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01-07-2012 | Translational Research and Biomarkers

Axl Is a Prognostic Marker in Oral Squamous Cell Carcinoma

Authors: Chien-Hsing Lee, MD, PHD, Ching-Yu Yen, DDS, Shyun-Yeu Liu, DDS, Chi-Kang Chen, MD, Chi-Fu Chiang, MD, Shine-Gwo Shiah, PHD, Pei-Hsuan Chen, DDS, Yi-Shing Shieh, DDS, PHD

Published in: Annals of Surgical Oncology | Special Issue 3/2012

Abstract

Background

Overexpression of the receptor tyrosine kinase Axl is implicated in several diseases. The present study was conducted to determine the biologic and clinical significance of Axl in oral squamous cell carcinoma (OSCC).

Methods

The expression of Axl was examined in a panel of OSCC cell lines. Activation of Axl by Gas6 treatment and silencing of Axl via Axl shRNA were used to examine the effect of Axl on OSCC cell line. Expression of Axl in cancer tissues were examined by immunohistochemical staining. The associations between Axl expression and clinicopathologic features and prognosis were analyzed.

Results

Varied Axl expression was noted in OSCC cell lines. Compared with control cells, modulated Axl signal affected epithelial-mesenchymal gene expression and cell invasion and migration. The immunoreactivity of Axl was low in normal epithelium, and a progressively increased positive percentage was noted, from normal/hyperplastic epithelium (10.9%) to dysplasia (30.8%) to cancer tissue (54.5%). Axl expression correlated with lymph node status (P = .001) and clinical stage (P = .014) of OSCC. Patients with high expression of Axl showed poor prognosis compared with those with low Axl expression patients (P < .001). In multivariate prognostic analysis according to the Cox proportional hazard regression model, Axl expression remained as an independent prognostic factor (P = .037; CI, 1.042–3.839).

Conclusions

Our data indicated that Axl signal promotes OSCC carcinogenesis and progression. The expression of Axl is a valuable marker for OSCC aggressiveness and clinical outcome.

Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer. 2005;5:127–35.PubMedCrossRef

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.PubMedCrossRef

Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345:1890–900.PubMedCrossRef

Beenken SW, Krontiras H, Maddox WA, Peters GE, Soong S, Urist MM. T1 and T2 squamous cell carcinoma of the oral tongue: prognostic factors and the role of elective lymph node dissection. Head Neck. 1999;21:124–30.PubMedCrossRef

Sciubba JJ. Improving detection of precancerous and cancerous oral lesions. Computer-assisted analysis of the oral brush biopsy. U.S. Collaborative OralCDx Study Group. J Am Dent Assoc. 1999;130:1445–57.PubMed

Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF, et al. A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene. 1991;6:2113–20.PubMed

O’Bryan JP, Frye RA, Cogswell PC, Cogswell PC, Neubauer A, Kitch B, et al. Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991;11:5016–31.PubMed

Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol. 1993;13:4976–85.PubMed

Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988;54:787–93.PubMedCrossRef

10.

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;204:36–44.PubMedCrossRef

11.

Sawabu T, Seno H, Kawashima T, Fukuda A, Uenoyama Y, Kawada M, et al. Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway. Mol Carcinog. 2007;46:155–64.PubMedCrossRef

12.

Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268:314–24.PubMedCrossRef

13.

Lee WP, Wen Y, Varnum B, Hung MC. Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis. Oncogene. 2002;21:329–36.PubMedCrossRef

14.

Keating AK, Kim GK, Jones AE, Donson AM, Ware K, Mulcahy JM, et al. Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Mol Cancer Ther. 2010;9:1298–307.PubMedCrossRef

15.

Goruppi S, Ruaro E, Varnum B, Schneider C. Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts. Mol Cell Biol. 1997;17:4442–53.PubMed

16.

Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C. Gas6 anti-apoptotic signaling requires NF-kappa B activation. J Biol Chem. 2001;276:31738–44.PubMedCrossRef

17.

Allen MP, Zeng C, Schneider K, Xiong X, Meintzer MK, Bellosta P, et al. Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Mol Endocrinol. 1999;13:191–201.PubMedCrossRef

18.

Shankar SL, O’Guin K, Cammer M, McMorris FA, Stitt TN, Basch RS,et al. The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci. 2003;23:4208–18.PubMed

19.

Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC. Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. Ann Oncol. 2001;12:819–24.PubMedCrossRef

20.

Craven RJ, Xu LH, Weiner TM, Fridell YW, Dent GA, Srivastava S, et al. Receptor tyrosine kinases expressed in metastatic colon cancer. Int J Cancer. 1995;60:791–7.PubMedCrossRef

21.

Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, et al. Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia. 2005;7:1058–64.PubMedCrossRef

22.

Sun W, Fujimoto J, Tamaya T. Coexpression of Gas6/Axl in human ovarian cancers. Oncology. 2004;66:450–7.PubMedCrossRef

23.

Liu SY, Chang LC, Pan LF, Hung YJ, Lee CH, Shieh YS. Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol. 2008;44:277–85.PubMedCrossRef

24.

Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA. 2010;107:1124–9.PubMedCrossRef

25.

Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83.PubMedCrossRef

26.

Hafizi S, Dahlback B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006;17:295–304.PubMedCrossRef

27.

Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H, et al. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem. 1996;271:30022–7.PubMedCrossRef

28.

Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, et al. Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14:130–8.PubMedCrossRef

29.

Holland SJ, Powell MJ, Franci C, Chan EW, Friera AM, Atchison RE, et al. Multiple roles for the receptor tyrosine kinase axl in tumor formation. Cancer Res. 2005;65:9294–303.PubMedCrossRef

30.

Koorstra JB, Karikari CA, Feldmann G, Bisht S, Rojas PL, Offerhaus GJ, et al. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009;8:618–26.PubMedCrossRef

31.

Jacob AN, Kalapurakal J, Davidson WR, Kandpal G, Dunson N, Prashar Y, et al. A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145. Cancer Detect Prev. 1999;23:325–32.PubMedCrossRef

32.

Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H, et al. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci USA. 2006;103:5799–804.PubMedCrossRef

33.

Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000;406:536–40.PubMedCrossRef

34.

Nakano T, Tani M, Ishibashi Y, Kimura K, Park YB, Imaizumi N, et al. Biological properties and gene expression associated with metastatic potential of human osteosarcoma. Clin Exp Metastasis. 2003;20:665–74.PubMedCrossRef

35.

Gustafsson A, Martuszewska D, Johansson M, Ekman C, Hafizi S, Ljungberg B, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009;15:4742–9.PubMedCrossRef

Title: Axl Is a Prognostic Marker in Oral Squamous Cell Carcinoma
Authors: Chien-Hsing Lee, MD, PHD
Ching-Yu Yen, DDS
Shyun-Yeu Liu, DDS
Chi-Kang Chen, MD
Chi-Fu Chiang, MD
Shine-Gwo Shiah, PHD
Pei-Hsuan Chen, DDS
Yi-Shing Shieh, DDS, PHD
Publication date: 01-07-2012
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue Special Issue 3/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-011-1985-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Axl Is a Prognostic Marker in Oral Squamous Cell Carcinoma

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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