Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma

Lee, Hsin‐Jung; Jeng, Yung‐Ming; Chen, Yuling; Chung, Ling Yen; Yuan, Ray-Hwang

doi:10.1093/carcin/bgt372

Cited by 106 publications

(91 citation statements)

References 34 publications

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“…Slug-induced expression of cyclin D1 was also reduced following suppression of Axl. Slug-mediated activation of ERK1/2 and JNK, which are downstream signaling molecules of Axl [29, 30], was reduced by knockdown of Axl (Figure 4H). A reporter assay showed that AP-1 activation by Slug was decreased by suppression of Axl (Figure 4I, upper).…”

Section: Resultsmentioning

confidence: 99%

“…For example, Axl is upregulated by Slug and Snail in MCF10A immortalized breast epithelial cells and plays a critical role in breast cancer cell invasion [26], and Slug induces the expression of Axl among 49 receptor tyrosine kinases at the transcriptional level to activate Axl, which maintains Slug expression through a positive feedback loop [28]. In addition, the Gas6/Axl pathway upregulates Slug expression through MAPK [29, 51], suggesting a positive feedback loop between Slug and Axl during cancer progression. On the other hand, we previously reported that ZEB2 directly interacts/cooperates with Sp1 to function as a transcriptional activator of mesenchymal genes (vimentin, integrin α5, and cadherin-11) to induce invasion [53].…”

Section: Discussionmentioning

confidence: 99%

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TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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“…Hence, it has been studied in many conditions. Gas6 and TAM regulate cell growth and an overactivation of the system has been associated to several neoplastic conditions and proposed as a novel therapeutic target [37,38,39,40,41,42,43,44,45,46,47,48]. Furthermore, TAM receptors are involved in haemostasis.…”

Section: The Gas6/tam Receptors Systemmentioning

confidence: 99%

The Gas6/TAM System and Multiple Sclerosis

Bellan

Pirisi

Sainaghi

2016

IJMS

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Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS.

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“…9,10 AXL is frequently overexpressed in human cancers including lymphocytic leukemia, breast, colon, skin, thyroid and prostate cancer. [11][12][13][14][15][16][17] Down-regulation of AXL by siRNA attenuates the migration and invasion of breast, 18 ovarian, 19 hepatocellular carcinoma, 20 mesothelioma, 21 prostate 22 and pancreatic cancer. 23 Furthermore it has been shown that the inhibition of AXL results in the reduction of cancer progression and metastatic potential and induces apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

Pénzes

Baumann

Szabadkai³

et al. 2014

Cancer Biology & Therapy

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Abbreviations: AKT, RAC-a serine/threonine-protein kinase; FAK, focal adhesion kinase; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbant assay; Gas6, growth arrest specific 6; MAPK, mitogen activated protein kinases; PI3K, phosphatidylinositol 3-kinase; Pyk2, proline-rich tyrosine kinase 2; RTK, receptor tyrosine kinase; siRNA, short interfering RNA; TKI, tyrosine kinase inhibitor; TNBC, triple negative breast cancerBlocking the migration of metastatic cancer cells is a major goal in the therapy of cancer. The receptor tyrosine kinase AXL is one of the main triggers for cancer cell migration in neoplasia of breast, colon, skin, thyroid and prostate. In our study we analyzed the effect of AXL inhibition on cell motility and viability in triple negative breast cancer cell lines overexpressing AXL. Thereby we reveal that the compound BMS777607, exhibiting the lowest IC 50 values for inhibition of AXL kinase activity in the studied cell lines, attenuates cell motility to a lower extent than the kinase inhibitors MPCD84111 and SKI606. By analyzing the target kinases of MPCD84111 and SKI606 with kinase profiling assays we identified Lyn, a Src family kinase, as a target of both compounds. Knockdown of Lyn and the migrationrelated CRK-associated substrate (p130Cas), had a significant inhibitory effect on cell migration. Taken together, our findings highlight the importance of combinatorial or multikinase inhibition of non-receptor tyrosine kinases and AXL receptor tyrosine kinase in the therapy of triple negative breast cancer.

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Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma

Cited by 106 publications

References 34 publications

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

The Gas6/TAM System and Multiple Sclerosis

Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

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