colorectal carcinoma. Dig Dis Sci 2006; 55: 2219–2226.

    Article  Google Scholar 

  17. Tong X, Li K, Luo Z, Lu B, Liu X, Wang T et al. Decreased TIP30 Expression Promotes Tumor Metastasis in Lung Cancer. Am J Pathol 2009; 174: 1931–1939.

    Article  CAS  Google Scholar 

  18. Pecha J, Ankrapp D, Jiang C, Tang W, Hoshino I, Bruck K et al. Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene 2007; 26: 7423–7431.

    Article  CAS  Google Scholar 

  19. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121: 823–835.

    Article  CAS  Google Scholar 

  20. Zhang C, Mori M, Gao S, Li A, Hoshino I, Aupperlee MD et al. Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors. Cancer Res 2010; 70: 10224–10233.

    Article  CAS  Google Scholar 

  21. Zhang C, Li A, Zhang X, Xiao H . A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation. J Biol Chem 2011; 286: 9373–9381.

    Article  CAS  Google Scholar 

  22. Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL et al. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 2008; 14: 822–827.

    Article  CAS  Google Scholar 

  23. Chen V, Shtivelman E . CC3/TIP30 regulates metabolic adaptation of tumor cells to glucose limitation. Cell Cycle 2010; 9: 4941–4953.

    Article  CAS  Google Scholar 

  24. Fong S, King F, Shtivelman E . CC3/TIP30 affects DNA damage repair. BMC Cell Biol 2010; 11: 23.

    Article  Google Scholar 

  25. Xiao H, Palhan V, Yang Y, Roeder RG . TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. EMBO J 2000; 19: 956–963.

    Article  CAS  Google Scholar 

  26. Jiang C, Ito M, Piening V, Bruck K, Roeder RG, Xiao H . TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription. J Biol Chem 2004; 279: 27781–27789.

    Article  CAS  Google Scholar 

  27. King FW, Shtivelman E . Inhibition of nuclear import by the proapoptotic protein CC3. Mol Cell Biol 2004; 24: 7091–7101.

    Article  CAS  Google Scholar 

  28. Zhao J, Lu B, Xu H, Tong X, Wu G, Zhang X et al. Thirty-kilodalton Tat-interacting protein suppresses tumor metastasis by inhibition of osteopontin transcription in human hepatocellular carcinoma. Hepatology 2008; 48: 265–275.

    Article  CAS  Google Scholar 

  29. Lin S-Y, Makino K, Xia W, Matin A, Wen Y, Kwong KY et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 2001; 3: 802–808.

    Article  CAS  Google Scholar 

  30. Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 2006; 8: 1359–1368.

    Article  CAS  Google Scholar 

  31. Besson A, Hwang HC, Cicero S, Donovan SL, Gurian-West M, Johnson D et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev 2007; 21: 1731–1746.

    Article  CAS  Google Scholar 

  32. Morimoto M, Kopan R . rtTA toxicity limits the usefulness of the SP-C-rtTA transgenic mouse. Dev Biol 2009; 325: 171–178.

    Article  CAS  Google Scholar 

  33. Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M et al. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest 2007; 117: 2929–2940.

    Article  CAS  Google Scholar 

  34. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.

    Article  CAS  Google Scholar 

  35. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500.

    Article  CAS  Google Scholar 

  36. Sun S, Schiller JH, Spinola M, Minna JD . New molecularly targeted therapies for lung cancer. J Clin Invest 2007; 117: 2740–2750.

    Article  CAS  Google Scholar 

  37. Pao W, Chmielecki J . Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010; 10: 760–774.

    Article  CAS  Google Scholar 

  38. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957.

    Article  CAS  Google Scholar 

  39. Yang CH, Yu CJ, Shih JY, Chang YC, Hu FC, Tsai MC et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 2008; 26: 2745–2753.

    Article  CAS  Google Scholar 

  40. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005; 97: 643–655.

    Article  CAS  Google Scholar 

  41. Nikitin AY, Alcaraz A, Anver MR, Bronson RT, Cardiff RD, Dixon D et al. Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium. Cancer Res 2004; 64: 2307–2316.

    Article  CAS  Google Scholar 

  42. Bitler BG, Goverdhan A, Schroeder JA . MUC1 regulates nuclear localization and function of the epidermal growth factor receptor. J Cell Sci 2010; 123: 1716–1723.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Jill Pecha for backcrossing Tip30 knockout gene into Balb/c mice, Ying Qin and Zuguo Li for histological examination of preneoplastic lesions and tumors, Eran Andrechek and Inez Yuwanita for helping patient survival analysis, and Sandra Z Haslam for critical reading of the manuscript. This work was supported by grants RO1 DK066110-01 and W81XWH-08-1-0377 (to HX) from NIDDK, NIH and DOD. AL is partly supported by a fellowship from Nanfang Hospital, China.

Author information

Author notes

  1. S Gao and F Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Michigan State University, East Lansing, MI, USA

    A Li, C Zhang, S Gao, F Chen, C Yang & H Xiao

  2. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    A Li, F Chen & R Luo

  3. Genetics Program, Michigan State University, East Lansing, MI, USA

    C Zhang

  4. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA

    S Gao

Authors
  1. A Li
    View author publications

    Search author on:PubMed Google Scholar

  2. C Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. S Gao
    View author publications

    Search author on:PubMed Google Scholar

  4. F Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. C Yang
    View author publications

    Search author on:PubMed Google Scholar

  6. R Luo
    View author publications

    Search author on:PubMed Google Scholar

  7. H Xiao
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to R Luo or H Xiao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, A., Zhang, C., Gao, S. et al. TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. Oncogene 32, 2273–2281 (2013). https://doi.org/10.1038/onc.2012.253

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/onc.2012.253

Keywords

Search

Advanced search

Quick links