Skip to main content
Erschienen in: Tumor Biology 4/2015

01.04.2015 | Research Article

Clinicopathological and cellular signature of PAK1 in human bladder cancer

verfasst von: Kai Huang, Gang Chen, Jingfang Luo, Youyuan Zhang, Guoxiong Xu

Erschienen in: Tumor Biology | Ausgabe 4/2015

Einloggen, um Zugang zu erhalten

Abstract

Bladder cancer (BC) is the ninth most common cancer and the 13th most common cause of cancer death. Although p21 protein-activated kinase (PAK) regulates cell growth, motility, and morphology, the expression and function of PAK1 associated with the clinicopathological and cellular signature of human BC are not clear. This study was to examine the expression of PAK1 in human BC, the association of PAK1 with clinicopathological features, and the effect of PAK1 on cell proliferation, migration, and invasion in BC cells. A total of 54 BC and 12 normal bladder tissue specimens were retrieved. Among 54 BC patients, 39 cases were superficial BC and 15 cases were invasive BC. Histological examination revealed 29 patients with low-grade and 25 patients with high-grade papillary urothelial carcinomas. Immunohistochemical staining showed that PAK1 was overexpressed in BC tissue compared with normal bladder tissue. The overexpression of PAK1 was significantly associated with tumor size, histological grade, and lymph node metastasis, but not with gender, age, clinical stage, tumor number, and recurrence. Furthermore, the cytoplasmic distribution of PAK1 was observed in BC cells. Knocking down of PAK1 using lentiviral transduction decreased BC cell proliferation, migration, and invasion. In conclusion, we demonstrated that the overexpression of PAK1 is closely associated with the clinicopathological features of BC, suggesting that PAK1 may play an important role in the development and progression of BC and may be a potential therapeutic target for the treatment of BC.
Literatur
1.
Zurück zum Zitat Sauter G, Amin MB, Kogevinas M, Simon R. Bladder cancer. In: Stewart BW, Wild CP, editors. World cancer report 2014. Lyon: International Agency for Research on Cancer; 2014. p. 632–44. Sauter G, Amin MB, Kogevinas M, Simon R. Bladder cancer. In: Stewart BW, Wild CP, editors. World cancer report 2014. Lyon: International Agency for Research on Cancer; 2014. p. 632–44.
2.
Zurück zum Zitat Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.CrossRefPubMed Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.CrossRefPubMed
3.
Zurück zum Zitat Di Stasi SM, Valenti M, Verri C, Liberati E, Giurioli A, Leprini G, et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. Lancet Oncol. 2011;12(9):871–9.CrossRefPubMed Di Stasi SM, Valenti M, Verri C, Liberati E, Giurioli A, Leprini G, et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial. Lancet Oncol. 2011;12(9):871–9.CrossRefPubMed
4.
Zurück zum Zitat Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466–5. discussion 75–7.CrossRefPubMed Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466–5. discussion 75–7.CrossRefPubMed
5.
Zurück zum Zitat Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.CrossRefPubMed Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.CrossRefPubMed
6.
Zurück zum Zitat DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, Yu X, et al. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012;7(5):e36669.CrossRefPubMedPubMedCentral DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, Yu X, et al. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012;7(5):e36669.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat King H, Nicholas NS, Wells CM. Role of p-21-activated kinases in cancer progression. Int Rev Cell Mol Biol. 2014;309:347–87.CrossRefPubMed King H, Nicholas NS, Wells CM. Role of p-21-activated kinases in cancer progression. Int Rev Cell Mol Biol. 2014;309:347–87.CrossRefPubMed
8.
Zurück zum Zitat Eswaran J, Li DQ, Shah A, Kumar R. Molecular pathways: targeting p21-activated kinase 1 signaling in cancer—opportunities, challenges, and limitations. Clin Cancer Res. 2012;18(14):3743–9.CrossRefPubMedPubMedCentral Eswaran J, Li DQ, Shah A, Kumar R. Molecular pathways: targeting p21-activated kinase 1 signaling in cancer—opportunities, challenges, and limitations. Clin Cancer Res. 2012;18(14):3743–9.CrossRefPubMedPubMedCentral
11.
13.
Zurück zum Zitat Chow HY, Jubb AM, Koch JN, Jaffer ZM, Stepanova D, Campbell DA, et al. p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model. Cancer Res. 2012;72(22):5966–75.CrossRefPubMedPubMedCentral Chow HY, Jubb AM, Koch JN, Jaffer ZM, Stepanova D, Campbell DA, et al. p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model. Cancer Res. 2012;72(22):5966–75.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Dammann K, Khare V, Gasche C. Tracing PAKs from GI inflammation to cancer. Gut. 2014;63(7):1173–84.CrossRefPubMed Dammann K, Khare V, Gasche C. Tracing PAKs from GI inflammation to cancer. Gut. 2014;63(7):1173–84.CrossRefPubMed
15.
Zurück zum Zitat Ye DZ, Jin S, Zhuo Y, Field J. p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112. PLoS One. 2011;6(11):e27637.CrossRefPubMedPubMedCentral Ye DZ, Jin S, Zhuo Y, Field J. p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112. PLoS One. 2011;6(11):e27637.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Goc A, Al-Azayzih A, Abdalla M, Al-Husein B, Kavuri S, Lee J, et al. P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor beta expression and enhanced matrix metalloproteinase 9 secretion. J Biol Chem. 2013;288(5):3025–35.CrossRefPubMed Goc A, Al-Azayzih A, Abdalla M, Al-Husein B, Kavuri S, Lee J, et al. P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor beta expression and enhanced matrix metalloproteinase 9 secretion. J Biol Chem. 2013;288(5):3025–35.CrossRefPubMed
17.
Zurück zum Zitat Xu G, Barrios-Rodiles M, Jerkic M, Turinsky AL, Nadon R, Vera S, et al. Novel protein interactions with endoglin and activin receptor-like kinase 1: potential role in vascular networks. Mol Cell Proteomics. 2014;13(2):489–502.CrossRefPubMed Xu G, Barrios-Rodiles M, Jerkic M, Turinsky AL, Nadon R, Vera S, et al. Novel protein interactions with endoglin and activin receptor-like kinase 1: potential role in vascular networks. Mol Cell Proteomics. 2014;13(2):489–502.CrossRefPubMed
18.
Zurück zum Zitat Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994;367(6458):40–6.CrossRefPubMed Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994;367(6458):40–6.CrossRefPubMed
19.
Zurück zum Zitat Kou B, Gao Y, Du C, Shi Q, Xu S, Wang CQ, et al. miR-145 inhibits invasion of bladder cancer cells by targeting PAK1. Urol Oncol. 2014;32:846–854 Kou B, Gao Y, Du C, Shi Q, Xu S, Wang CQ, et al. miR-145 inhibits invasion of bladder cancer cells by targeting PAK1. Urol Oncol. 2014;32:846–854
20.
21.
Zurück zum Zitat Nikolic M. The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain. Mol Neurobiol. 2008;37(2–3):187–202.CrossRefPubMed Nikolic M. The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain. Mol Neurobiol. 2008;37(2–3):187–202.CrossRefPubMed
22.
Zurück zum Zitat Rayala SK, Molli PR, Kumar R. Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Cancer Res. 2006;66(12):5985–8.CrossRefPubMed Rayala SK, Molli PR, Kumar R. Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Cancer Res. 2006;66(12):5985–8.CrossRefPubMed
23.
Zurück zum Zitat Kamai T, Shirataki H, Nakanishi K, Furuya N, Kambara T, Abe H, et al. Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer. BMC Cancer. 2010;10:164.CrossRefPubMedPubMedCentral Kamai T, Shirataki H, Nakanishi K, Furuya N, Kambara T, Abe H, et al. Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer. BMC Cancer. 2010;10:164.CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Li LH, Luo Q, Zheng MH, Pan C, Wu GY, Lu YZ, et al. P21-activated protein kinase 1 is overexpressed in gastric cancer and induces cancer metastasis. Oncol Rep. 2012;27(5):1435–42.PubMed Li LH, Luo Q, Zheng MH, Pan C, Wu GY, Lu YZ, et al. P21-activated protein kinase 1 is overexpressed in gastric cancer and induces cancer metastasis. Oncol Rep. 2012;27(5):1435–42.PubMed
25.
Zurück zum Zitat Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, Tam KF, et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer. 2010;127(1):21–31.CrossRefPubMed Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, Tam KF, et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer. 2010;127(1):21–31.CrossRefPubMed
26.
Zurück zum Zitat Siu MK, Yeung MC, Zhang H, Kong DS, Ho JW, Ngan HY, et al. p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease. Am J Pathol. 2010;176(6):3015–22.CrossRefPubMedPubMedCentral Siu MK, Yeung MC, Zhang H, Kong DS, Ho JW, Ngan HY, et al. p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease. Am J Pathol. 2010;176(6):3015–22.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Ito M, Nishiyama H, Kawanishi H, Matsui S, Guilford P, Reeve A, et al. P21-activated kinase 1: a new molecular marker for intravesical recurrence after transurethral resection of bladder cancer. J Urol. 2007;178(3 Pt 1):1073–9.CrossRefPubMed Ito M, Nishiyama H, Kawanishi H, Matsui S, Guilford P, Reeve A, et al. P21-activated kinase 1: a new molecular marker for intravesical recurrence after transurethral resection of bladder cancer. J Urol. 2007;178(3 Pt 1):1073–9.CrossRefPubMed
28.
Zurück zum Zitat Redelman-Sidi G, Iyer G, Solit DB, Glickman MS. Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells. Cancer Res. 2013;73(3):1156–67.CrossRefPubMedPubMedCentral Redelman-Sidi G, Iyer G, Solit DB, Glickman MS. Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells. Cancer Res. 2013;73(3):1156–67.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Wang X, Gui L, Zhang Y, Zhang J, Shi J, Xu G. Cystatin B is a progression marker of human epithelial ovarian tumors mediated by the TGF-beta signaling pathway. Int J Oncol. 2014;44(4):1099–106.PubMedPubMedCentral Wang X, Gui L, Zhang Y, Zhang J, Shi J, Xu G. Cystatin B is a progression marker of human epithelial ovarian tumors mediated by the TGF-beta signaling pathway. Int J Oncol. 2014;44(4):1099–106.PubMedPubMedCentral
31.
Zurück zum Zitat Ong CC, Jubb AM, Haverty PM, Zhou W, Tran V, Truong T, et al. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2011;108(17):7177–82.CrossRefPubMedPubMedCentral Ong CC, Jubb AM, Haverty PM, Zhou W, Tran V, Truong T, et al. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2011;108(17):7177–82.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Qing H, Gong W, Che Y, Wang X, Peng L, Liang Y, et al. PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour Biol. 2012;33(4):985–94.CrossRefPubMed Qing H, Gong W, Che Y, Wang X, Peng L, Liang Y, et al. PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour Biol. 2012;33(4):985–94.CrossRefPubMed
33.
Zurück zum Zitat Lu W, Qu JJ, Li BL, Lu C, Yan Q, Wu XM, et al. Overexpression of p21-activated kinase 1 promotes endometrial cancer progression. Oncol Rep. 2013;29(4):1547–55.PubMed Lu W, Qu JJ, Li BL, Lu C, Yan Q, Wu XM, et al. Overexpression of p21-activated kinase 1 promotes endometrial cancer progression. Oncol Rep. 2013;29(4):1547–55.PubMed
34.
Zurück zum Zitat Park J, Kim JM, Park JK, Huang S, Kwak SY, Ryu KA, et al. Association of p21-activated kinase-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head Neck. 2014. Park J, Kim JM, Park JK, Huang S, Kwak SY, Ryu KA, et al. Association of p21-activated kinase-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head Neck. 2014.
35.
Zurück zum Zitat Shrestha Y, Schafer EJ, Boehm JS, Thomas SR, He F, Du J, et al. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene. 2012;31(29):3397–408.CrossRefPubMed Shrestha Y, Schafer EJ, Boehm JS, Thomas SR, He F, Du J, et al. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene. 2012;31(29):3397–408.CrossRefPubMed
36.
Zurück zum Zitat McCarty SK, Saji M, Zhang X, Jarjoura D, Fusco A, Vasko VV, et al. Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion. Endocr-Relat Cancer. 2010;17(4):989–99.CrossRefPubMedPubMedCentral McCarty SK, Saji M, Zhang X, Jarjoura D, Fusco A, Vasko VV, et al. Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion. Endocr-Relat Cancer. 2010;17(4):989–99.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Wang Z, Fu M, Wang L, Liu J, Li Y, Brakebusch C, et al. p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. J Biol Chem. 2013;288(27):20093–9.CrossRefPubMedPubMedCentral Wang Z, Fu M, Wang L, Liu J, Li Y, Brakebusch C, et al. p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. J Biol Chem. 2013;288(27):20093–9.CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Orr AW, Hahn C, Blackman BR, Schwartz MA. p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow. Circ Res. 2008;103(6):671–9.CrossRefPubMedPubMedCentral Orr AW, Hahn C, Blackman BR, Schwartz MA. p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow. Circ Res. 2008;103(6):671–9.CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Lee SH, Jung YS, Chung JY, Oh AY, Lee SJ, Choi DH, et al. Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway. Cell Death Dis. 2011;2:e235.CrossRefPubMedPubMedCentral Lee SH, Jung YS, Chung JY, Oh AY, Lee SJ, Choi DH, et al. Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway. Cell Death Dis. 2011;2:e235.CrossRefPubMedPubMedCentral
Metadaten
Titel
Clinicopathological and cellular signature of PAK1 in human bladder cancer
verfasst von
Kai Huang
Gang Chen
Jingfang Luo
Youyuan Zhang
Guoxiong Xu
Publikationsdatum
01.04.2015
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 4/2015
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2843-7

Weitere Artikel der Ausgabe 4/2015

Tumor Biology 4/2015 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.