Skip to main content

Advertisement

SpringerLink
Log in

Clinical significance and biological roles of CRKL in human bladder carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

CRKL encodes an adaptor protein that has been recently reported to be overexpressed in various cancers and associate with the malignant behavior of cancer cells. However, the expression pattern of CRKL protein and its clinical significance in human bladder cancer have not been well characterized to date. In the present study, CRKL expression was analyzed in 82 archived bladder cancer specimens using immunohistochemistry, and the correlations between CRKL expression and clinicopathological parameters were evaluated. We found that CRKL was overexpressed in 31 of 82 (37.8 %) bladder cancer specimens. A significant association was observed between CRKL overexpression and tumor status (p = 0.019). To further explore the biological functions of CRKL in bladder cancer, we overexpressed CRKL in BIU-87 and 5637 cell lines. Using CCK8 assay and colony formation assay, we showed that CRKL upregulation increased cell proliferation. In addition, transwell assay showed that CRKL could also facilitate invasion. Further study demonstrated that CRKL upregulation increased cyclin D1 expression and ERK phosphorylation. In conclusion, CRKL is overexpressed in bladder cancer and regulates malignant cell growth and invasion, which makes CRKL a candidate therapeutic target for bladder cancer.

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. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  2. Liang PY, Li HY, Zhou ZY, Jin YX, et al. Overexpression of immunoglobulin G prompts cell proliferation and inhibits cell apoptosis in human urothelial carcinoma. Tumour Biol. 2013;34:1783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tian F, Xu F, Zhang ZY, Ge JP, et al. Expression of CHD1L in bladder cancer and its influence on prognosis and survival. Tumour Biol. 2011;34:3687–90.

    Article  Google Scholar 

  4. Sapre, N, Anderson PD, Costello AJ, Hovens CM, et al., Gene-based urinary biomarkers for bladder cancer: an unfulfilled promise? Urol Oncol. 2013 Oct 17. pii: S1078-1439(13)00289-5. doi: 10.1016/j.urolonc.2013.07.002. [Epub ahead of print]

  5. Sanchez-Carbayo M. Hypermethylation in bladder cancer: biological pathways and translational applications. Tumour Biol. 2012;33:347–61.

    Article  CAS  PubMed  Google Scholar 

  6. Shan GY, Zhang Z, Chen QG, Yu XY, et al. Overexpression of RIN1 associates with tumor grade and progression in patients of bladder urothelial carcinoma. Tumour Biol. 2012;33:847–55.

    Article  CAS  PubMed  Google Scholar 

  7. Atkins CD, Wrzesinski SH. Radiotherapy plus chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2010;367:380. author reply 380-1.

    Google Scholar 

  8. ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, et al. Tyrosine phosphorylation of CRKL in Philadelphia + leukemia. Blood. 1994;84:1731–6.

    PubMed  Google Scholar 

  9. ten Hoeve J, Morris C, Heisterkamp N, Groffen J. Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene. 1993;8:2469–74.

    PubMed  Google Scholar 

  10. Feller SM. Crk family adaptors-signalling complex formation and biological roles. Oncogene. 2001;20:6348–71.

    Article  CAS  PubMed  Google Scholar 

  11. Zhao T, Miao Z, Wang Z, Xu Y, et al. Overexpression of CRKL correlates with malignant cell proliferation in breast cancer. Tumour Biol. 2013;34:2891–7.

    Article  CAS  PubMed  Google Scholar 

  12. Singer CF, Hudelist G, Lamm W, Mueller R, et al. Active (p)CrkL is overexpressed in human malignancies: potential role as a surrogate parameter for therapeutic tyrosine kinase inhibition. Oncol Rep. 2006;15:353–9.

    CAS  PubMed  Google Scholar 

  13. Kim YH, Kwei KA, Girard L, Salari K, et al. Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. Oncogene. 2009;29:1421–30.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ladanyi M. CRKL as a lung cancer oncogene and mediator of acquired resistance to EGFR inhibitors: is it all that it is cracked up to be? Cancer Discov. 2011;1:560–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang Y, Dong QZ, Fu L, Stoecker M, et al. Overexpression of Crkl correlates with poor prognosis and cell proliferation in non-small cell lung cancer. Mol Carcinog. 2011;52:890–9.

    Article  Google Scholar 

  16. Tashiro E, Tsuchiya A, Imoto M. Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci. 2007;98:629–35.

    Article  CAS  PubMed  Google Scholar 

  17. Witzel II, Koh LF, Perkins ND. Regulation of cyclin D1 gene expression. Biochem Soc Trans. 2010;38:217–22.

    Article  CAS  PubMed  Google Scholar 

  18. Fristrup N, Birkenkamp-Demtroder K, Reinert T, Sanchez-Carbayo M, et al. Multicenter validation of cyclin D1, MCM7, TRIM29, and UBE2C as prognostic protein markers in non-muscle-invasive bladder cancer. Am J Pathol. 2013;182:339–49.

    Article  CAS  PubMed  Google Scholar 

  19. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937–47.

    Article  CAS  PubMed  Google Scholar 

  20. Webb CP, Van Aelst L, Wigler MH, Vande Woude GF. Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci U S A. 1998;95:8773–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arai A, Aoki M, Weihua Y, Jin A, et al. CrkL plays a role in SDF-1-induced activation of the Raf-1/MEK/Erk pathway through Ras and Rac to mediate chemotactic signaling in hematopoietic cells. Cell Signal. 2006;18:2162–71.

    Article  CAS  PubMed  Google Scholar 

  22. Xu YY, Mao XY, Song YX, Zhao F, et al. Midkine confers adriamycin resistance in human gastric cancer cells. Tumour Biol. 2012;33:1543–8.

    Article  CAS  PubMed  Google Scholar 

  23. Hu L, Xia L, Zhou H, Wu B, et al. TF/FVIIa/PAR2 promotes cell proliferation and migration via PKCalpha and ERK-dependent c-Jun/AP-1 pathway in colon cancer cell line SW620. Tumour Biol. 2002;34:2573–81.

    Article  Google Scholar 

  24. Lee EJ, Lee SJ, Kim S, Cho SC, et al. Interleukin-5 enhances the migration and invasion of bladder cancer cells via ERK1/2-mediated MMP-9/NF-kappaB/AP-1 pathway: involvement of the p21WAF1 expression. Cell Signal. 2013;25:2025–38.

    Article  CAS  PubMed  Google Scholar 

  25. Yang C, Klein EA, Assoian RK, Kazanietz MG. Heregulin beta1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1. Biochem J. 2008;410:167–75.

    Article  CAS  PubMed  Google Scholar 

  26. Dong QZ, Wang Y, Tang ZP, Fu L, et al. Derlin-1 is overexpressed in non-small cell lung cancer and promotes cancer cell invasion via EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9. Am J Pathol. 2013;182:954–64.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Bin Han, Zhenqun Xu & Bin Wu

  2. Department of Pathology, Fengtian Hospital Affiliated to Shenyang Medical College, Shenyang, 110021, China

    Lan Luan

Authors
  1. Bin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lan Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenqun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, B., Luan, L., Xu, Z. et al. Clinical significance and biological roles of CRKL in human bladder carcinoma. Tumor Biol. 35, 4101–4106 (2014). https://doi.org/10.1007/s13277-013-1536-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-1536-y

Keywords

Search

Navigation