Skip to main content
SpringerLink
Log in

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

The phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway plays a critical role in human cancer. We determined the expression patterns of class I PI3K catalytic subunits and evaluated their importance in the development or progression of colorectal cancer (CRC). For this purpose, expression of class I PI3K isoforms was evaluated in 82 primary CRC and paired non-cancerous mucosa samples by qRT-PCR. P-AKT-Ser473 and P-AKT-Thr308 expression were measured by western blot. We found that, compared with paired non-cancerous mucosa samples, mRNA expression of p110α and p110β in CRCs was significantly increased to 2.02-fold (95% confidence interval [CI] 1.25–3.28 fold) and 1.76-fold (95% CI 1.19–2.60 fold), respectively; while slight differences were found regarding the expression of p110δ (0.57-fold; 95% CI 0.31–1.07 fold) and p110γ (0.97-fold; 95% CI 0.50–1.88 fold). Increased p110α and p110β expression correlated with primary tumor size, regional lymph node metastases, and AJCC stage. Increased p110β expression also correlated with distant metastasis. P-AKT-Thr308 and P-AKT-Ser473 expression showed significant direct correlations with p110α and p110β mRNA expression. Besides, CRC patients with p110β mRNA overexpression had a worse disease-free survival after radical surgery compared with those with normal or decreased levels (P = 0.043). It was, therefore, concluded that the altered p110α and p110β expression might contribute to the CRC development or progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., & Thun, M. J. (2009). Cancer statistics 2009. CA: A Cancer Journal for Clinicians, 59, 225–249.

    Article  Google Scholar 

  2. Moertel, C. G., Fleming, T. R., Macdonald, J. S., et al. (1990). Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. The New England Journal of Medicine, 322, 352–358.

    Article  PubMed  CAS  Google Scholar 

  3. Krook, J. E., Moertel, C. G., Gunderson, L. L., et al. (1991). Effective surgical adjuvant therapy for high-risk rectal carcinoma. The New England Journal of Medicine, 324, 709–715.

    Article  PubMed  CAS  Google Scholar 

  4. Hahn, W. C., & Weinberg, R. A. (2002). Rules for making human tumor cells. The New England Journal of Medicine, 347, 1593–1603.

    Article  PubMed  CAS  Google Scholar 

  5. Niedermeier, M., Hennessy, B. T., Knight, Z. A., et al. (2009). Isoform-selective phosphoinositide 3’-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood, 113, 5549–5557.

    Article  PubMed  CAS  Google Scholar 

  6. Bader, A. G., Kang, S., Zhao, L., & Vogt, P. K. (2005). Oncogenic PI3K deregulates transcription and translation. Nature Review Cancer, 5, 921–929.

    Article  CAS  Google Scholar 

  7. Carracedo, A., & Pandolfi, P. P. (2008). The PTEN-PI3K pathway of feedbacks and cross-talks. Oncogene, 27, 5527–5541.

    Article  PubMed  CAS  Google Scholar 

  8. Liu, P., Cheng, H., Roberts, T. M., & Zhao, J. J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Review Drug Discovery, 8, 627–644.

    Article  CAS  Google Scholar 

  9. Garcia-Echeverria, C., & Sellers, W. R. (2008). Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene, 27, 5511–5526.

    Article  PubMed  CAS  Google Scholar 

  10. Chen, J. (2008). Is src the key to understanding metastasis and developing new treatments for colon cancer? Nature Clinical Practice Gastroenterology Hepatology, 5, 306–307.

    Article  PubMed  CAS  Google Scholar 

  11. Cantley, L. C. (2002). The phosphoinositide 3-kinase pathway. Science, 296, 1655–1657.

    Article  PubMed  CAS  Google Scholar 

  12. Wymann, M. P., Zvelebil, M., & Laffargue, M. (2003). Phosphoinositide 3-kinase signalling—which way to target? Trends in Pharmacological Sciences, 24, 366–376.

    Article  PubMed  CAS  Google Scholar 

  13. Edgar, K. A., Wallin, J. J., Berry, M., et al. (2010). Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Research, 70, 1164–1172.

    Article  PubMed  CAS  Google Scholar 

  14. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., & Bilanges, B. (2010). The emerging mechanisms of isoform-specific PI3K signalling. Nature Review Molecular Cell Biology, 11, 329–341.

    Article  CAS  Google Scholar 

  15. Graupera, M., Guillermet-Guibert, J., Foukas, L. C., et al. (2008). Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature, 453, 662–666.

    Article  PubMed  CAS  Google Scholar 

  16. Guillermet-Guibert, J., Bjorklof, K., Salpekar, A., et al. (2008). The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proceedings of the National Academy of Sciences of the United States of America, 105, 8292–8297.

    Article  PubMed  CAS  Google Scholar 

  17. Gilio, K., Munnix, I. C., Mangin, P., et al. (2009). Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signaling and thrombus formation. The Journal of Biological Chemistry, 284, 33750–33762.

    Article  PubMed  CAS  Google Scholar 

  18. Ghigo, A., & Hirsch, E. (2008). Isoform selective phosphoinositide 3-kinase gamma and delta inhibitors and their therapeutic potential. Recent Patents on Inflammation & Allergy Drug Discovery, 2, 1–10.

    Article  CAS  Google Scholar 

  19. Ogino, S., Nosho, K., Kirkner, G. J., et al. (2009). PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. Journal of Clinical Oncology, 27, 1477–1484.

    Article  PubMed  CAS  Google Scholar 

  20. Barault, L., Veyrie, N., Jooste, V., et al. (2008). Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. International Journal of Cancer, 122, 2255–2259.

    Article  CAS  Google Scholar 

  21. Sujobert, P., Bardet, V., Cornillet-Lefebvre, P., et al. (2005). Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood, 106, 1063–1066.

    Article  PubMed  CAS  Google Scholar 

  22. Hickey, F. B., & Cotter, T. G. (2006). BCR-ABL regulates phosphatidylinositol 3-kinase-p110gamma transcription and activation and is required for proliferation and drug resistance. The Journal of Biological Chemistry, 281, 2441–2450.

    Article  PubMed  CAS  Google Scholar 

  23. Mizoguchi, M., Nutt, C. L., Mohapatra, G., & Louis, D. N. (2004). Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathology, 14, 372–377.

    Article  PubMed  CAS  Google Scholar 

  24. Kang, S., Denley, A., Vanhaesebroeck, B., & Vogt, P. K. (2006). Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proceedings of the National Academy of Sciences of the United States of America, 103, 1289–1294.

    Article  PubMed  CAS  Google Scholar 

  25. Bénistant, C., Chapuis, H., & Roche, S. (2000). A specific function for phosphatidylinositol 3-kinase alpha (p85alpha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells. Oncogene, 19, 5083–5090.

    Article  PubMed  Google Scholar 

  26. Yuan, T. L., & Cantley, L. C. (2008). PI3K pathway alterations in cancer: variations on a theme. Oncogene, 27, 5497–5510.

    Article  PubMed  CAS  Google Scholar 

  27. Martin-Berenjeno, I., & Vanhaesebroeck, B. (2009). PI3K regulatory subunits lose control in cancer. Cancer Cell, 16, 449–450.

    Article  PubMed  CAS  Google Scholar 

  28. Wee, S., Wiederschain, D., Maira, S. M., et al. (2008). PTEN-deficient cancers depend on PIK3CB. Proceedings of the National Academy of Sciences of the United States of America, 105, 13057–13062.

    Article  PubMed  CAS  Google Scholar 

  29. Boller, D., Schramm, A., Doepfner, K. T., et al. (2008). Targeting the phosphoinositide 3-kinase isoform p110delta impairs growth and survival in neuroblastoma cells. Clinical Cancer Research, 14, 1172–1181.

    Article  PubMed  CAS  Google Scholar 

  30. Ikenoue, T., Kanai, F., Hikiba, Y., et al. (2005). Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Research, 65, 4562–4567.

    Article  PubMed  CAS  Google Scholar 

  31. Sartore-Bianchi, A., Martini, M., Molinari, F., et al. (2009). PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Research, 69, 1851–1857.

    Article  PubMed  CAS  Google Scholar 

  32. Ekstrand, A. I., Jönsson, M., Lindblom, A., Borg, A., & Nilbert, M. (2010). Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer. Familial Cancer, 9, 125–129.

    Article  PubMed  CAS  Google Scholar 

  33. Bader, A. G., Kang, S., & Vogt, P. K. (2006). Cancer-specific mutations in PIK3CA are oncogenic. Proceedings of the National Academy of Sciences of the United States of America, 103, 1475–1479.

    Article  PubMed  CAS  Google Scholar 

  34. Zhao, J. J., Liu, Z., Wang, L., Shin, E., Loda, M. F., & Roberts, T. M. (2005). The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 18443–18448.

    Article  PubMed  CAS  Google Scholar 

  35. Colakoglu, T., Yildirim, S., Kayaselcuk, F., et al. (2008). Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: Is PTEN loss predictor of local recurrence? American Journal of Surgery, 195, 719–725.

    Article  PubMed  CAS  Google Scholar 

  36. Bi, L., Okabe, I., Bernard, D. J., & Nussbaum, R. L. (2002). Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mammalian Genome, 13, 169–172.

    PubMed  CAS  Google Scholar 

  37. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A., & Nussbaum, R. L. (1999). Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. The Journal of Biological Chemistry, 274, 10963–10968.

    Article  PubMed  CAS  Google Scholar 

  38. Ali, K., Bilancio, A., Thomas, M., et al. (2004). Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature, 431, 1007–1011.

    Article  PubMed  CAS  Google Scholar 

  39. Okkenhaug, K., Bilancio, A., Farjot, G., et al. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science, 297, 1031–1034.

    PubMed  CAS  Google Scholar 

  40. Sasaki, T., Irie-Sasaki, J., Horie, Y., et al. (2000). Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)K-gamma. Nature, 406, 897–902.

    Article  PubMed  CAS  Google Scholar 

  41. Semba, S., Itoh, N., Ito, M., et al. (2002). Down-regulation of PIK3CG, a catalytic subunit of phosphatidylinositol 3-OH kinase, by CpG hypermethylation in human colorectal carcinoma. Clinical Cancer Research, 8, 3824–3831.

    PubMed  CAS  Google Scholar 

  42. Barbier, M., Attoub, S., Calvez, R., et al. (2001). Tumour biology. Weakening link to colorectal cancer? Nature, 413, 796.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the Natural Science Foundation of Heilongjiang Province (Grant # D2007-79), NSFC(30972561), Heilongjiang Postdoctoral Science-Research Foundation and Scientific Research Fund of Heilongjiang Provincial Education Department (Grant # 11541129) for financial support.

Author information

Authors and Affiliations

  1. Department of Colorectal Surgery, The Affiliated 3rd Hospital, Harbin Medical University, Harbin, People’s Republic of China

    Binbin Cui

  2. Department of Medical Oncology, The Affiliated 3rd Hospital, Harbin Medical University, Harbin, People’s Republic of China

    Ji Tao

  3. Cancer Research Institute, Harbin Medical University, Harbin, 150081, People’s Republic of China

    Yanmei Yang

Authors
  1. Binbin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanmei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanmei Yang.

Additional information

Binbin Cui and Ji Tao have contributed equally to this work as co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cui, B., Tao, J. & Yang, Y. Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer. Cell Biochem Biophys 62, 47–54 (2012). https://doi.org/10.1007/s12013-011-9257-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-011-9257-6

Keywords

Search

Navigation