Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

Authors: Chen-Yun Yeh, Shin-Mei Shin, Hsuan-Heng Yeh, Tsung-Jung Wu, Jyh-Wei Shin, Tsuey-Yu Chang, Giri Raghavaraju, Chung-Ta Lee, Jung-Hsien Chiang, Vincent S Tseng, Yuan-Chii G Lee, Cheng-Huang Shen, Nan-Haw Chow, Hsiao-Sheng Liu

Published in: BMC Cancer | Issue 1/2011

Login to get access

Abstract

Background

A cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.

Methods

Both NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients.

Results

A positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival (p < 0.01).

Conclusions

In addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.
Appendix
Available only for authorised users
Literature
1.
Stuart KA, Riordan SM, Lidder S, Crostella L, Williams R, Skouteris GG: Hepatocyte growth factor/scatter factor-induced intracellular signalling. Int J Exp Pathol. 2000, 81 (1): 17-30. 10.1046/j.1365-2613.2000.00138.x.CrossRefPubMedPubMedCentral
2.
Li B, Kanamaru H, Noriki S, Fukuda M, Okada K: Differential expression of hepatocyte growth factor in papillary and nodular tumors of the bladder. Int J Urol. 1998, 5 (5): 436-440. 10.1111/j.1442-2042.1998.tb00383.x.CrossRefPubMed
3.
Peschard P, Park M: From Tpr-Met to Met, tumorigenesis and tubes. Oncogene. 2007, 26 (9): 1276-1285. 10.1038/sj.onc.1210201.CrossRefPubMed
4.
Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM: Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol. 2001, 153 (5): 1023-1034. 10.1083/jcb.153.5.1023.CrossRefPubMedPubMedCentral
5.
Cheng HL, Trink B, Tzai TS, Liu HS, Chan SH, Ho CL, Sidransky D, Chow NH: Overexpression of c-met as a prognostic indicator for transitional cell carcinoma of the urinary bladder: a comparison with p53 nuclear accumulation. J Clin Oncol. 2002, 20 (6): 1544-1550. 10.1200/JCO.20.6.1544.CrossRefPubMed
6.
Cheng HL, Liu HS, Lin YJ, Chen HH, Hsu PY, Chang TY, Ho CL, Tzai TS, Chow NH: Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005, 92 (10): 1906-1914. 10.1038/sj.bjc.6602593.CrossRefPubMedPubMedCentral
7.
Miyata Y, Sagara Y, Kanda S, Hayashi T, Kanetake H: Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin. Hum Pathol. 2009, 40 (4): 496-504. 10.1016/j.humpath.2008.09.011.CrossRefPubMed
8.
Capdeville R, Buchdunger E, Zimmermann J, Matter A: Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002, 1 (7): 493-502. 10.1038/nrd839.CrossRefPubMed
9.
Dussault I, Bellon SF: From concept to reality: the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer. Anticancer Agents Med Chem. 2009, 9 (2): 221-229.CrossRefPubMed
10.
Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R: A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 2007, 67 (8): 3529-3534. 10.1158/0008-5472.CAN-06-4416.CrossRefPubMed
11.
Heldin CH: Dimerization of cell surface receptors in signal transduction. Cell. 1995, 80 (2): 213-223. 10.1016/0092-8674(95)90404-2.CrossRefPubMed
12.
Chen Q, Seol DW, Carr B, Zarnegar R: Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology. 1997, 26 (1): 59-66.PubMed
13.
Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res. 2001, 7 (7): 1957-1962.PubMed
14.
Maggiora P, Lorenzato A, Fracchioli S, Costa B, Castagnaro M, Arisio R, Katsaros D, Massobrio M, Comoglio PM, Flavia Di Renzo M: The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res. 2003, 288 (2): 382-389. 10.1016/S0014-4827(03)00250-7.CrossRefPubMed
15.
Hsu PY, Liu HS, Cheng HL, Tzai TS, Guo HR, Ho CL, Chow NH: Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol. 2006, 176 (5): 2262-2267. 10.1016/j.juro.2006.07.048.CrossRefPubMed
16.
Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC: Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem. 2000, 275 (12): 8806-8811. 10.1074/jbc.275.12.8806.CrossRefPubMed
17.
Chow NH, Trink B, Eisenberger C, Sidransky D: Tyrosine kinase profile of bladder cancer. J Urol. 1998, 159: 1096-
18.
Meric F, Lee WP, Sahin A, Zhang H, Kung HJ, Hung MC: Expression profile of tyrosine kinases in breast cancer. Clin Cancer Res. 2002, 8 (2): 361-367.PubMed
19.
Wu CW, Li AF, Chi CW, Lai CH, Huang CL, Lo SS, Lui WY, Lin WC: Clinical significance of AXL kinase family in gastric cancer. Anticancer Res. 2002, 22 (2B): 1071-1078.PubMed
20.
Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey TW: Expression of the proto-oncogene Axl in renal cell carcinoma. DNA Cell Biol. 2003, 22 (8): 533-540. 10.1089/10445490360708946.CrossRefPubMed
21.
Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW: Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia. 2005, 7 (12): 1058-1064. 10.1593/neo.05640.CrossRefPubMedPubMedCentral
22.
Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC: Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol. 2005, 204 (1): 36-44. 10.1002/jcp.20265.CrossRefPubMed
23.
Carvalho I, Milanezi F, Martins A, Reis RM, Schmitt F: Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res. 2005, 7 (5): R788-795. 10.1186/bcr1304.CrossRefPubMedPubMedCentral
24.
Dabrow MB, Francesco MR, McBrearty FX, Caradonna S: The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecol Oncol. 1998, 71 (1): 29-37. 10.1006/gyno.1998.5121.CrossRefPubMed
25.
Fudge K, Bostwick DG, Stearns ME: Platelet-derived growth factor A and B chains and the alpha and beta receptors in prostatic intraepithelial neoplasia. Prostate. 1996, 29 (5): 282-286. 10.1002/(SICI)1097-0045(199611)29:5<282::AID-PROS2>3.0.CO;2-C.CrossRefPubMed
26.
Stock P, Monga D, Tan X, Micsenyi A, Loizos N, Monga SP: Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer. Mol Cancer Ther. 2007, 6 (7): 1932-1941. 10.1158/1535-7163.MCT-06-0720.CrossRefPubMed
27.
Tawfik OW, Kramer B, Shideler B, Danley M, Kimler BF, Holzbeierlein J: Prognostic significance of CD44, platelet-derived growth factor receptor alpha, and cyclooxygenase 2 expression in renal cell carcinoma. Arch Pathol Lab Med. 2007, 131 (2): 261-267.PubMed
28.
Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Busund LT, Bremnes RM: Prognostic impact of platelet-derived growth factors in non-small cell lung cancer tumor and stromal cells. J Thorac Oncol. 2008, 3 (9): 963-970. 10.1097/JTO.0b013e3181834f52.CrossRefPubMed
29.
Lin YS, Su LJ, Yu CT, Wong FH, Yeh HH, Chen SL, Wu JC, Lin WJ, Shiue YL, Liu HS, et al: Gene expression profiles of the aurora family kinases. Gene Expr. 2006, 13 (1): 15-26. 10.3727/000000006783991962.CrossRefPubMed
30.
Chang TY, Wen YY, Yeh HH, Wang ST, Su IJ, Liu HS: Plasmid harboring lac repressor and tTA activator genes can regulate two inducible genes in mammalian cells. Biotechniques. 1999, 27 (3): 466-469.PubMed
31.
Robinson DR, Wu YM, Lin SF: The protein tyrosine kinase family of the human genome. Oncogene. 2000, 19 (49): 5548-5557. 10.1038/sj.onc.1203957.CrossRefPubMed
32.
Novoradovskaya N, Whitfield ML, Basehore LS, Novoradovsky A, Pesich R, Usary J, Karaca M, Wong WK, Aprelikova O, Fero M, et al: Universal Reference RNA as a standard for microarray experiments. BMC Genomics. 2004, 5 (1): 20-10.1186/1471-2164-5-20.CrossRefPubMedPubMedCentral
33.
Ben-Dor A, Shamir R, Yakhini Z: CAST - Clustering Affinity Search Technique. J Comput Biol. 1999, 6: 281-297. 10.1089/106652799318274.CrossRefPubMed
34.
Eble JNSG, Epstein JI, Sesterhenn IA, (Eds): Multilocular cystic renal cell carcinoma In: World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. 2004, 26-
35.
Chen CC, Shieh B, Jin YT, Liau YE, Huang CH, Liou JT, Wu LW, Huang W, Young KC, Lai MD, et al: Microarray profiling of gene expression patterns in bladder tumor cells treated with genistein. J Biomed Sci. 2001, 8 (2): 214-222. 10.1007/BF02256415.CrossRefPubMed
36.
Mitra AK, Sawada K, Tiwari P, Mui K, Gwin K, Lengyel E: Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin regulates ovarian cancer invasion and metastasis. Oncogene. 2010, 30 (13): 1566-1576. 10.1038/onc.2010.532.CrossRefPubMedPubMedCentral
37.
Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, Tiron C, Lorens JB, Ivaska J: Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2010, 30 (12): 1436-1448. 10.1038/onc.2010.509.CrossRefPubMed
38.
He L, Zhang J, Jiang L, Jin C, Zhao Y, Yang G, Jia L: Differential expression of Axl in hepatocellular carcinoma and correlation with tumor lymphatic metastasis. Mol Carcinog. 2010, 49 (10): 882-891. 10.1002/mc.20664.CrossRefPubMed
39.
Gotzmann J, Fischer AN, Zojer M, Mikula M, Proell V, Huber H, Jechlinger M, Waerner T, Weith A, Beug H, et al: A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene. 2006, 25 (22): 3170-3185. 10.1038/sj.onc.1209083.CrossRefPubMed
40.
Black PC, Brown GA, Inamoto T, Shrader M, Arora A, Siefker-Radtke AO, Adam L, Theodorescu D, Wu X, Munsell MF, et al: Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clin Cancer Res. 2008, 14 (5): 1478-1486. 10.1158/1078-0432.CCR-07-1593.CrossRefPubMed
41.
Mudduluru G, Allgayer H: The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008, 28 (3): 161-176.PubMed
42.
Bonello MR, Khachigian LM: Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter. J Biol Chem. 2004, 279 (4): 2377-2382. 10.1074/jbc.M308254200.CrossRefPubMed
43.
Kawagishi J, Kumabe T, Yoshimoto T, Yamamoto T: Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA. Genomics. 1995, 30 (2): 224-232. 10.1006/geno.1995.9883.CrossRefPubMed
44.
Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, Reveneau S, Vandenbunder B, Fafeur V: Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene. 2002, 21 (15): 2309-2319. 10.1038/sj.onc.1205297.CrossRefPubMed
45.
Reisinger K, Kaufmann R, Gille J: Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription. J Cell Sci. 2003, 116 (Pt 2): 225-238. 10.1242/jcs.00237.CrossRefPubMed
46.
Joseph A, Weiss GH, Jin L, Fuchs A, Chowdhury S, O'Shaugnessy P, Goldberg ID, Rosen EM: Expression of scatter factor in human bladder carcinoma. J Natl Cancer Inst. 1995, 87 (5): 372-377. 10.1093/jnci/87.5.372.CrossRefPubMed
47.
Su LJ, Hsu SL, Yang JS, Tseng HH, Huang SF, Huang CY: Global gene expression profiling of dimethylnitrosamine-induced liver fibrosis: from pathological and biochemical data to microarray analysis. Gene Expr. 2006, 13 (2): 107-132. 10.3727/000000006783991872.CrossRefPubMed
48.
Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, et al: A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007, 26 (27): 3909-3919. 10.1038/sj.onc.1210173.CrossRefPubMed
49.
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, et al: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007, 131 (6): 1190-1203. 10.1016/j.cell.2007.11.025.CrossRefPubMed
50.
Olaussen KA, Commo F, Tailler M, Lacroix L, Vitale I, Raza SQ, Richon C, Dessen P, Lazar V, Soria JC, et al: Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines. Oncogene. 2009, 28 (48): 4249-4260. 10.1038/onc.2009.277.CrossRefPubMed
Metadata
Title
Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer
Authors
Chen-Yun Yeh
Shin-Mei Shin
Hsuan-Heng Yeh
Tsung-Jung Wu
Jyh-Wei Shin
Tsuey-Yu Chang
Giri Raghavaraju
Chung-Ta Lee
Jung-Hsien Chiang
Vincent S Tseng
Yuan-Chii G Lee
Cheng-Huang Shen
Nan-Haw Chow
Hsiao-Sheng Liu
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-139

Other articles of this Issue 1/2011

BMC Cancer 1/2011 Go to the issue

Research article

Single-agent pegylated liposomal doxorubicin (PLD) in the treatment of metastatic breast cancer: results of an Austrian observational trial

Research article

The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development

Research article

Adenoviral infectivity of exfoliated viable cells in urine: Implications for the detection of bladder cancer

Research article

Gain of DNA methylation is enhanced in the absence of CTCF at the human retinoblastoma gene promoter

Review

Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies

Research article

Incidence of bone metastases and skeletal-related events in breast cancer patients: A population-based cohort study in Denmark
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits