- Open Access
JAG1 overexpression contributes to Notch1 signaling and the migration of HTLV-1-transformed ATL cells
© The Author(s). 2018
- Received: 9 April 2018
- Accepted: 10 September 2018
- Published: 19 September 2018
HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms.
We analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells.
Here, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells.
Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.
The Notch pathway is one of the most frequently activated signaling pathways in human malignancies. Activating mutations or amplification of the Notch pathway is commonly reported in various types of human cancer. T cell and glial cell cancers are especially prone to having an oncogenic Notch pathway, since Notch plays a key role in differentiation and development in these cell types . Activated Notch1 has also been shown to play important roles in virus-associated cancers such as Kaposi’s sarcoma (KSHV)  and HCV- or EBV-associated lymphoma [3, 4]. The human Notch family includes four receptors, Notch 1–4, and five ligands, delta-like ligand 1 (DLL1), delta-like ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2) . In physiological conditions, interactions between these ligands and the extracellular domain of the Notch receptor, which is located on the cellular surface of neighboring cells, lead to the proteolytic cleavage and release of the Notch intracellular domain (NICD). NICD then translocates to the nucleus where it interacts with DNA-binding proteins and activates target genes. Termination of Notch1 signaling can occur at, or downstream of, the Notch receptor through ubiquitin ligases Itch/AIP4 (itchy E3 ubiquitin protein ligase) or Nedd4 (neural precursor cell-expressed developmentally downregulated protein 4) [6, 7]. NICD can also be phosphorylated by glycogen synthase kinase 3 beta (GSK3β), which regulates its interaction with the E3 ubiquitin ligase, FBXW7 (F-box and WD repeat domain containing 7). This promotes ubiquitination and proteasome-mediated degradation of NICD .
The average life expectancy for HTLV-I-associated acute adult T cell leukemia (ATL) is less than 12 months, and since there is no cure for the disease and treatment options are very limited, new therapeutic targets are greatly needed . Although the etiologic agent has been well characterized, a mechanistic understanding of the initiation and progression of this disease has been elusive. The low incidence and long latency of HTLV-I-associated ATL suggest that in addition to viral infection, accumulation of genetic mutations and genomic alterations is required for cellular transformation . In the early stages of the transformation process, the viral transcriptional activator protein Tax plays an essential role by disrupting the normal state of many cellular signaling pathways, inactivating tumor suppressors, increasing the mutation rate, and inhibiting DNA repair pathways [11, 12]. We have previously demonstrated that HTLV-I-transformed cells and ATL cells display constitutive activation of Notch1 signaling . We further demonstrated that inhibition of Notch1 signaling by a gamma-secretase inhibitor (GSI) reduced ATL tumor cell proliferation and tumor formation in a xenograft mouse model of ATL .
Notch1 activating mutations have been reported in various cancers . Genetic aberrations in hematological malignancies frequently involve Notch receptors or its regulators, such as FBXW7. In T cell acute lymphocytic leukemia (T-ALL) patients, these mutations usually cluster at the hetero-dimerization (HD) and proline-glutamate-serine-threonine-rich (PEST) domains of Notch . HD domain mutations are characterized by ligand-independent constitutive cleavage of the Notch1 receptor, resulting in increased expression of NICD. In contrast, mutations in ATL patients do not occur in the HD domain, but instead occur solely in the PEST domain of NICD. Mutations in the PEST domain have been shown to increase the stability of NICD. As much as 30% of ATL patients harbor mutations within the PEST domain of NICD, thereby preventing proper ubiquitination and NICD proteasome degradation . These observations and the lack of mutations within the HD domain of NICD in ATL patients suggests that interaction between the Notch receptor and one of its ligands is required for activation of Notch signaling in ATL cells.
To better understand the regulation of the Notch signaling pathway in ATL, we investigated the expression of Notch receptor ligands. Here, we show that HTLV-I-transformed and fresh uncultured ATL cells overexpress JAG1 and to a lesser extent DLL4. We further demonstrate that the viral Tax protein, but not HBZ, stimulates expression of JAG1 in part through activation of the nuclear factor kappa B (NF-κB) pathway. In ATL cells, the expression of JAG1 is also correlated with the transcriptional regulators, STAT3 (signal transducer and activator of transcription 3) and NFATc1 (nuclear factor of activated T cells 1). We also show that miR-124 expression can target STAT3 and NFATc1 to lower JAG1 expression in ATL cells. Finally, we found that blockade of JAG1 signaling by shRNA or neutralizing antibodies dampened Notch signaling and limited cell migration of transformed ATL cells. Our results suggest that JAG1 may represent a new target for immunotherapy in ATL patients.
Cell cultures and ATL patient samples
The HTLV-I-transformed (IL-2 independent) cell lines (MT2, MT4, C8166, and C91PL), ATL-like cell lines (ATLT, ATL25, ED-40515(−), and TL-Om1), and ALL cell lines (Jurkat and Molt4) were grown in RPMI 1640 with 10% fetal bovine serum. The HTLV-I-immortalized (IL-2 dependent) cell lines (LAF and 1185) and the ATL-like cell lines (ATL43T, ATL55T, KOB, KK1, SO4, and LM-Y1) were grown in media with 20% serum and 50 U/mL IL-2. The ATL patient samples used in this study were previously described in another publication [13, 16]. Samples were obtained after informed consent after internal institutional review board approval, respecting the regulations for the protection of human subjects. The present study control samples consist of isolated peripheral blood mononuclear cells (PBMCs) from healthy HTLV-1-negative donors that have been previously reported . Pharmacological inhibitors used to treat cells include STAT3 inhibitor, S3I-201 (Calbiochem), and NFAT inhibitor (Cayman Chemical Company).
RNA extraction and RT-PCR
RNA was extracted using TRIzol (Invitrogen) followed by DNase I treatment and reverse transcription with an RNA-to-cDNA synthesis kit (Applied Biosystems). The StepOnePlus Real-time PCR System (Applied Biosystems) was used in the study to quantify the expression of the genes of interest. The following primers were used in this study with iTaq Universal SYBR green (Bio-Rad): GAPDH (S-GAAGGTGAAGGTCGGAGTC and AS-GAAGATGGTGATGGGATTTC), STAT3 (S-GATTGACCAGCAGTATAGCCGCTTC and AS-CTGCAGTCTGTAGAAGGCGTG), pre-miR-124a (S-AGGCCTCTCTCTCCGTGTTC and AS-CAGCCCCATTCTTGGCATTC), JAG1 (S-ATCGTGCTGCCTTTCAGTTT and AS-GATCATGCCCGAGTGAGAA), JAG2 (S-GTCGTCATCCCCTTCCAGT and AS-CTCCTCATTCGGGGTGGTAT), DLL4 (S-AGGCCTGTTTTGTGACCAAG and AS-GTGCAGGTGTAGCTTCGCT), IL-8 (S-CTGATTTCTGCAGCTCTGTGTG and AS-CAGACAGAGCTCTCTTCCATCAG), RelA (S-CTCTGCTTCCAGGTGACAGT and AS-TCCTCTTTCTGCACCTTGTC), Hes1 (S-CTGGAAATGACAGTGAAGCACCT and AS-ATTGATCTGGGTCATGCAGTTG), Hey1 (S-CCGAGATCCTGCAGATGACC and AS-CCCGAAATCCCAAACTCCGA), and VEGF (S-TCTACCTCCACCATGCCAAGT and AS- GATGATTCTGCCCTCCTCCTT). NFATc1 was detected using iTaq Universal Probes (Bio-Rad) with the following primers: NFATc1 (S-CCATCCTCTCCAACACCAAA, AS-GTCTCTCCTTTCCGAAGTTCAA, and probe-ACTGTGCCGGAATCCTGAAACTCA).
Antibody staining and fluorescence-activated cell sorting (FACS)
Cells were collected, washed twice with PBS, and stained with the antibodies according to the manufacturer’s instructions. The samples were then washed twice with PBS before analysis with a LSR II flow cytometer. Fixation with PFA 4% was included for JAG1 antibody staining before incubation with the antibody. The following antibodies were used: FITC anti-human JAG1 (Sino Biological Inc.), FITC Mouse IgG2a isotype control (BD PharMingen), and PE anti-Human DLL4 (Biolegend).
Cells were grown on a coverslip slide coated with poly-Lysine or cytospined onto a coverslip. Cells were then fixed with 4% PFA. Immunohistochemistry (IHC) was performed using an EXPOSE HRP/DAB Detection IHC Kit (Abcam), with JAG1 (R&D Systems) and DLL4 (Abcam) antibodies, counterstaining with Mayer’s hematoxylin (Lillie’s modification) and Bluing reagent (ScyTek). Images were taken with a Nikon Eclipse 80i microscope (Nikon Instruments, Inc., Melville, NY) with a × 60 objective lens and a Nikon DSFI1 camera.
The HTLV-1 Tax gene was cloned into the pTRIPZ, lentiviral inducible vector, engineered to become Tet-On. The pTRIPZ vector contains puromycin resistance, which was used to select a stable cell line. The stable cell lines were incubated in the absence or presence of doxycycline to induce the expression of the viral protein Tax. Tax and HBZ genes were also cloned in the pSIH1-green fluorescent protein (GFP) lentiviral vector. A shRNA against JAG1 was cloned into the pSIH1-GFP vector. The pTRIPZ and miR-124a/pTRIPZ stable lines and the miR-124a/pCDNA construct are previously described . Luciferase assays were performed using the Dual-Luciferase Reporter System (Promega). The wild-type 3′UTR of NFATc1 was cloned into a modified pGL3-Promoter luciferase vector (Promega) with the primers S-GGTCTAGATTGCCACATTGGAGCACTCAGTTCAGC and AS-CCGAATTCCGGCTTTATTGGATCTATTTCCTAACTAC. Mutant NFATC1 3′UTR sites were generated using the site-directed mutagenesis kit (Stratagene).
Cell lysates were separated on SDS-PAGE gels followed by electroblotting to polyvinylidene difluoride membranes and probed with Actin (sc-1615), NFATC1 (7A6), and a Tax mouse monoclonal antibody from the NIH AIDS Reagent Program, HTLV-I Tax Hybridoma (168B17), and with appropriate secondary antibodies from Santa Cruz Biotechnology.
XTT proliferation assays
Cell viability and proliferation were measured by Cell Proliferation Kit II (XTT) (Roche) according to the manufacturer’s instructions. One hundred microliters of cells were seeded in a 96-well plate, and 50 μL of XTT labeling mixture was added to each well and incubated for 4–6 h. Spectrophotometry was used to measure the absorbance at 450 and 620 nm. The results were plotted as mean, and the standard deviation is shown from at least two independent experiments.
Cells were plated in a 12-well plate, and when the cells reached confluence, they were treated with 3 μg/ml of JAG1-neutralizing antibody. After 3 days, the media was removed and replaced with fresh media with 3 μg/ml of JAG1-neutralizing antibody. After 3 days, the p1000 tip was used to scratch the plate. The plate was then washed twice with PBS, and fresh media with neutralizing antibody (3 μg/ml) was added. After 48 h, the cells were fixed with cold methanol (MeOH) and then stained with crystal violet dye (0.5% MeOH) for 20 min at room temperature. Images were taken with an Olympus 1x71 Inverted Microscope with a × 40 objective lens.
Experiments in figures were performed multiple times in duplicate. Representative results were shown in the final figures. P values were calculated by using paired and two-tailed Student’s t test. In the figures, asterisk indicates p value < .05, two asterisks indicate p value < .01, and three asterisks indicate p value < .001. Correlation analysis was performed by using Pearson’s correlation. The Pearson’s correlation coefficient, coefficient of determination, and p values are reported in the figures.
Overexpression of JAG1 in HTLV-I-transformed and ATL-derived patient cell lines
Virus-encoded Tax, but not HBZ, activates JAG1 expression through NF-κB
Regulation of JAG1 expression through direct and indirect mechanisms involving miR-124a, STAT3, and NFATc1 in ATL cells
Overexpression of JAG1 in vivo in freshly isolated uncultured ATL patient RNA samples
Inhibition of JAG1 signaling dampened Notch1 signaling and migration of ATL cells
In the present study, we investigated the molecular mechanisms that lead to constitutive Notch activation in HTLV-I-transformed and ATL cells. Among the Notch ligands, JAG1 was found to be significantly overexpressed both in virus-transformed cell lines and PBMCs isolated from acute ATL patients. Other Notch receptors, including JAG2, DLL1, and DLL4, were not significantly increased across all cells tested. JAG1 induction has been reported to affect both tumor cells and multiple components of the neoplastic microenvironment, including the vasculature and immune cells [26, 27]. Interestingly, several pieces of evidence demonstrate that JAG1 plays a role in some hematopoietic malignancies. For instance, in multiple myelomas, JAG1 is highly expressed and induces Notch activation, which in turn drives myeloma cell proliferation . JAG1 also induces Notch over-activation in B cell chronic lymphocytic leukemia, and JAG1 stimulation in ex vivo cultures protects from spontaneous apoptosis [29, 30]. This demonstrates that JAG1 is important in sustaining the survival of cancer cells. It has also been reported that JAG1 overexpression by bystander and adjacent tumor cells leads to Notch1 activation and promotes cell growth in Hodgkin’s and anaplastic large cell lymphoma , suggesting that high expression of JAG1 might have a role in the activation of Notch1 in HTLV-1-induced leukemia.
Our studies demonstrated that the Tax viral protein stimulates JAG1 gene expression in part through Tax-mediated NF-κB activation and was associated with increased JAG1 cell surface expression. In contrast, the viral gene HBZ had no significant effects on JAG1 expression. We then showed that the microRNA, miR-124a, significantly inhibited the expression of JAG1 in ATL-derived cell lines. The underlying mechanism was identified as miR-124a-mediated direct targeting of JAG1 mRNA as well as miR-124a-targeting STAT3 and NFATc1, two transcriptional factors controlling JAG1 gene expression. Our previous study described decreased expression of miR-124a in an HTLV-I context , suggesting that the absence of a negative regulator might contribute to JAG1 overexpression both in cell lines and ATL patients even in the absence of Tax expression. Consistent with this notion, the expression of STAT3 and NFATc1 were directly correlated to that of JAG1 in primary ATL patients, and pharmacological inhibition of either STAT3 or NFATc1 was associated with decreased JAG1 expression in ATL cell lines.
Activation of the Notch signaling pathway is particularly relevant in HTLV-1-infected cells because its prolonged pharmacological inhibition significantly reduces tumor size in an engrafted ATL mouse model . High expression of JAG1 has been associated with increased migration and invasion of tumor cells and metastasis and poor prognosis in non-small cell lung cancer (NSCLC) . JAG1 is also highly expressed in medulloblastoma and colorectal cancer, and JAG1 causes poorer overall survival in breast cancer [32–34]. Studies have demonstrated that JAG1 signaling in cancer cells can activate downstream pathways such as AP-1 (activator protein 1), MAPK (mitogen-activated protein kinases), EGFR (epidermal growth factor receptor), and NF-κB [27, 35–37]. Along these lines, AP-1, MAPK, and NF-κB have also been shown to be activated in ATL cells. Whether JAG1 overexpression is involved in these processes warrants additional investigation. We also found that inhibition of JAG1 signaling by using a neutralizing antibody or shRNA does not affect the short-term proliferation or survival of ATL cells. It is possible that JAG1 inhibition is not sufficient to completely abrogate Notch1 activation. This notion is supported by the fact that blocking JAG1 reduced expression of Notch1 downstream targets (Hes-1, Hey-1, and VEGF) by 50%. However, our data suggest that inhibition of JAG1 even transiently is sufficient to significantly affect ATL tumor cell migration, which may be a function of JAG1 independent of Notch signaling and warrants additional studies.
Our study demonstrates a significant overexpression of the Notch ligand JAG1 in ATL cells versus normal PBMCs. This overexpression was linked to viral Tax, miR-124a, STAT3, and NFATc1. JAG1 overexpression was associated with Notch1 signaling in ATL cells. Our data further suggests JAG1 as a possible candidate for the development of immunotherapy against ATL cells.
The authors would like to thank Brandi Miller for the editorial assistance.
This work was supported by grant AI103851 and CA141386 to Christophe Nicot.
Availability of data and materials
Materials are available upon request.
MB, RM, HC, and JP conducted the experiments. CN designed the study, interpreted the data, and wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The ATL patient samples were obtained after informed consent after internal institutional review board approval, respecting the regulations for the protection of human subjects. The present study control samples consist of isolated peripheral blood mononuclear cells (PBMCs) from healthy HTLV-1-negative donors previously reported .
Consent for publication
The authors declare that they have no competing interests.
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