CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer

A Corrigendum to this article was published on 01 October 2004

Abstract

Genomic amplification at 20q11–13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.

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Figure 1: Identification of germline translocation breakpoint and affected genes in proband.
Figure 2: FISH analysis of P1 region and expression status of candidate genes in bladder cancer cell lines and tissues.
Figure 3: Oncogenic assays for CDC91L1 and PINH.
Figure 4: Frequency of altered CDC91L1 expression in primary bladder cancer tissues.
Figure 5: Overexpression of GPI-anchored proteins in bladder cancer cell lines, and sensitivity to proaerolysin.

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References

  1. 1

    Bishop, J.M. Molecular themes in oncogenesis. Cell 64, 235–248 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Weinberg, R.A. The molecular basis of oncogenes and tumor suppressor genes. Ann. NY Acad. Sci. 758, 331–338 (1995).

    CAS  Article  Google Scholar 

  3. 3

    Weinberg, R.A. Oncogenes and tumor suppressor genes. CA Cancer J. Clin. 44, 160–170 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Dalla-Favera, R., Martinotti, S., Gallo, R.C., Erikson, J. & Croce, C.M. Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219, 963–967 (1983).

    CAS  Article  Google Scholar 

  5. 5

    Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl. Acad. Sci. USA 79, 7824–7827 (1982).

    CAS  Article  Google Scholar 

  6. 6

    Kallioniemi, O.P. et al. Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors. Semin. Cancer Biol. 4, 41–46 (1993).

    CAS  Google Scholar 

  7. 7

    Wu, G. et al. Structural analysis of the 17q22-23 amplicon identifies several independent targets of amplification in breast cancer cell lines and tumors. Cancer Res. 61, 4951–4955 (2001).

    CAS  Google Scholar 

  8. 8

    Wu, G.J. et al. 17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. Cancer Res. 60, 5371–5375 (2000).

    CAS  Google Scholar 

  9. 9

    Kallioniemi, A. et al. Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization. Genes Chromosomes Cancer 12, 213–219 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Kallioniemi, A. et al. Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc. Natl. Acad. Sci. USA 91, 2156–2160 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Muleris, M., Almeida, A., Gerbault-Seureau, M., Malfoy, B. & Dutrillaux, B. Detection of DNA amplification in 17 primary breast carcinomas with homogeneously staining regions by a modified comparative genomic hybridization technique. Genes Chromosomes Cancer 10, 160–170 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Forozan, F. et al. Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data. Cancer Res. 60, 4519–4525 (2000).

    CAS  Google Scholar 

  13. 13

    Guan, X.Y. et al. Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer. Cancer Res. 56, 3446–3450 (1996).

    CAS  Google Scholar 

  14. 14

    Savelieva, E. et al. 20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells. Oncogene 14, 551–560 (1997).

    CAS  Article  Google Scholar 

  15. 15

    Wimmer, K. et al. Co-amplification of a novel gene, NAG, with the N-myc gene in neuroblastoma. Oncogene 18, 233–238 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Pollack, J.R. et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc. Natl. Acad. Sci. USA 99, 12963–12968 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Anzick, S.L. et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965–968 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Mu, D. et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 3, 297–302 (2003).

    CAS  Article  Google Scholar 

  19. 19

    Maguire, R.T., Robins, T.S., Thorgeirsson, S.S. & Heilman, C.A. Expression of cellular myc and mos genes in undifferentiated B cell lymphomas of Burkitt and non-Burkitt types. Proc. Natl. Acad. Sci. USA 80, 1947–1950 (1983).

    CAS  Article  Google Scholar 

  20. 20

    Grieco, M. et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60, 557–563 (1990).

    CAS  Article  Google Scholar 

  21. 21

    Schoenberg, M., Kiemeney, L., Walsh, P.C., Griffin, C.A. & Sidransky, D. Germline translocation t(5;20)(p15;q11) and familial transitional cell carcinoma. J. Urol. 155, 1035–1036 (1996).

    CAS  Article  Google Scholar 

  22. 22

    Hong, Y. et al. Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins. Mol. Biol. Cell 14, 1780–1789 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Okamura, S. et al. p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol. Cell 8, 85–94 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Memarzadeh, S. et al. Urokinase plasminogen activator receptor: prognostic biomarker for endometrial cancer. Proc. Natl. Acad. Sci. USA 99, 10647–10652 (2002).

    Article  Google Scholar 

  25. 25

    Dumler, I. et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J. Biol. Chem. 273, 315–321 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Yeager, T.R. et al. Overcoming cellular senescence in human cancer pathogenesis. Genes Dev. 12, 163–174 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Tanner, M.M. et al. Increased copy number at 20q13 in breast cancer: defining the critical region and exclusion of candidate genes. Cancer Res. 54, 4257–4260 (1994).

    CAS  Google Scholar 

  28. 28

    Fukushige, S. et al. Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma. Genes Chromosomes Cancer 19, 161–169 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Tanner, M.M. et al. Independent amplification and frequent co-amplification of three nonsyntenic regions on the long arm of chromosome 20 in human breast cancer. Cancer Res. 56, 3441–3445 (1996).

    CAS  Google Scholar 

  30. 30

    Fitzgerald, J.M. et al. Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. J. Natl. Cancer Inst. 87, 129–133 (1995).

    CAS  Article  Google Scholar 

  31. 31

    Hovey, R.M. et al. Genetic alterations in primary bladder cancers and their metastases. Cancer Res. 58, 3555–3560 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Bringuier, P.P., Tamimi, Y., Schuuring, E. & Schalken, J. Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene 12, 1747–1753 (1996).

    CAS  Google Scholar 

  33. 33

    Friedmann, E., Salzberg, Y., Weinberger, A., Shaltiel, S. & Gerst, J.E. YOS9, the putative yeast homolog of a gene amplified in osteosarcomas, is involved in the endoplasmic reticulum (ER)-Golgi transport of GPI-anchored proteins. J. Biol. Chem. 277, 35274–35281 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator. Nat. Rev. Mol. Cell. Biol. 3 932–943 (2002).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank F. Wu, N. Vij, K. Irani and A. Haile for technical support and Ras-transformed NIH3T3 cells. This work was supported by grant 5P01CA77664 from the National Cancer Institute, and by a grant from the Flight Attendant Medical Research Institute.

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Correspondence to David Sidransky or Barry Trink.

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Guo, Z., Linn, J., Wu, G. et al. CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer. Nat Med 10, 374–381 (2004). https://doi.org/10.1038/nm1010

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