Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma

Lai, Stephen Y.; Childs, Erin E.; Xi, Sichuan; Coppelli, Francesca M.; Gooding, William E.; Wells, Alan; Ferris, Robert L.; Grandis, Jennifer R.

doi:10.1038/sj.onc.1208635

Cited by 151 publications

(109 citation statements)

References 38 publications

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“…It has been repeatedly reported that enhanced JAK activity promotes cell proliferation and survival in both malignant and benign tumors (16,18,29,38,42,56). Neither RCC cell line demonstrated significant differences in proliferatiion or apoptosis, so the effect of JAK inhibition could not be determined for these phenotypes.…”

Section: Discussionmentioning

confidence: 99%

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Miao²,

Khan³

2007

American Journal of Physiology-Renal Physiology

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Wu KL, Miao H, Khan S. JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism. Am J Physiol Renal Physiol 293: F1836-F1846, 2007. First published September 26, 2007; doi:10.1152/ajprenal.00096.2007 disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia-inducible factors (HIFs). Janus kinases (JAK1, 2, 3, and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3, and TYK2 activities are increased in RCC cell lines, even after serum deprivation or coincubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2␣ shRNA. Invasion through Matrigel and migration in woundhealing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared with wild-type cells, and blocked by dominant-negative JAK expression or JAK inhibitors. Finally, we observe enhanced SOCS2/SOCS1 coprecipitation and reduced SOCS1 expression due to proteasomal degradation in VHLnull RCC compared with wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which lead to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach. Janus kinase; suppressor of cytokine signaling; von Hippel-Lindau syndrome VON HIPPEL-LINDAU (VHL) disease is a heritable multisystem cancer syndrome caused by germline mutations in VHL, which is located on chromosome 3p25 (30). The main causes of death are complications linked to highly angiogenic renal carcinomas and hemangioblastomas within the central nervous system (45, 59). The VHL gene is ubiquitously expressed (60) and the role of the VHL gene product (pVHL) in renal cell carcinoma (RCC) has been extensively studied (31, 49). There are currently no established, successful therapies, e.g., radiation or chemotherapy, for RCC other than nephrectomy in situations with no evidence of metastases.pVHL contains an ϳ100-residue NH 2 terminus (␤-domain) and a smaller COOH-terminal ␣-helix (␣-domain). Under normoxic conditions, the pVHL ␤-domain interacts with ␣-subunits of hypoxia-inducible factors (HIF)-1 and -2 transcription factors (48, 60), while the VHL ␣-domain and a small portion of the ␤-domain interact with Elongin C, a component of an E3 ubiquitin ligase complex that targets HIF-1␣ subunits for proteasomal degradation (31, 43, 64) and thereby prevents HIF transcription factor binding to target gene...

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Section: Discussionmentioning

confidence: 99%

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Miao²,

Khan³

2007

American Journal of Physiology-Renal Physiology

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“…However, further studies are needed with more specific antibodies and greater sample numbers to determine the prognostic significance of EpoR expression on tumors. The biological effects of Epo stimulation of tumor cells is still debated with reports of enhanced survival (8,11), proliferation (4,6,(38)(39)(40), resistance to treatment (38,41,42), tumor angiogenesis (43)(44)(45), chemotaxis (46), invasion (47)(48)(49)(50), and migration (40,46,51). Others have reported no discernible effects of Epo (52).…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

Shi

Hodges

Dunlop

et al. 2010

Molecular Cancer Research

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Erythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA-mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread. Mol Cancer Res; 8(4); 615-26. ©2010 AACR.

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“…9). The established proliferative, angiogenetic and antiapoptotic properties of EPO indicate novel functions of the molecule in tumor progression and invasion (10). These findings are of special concern about administration of recombinant human EPO in cancer patients with anemia.…”

Section: Introductionmentioning

confidence: 93%

Erythropoietin and Its Receptor in Breast Cancer: Correlation with Steroid Receptors and Outcome

Pelekanou

Kampa

Kafousi³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Autocrine/paracrine erythropoietin (EPO) action, promoting cell survival and mediated by its receptor (EPOR) in various solid tumors, including breast carcinoma, questions about the prognostic and therapeutic interest of this system. The expression of EPO/EPOR is steroid dependent in some tissues; however, a clear relationship of EPO/EPOR and steroid receptors in breast cancer has not been established thus far. Recently, the field of steroid receptors has expanded, including rapid effects mediated by membrane-associated receptors, regulating cell survival or apoptosis. The aim of this study was to evaluate EPO/EPOR and membrane-associated steroid receptor expression in breast carcinoma, in view of their prognostic significance, compared with other established markers [estrogen receptor (ER)-progesterone receptor (PR) status and Her2 expression] and hypoxia-induced factor 1 nuclear localization in 61 breast cancer specimens followed for V90 months. We report that EPO-EPOR were expressed in 80% and 84% of samples, although 8% and 2% of nontumoral fields expressed EPO/EPOR too. Membrane-associated receptors for estrogen (mER), progesterone (mPR), and androgen (mAR) were expressed in 96%, 94%, and 93% of cases. Significant correlations between EPO-hypoxiainduced factor 1A, mER-ER, mER-EPO, mAR-EPOR, and mER-mPR-Her2 were found. Finally, EPO, EPOR, and mAR are inversely related to disease-free and overall survival. However, in view of the above correlations, we conclude that EPO/EPOR and membrane steroid receptors are not independent prognostic markers as they are closely related to other established markers. In contrast, they may represent possible new therapeutic targets. (Cancer Epidemiol Biomarkers Prev 2007; 16(10):2016-23)

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Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma

Cited by 151 publications

References 38 publications

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

Erythropoietin-Induced Activation of the JAK2/STAT5, PI3K/Akt, and Ras/ERK Pathways Promotes Malignant Cell Behavior in a Modified Breast Cancer Cell Line

Erythropoietin and Its Receptor in Breast Cancer: Correlation with Steroid Receptors and Outcome

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