Expression of the Receptor Tyrosine Kinase Axl Promotes Ocular Melanoma Cell Survival

Ginkel, Paul R. van; Gee, Ricardo L.; Shearer, R. L.; Subramanian, Lalita; Walker, Teresa M.; Albert, Daniel M.; Meisner, Lorraine F.; Varnum, Brian; Polans, Arthur S.

doi:10.1158/0008-5472.can-03-0245

Cited by 79 publications

(55 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we confirm that overexpression of MZF1 is tumorigenic, and for the first time, we report that MZF1 induces tumor growth and metastasis through the transactivation of Axl, thus adding to the molecular targets and mechanisms that can mediate an oncogenic potential of MZF1 in epithelialderived tissues. Axl has been reported as a transforming gene (21) that is overexpressed in several tumors (22)(23)(24)(25)(26)(27), and the Gas6/Axl signaling pathway is known to induce cell proliferation, antiapoptosis, migration, invasion, and angiogenic processes, which are most likely mediated through Ras, Src, mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and NF-κB signaling pathways (14,15,19,29,31,32,(44)(45)(46)(47)(48)(49). However, still further studies are needed to enhance the understanding of the downstream components of the Gas6/Axl signaling axis in tumor formation.…”

Section: Discussionmentioning

confidence: 99%

“…Gas6 binds to TAM family members with different affinities. Gas6 was first discovered as an upregulated gene in growth-arrested cells (12), and further studies with Gas6 signaling suggested its role in cell survival (13,14), proliferation (15,16), stimulation of cell migration (17), and cell-cell adhesion through Axl (18). Intracellular signaling of Axl is also activated by its homophilic and heterophilic interactions (19), mediated mainly by a multisubstrate docking site (20).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

118

129

View full text Add to dashboard Cite

Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159-69. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

118

129

View full text Add to dashboard Cite

show abstract

“…On the other hand, TAM receptors have also been shown to increase proliferation without inhibiting apoptosis (Sainaghi et al, 2005). A third situation exists, whereby TAM receptors promote both survival and proliferation (van Ginkel et al, 2004). Each mechanism provides a means by which TAM receptors may contribute to tumor growth.…”

Section: Cell Survival and Tumor Growthmentioning

confidence: 99%

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Linger¹,

Keating²,

Earp

et al. 2008

Advances in Cancer Research

619

688

View full text Add to dashboard Cite

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

show abstract

“…Overexpression of Axl can transform fibroblasts even in the absence of a ligand (Burchert et al, 1998). Axl is known to induce cell survival (Melaragno et al, 2004;van Ginkel et al, 2004), proliferation (Stenhoff et al, 2004;Sainaghi et al, 2005), stimulation of cell migration and cell-cell adhesion (McCloskey et al, 1997). Moreover, an increased expression of Axl is associated with invasion, metastasis, angiogenesis, and is found in metastatic colon, prostate carcinoma, gastric and endometrial cancers, breast cancers, lung cancers and sarcomas (Hafizi and Dahlback, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

et al. 2011

View full text Add to dashboard Cite

Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3 0 -UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3 0 -UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n ¼ 44), miR34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

show abstract

Expression of the Receptor Tyrosine Kinase Axl Promotes Ocular Melanoma Cell Survival

Abstract: ABSTRACT

Cited by 79 publications

References 47 publications

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Contact Info

Product

Resources

About