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Jak3 Is Involved in CCR7-Dependent Migration and Invasion in Metastatic Squamous Cell Carcinoma of the Head and Neck

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Jak3 Is Involved in CCR7-Dependent Migration and Invasion in Metastatic Squamous Cell Carcinoma of the Head and Neck ONCOLOGY LETTERS 13: 3191-3197, 2017 Jak3 is involved in CCR7-dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck ZHONGTI ZHANG1, FAYU LIU2, ZHENNING LI2, DAN WANG1, RUIWU LI2* and CHANGFU SUN2* Departments of 1Prosthodontics and 2Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, P.R. China Received July 30, 2015; Accepted January 6, 2017 DOI: 10.3892/ol.2017.5861 Abstract. Patients with cervical lymph node metastasis in Introduction squamous cell carcinoma of the head and neck (SCCHN) exhibit a poor prognosis and low 5-year survival rate. It has Squamous cell carcinoma of the head and neck (SCCHN) is been proven that chemokine receptor 7 (CCR7) promotes a common and highly malignant tumor, typically identified in cellular migration and invasion in metastatic SCCHN. In the the middle or late stages of the disease, with a 5-year survival present study, the metastatic SCCHN PCI-37B cell line was rate of 30% (1). SCCHN accounts for >90% of all head and utilized to explore the role of Janus activated kinase-3 (Jak3) in neck tumors (2). Regional cervical metastasis is one of the the CCR7-mediated signaling pathway in metastatic SCCHN most significant biological behaviors of SCCHN. The extent cells. It was observed that phospho-Jak3 was expressed in to which the lymph nodes of various regions are involved and SCCHN tissues. In addition, when the PCI-37B cells were the sites of the cervical lymph node metastases are associated analyzed in response to chemokine ligand 19 (CCL19), the with poor patient prognosis (3,4). Demonstrating the molecular ligand of CCR7, at the indicated time points, the results of the mechanism of the development of cervical metastasis is neces- present study demonstrated that CCR7 induced Jak3 activa- sary in providing novel strategies of SCCHN therapy. tion, and inhibition of Jak3 activity using a specific inhibitor, It is known that chemokines and chemokine receptors ZM39923, significantly attenuated CCR7-induced Jak3 participate in the development of metastasis in various types phosphorylation. Migration and invasion assays and immuno- of cancer tissue (5,6). Among these chemokine receptors, it fluorescence staining experiments demonstrated that CCL19 has been observed that chemokine receptor 7 (CCR7) is highly promoted cell migration, invasion and F-actin rearrangment in expressed in metastatic lymph nodes and invasive SCCHN CCR7-expressing SCCHN cells partially due to the activation cells, promoting preferential lymph node metastasis (7). The of the Jak3 signaling pathway. These results demonstrate that interactions between CCR7 and its ligands serve a major role the Jak3 signaling pathway is important for the CCR7-induced in the malignant metastasis process of head and neck tumors, malignant biological behavior of SCCHN cells. and the upregulation of CCR7 significantly increases the migratory and invasive ability of SCCHN cells (8). Therefore, characterizing the specific role of the CCR7 signaling pathway in the malignant metastasis of SCCHN may be helpful to evaluate whether CCR7 acts as a novel target in SCCHN therapeutic strategies. As a non-receptor protein tyrosine kinase, Janus kinase (Jak) has been demonstrated to serve an important role in regu- Correspondence to: Dr Ruiwu Li or Dr Changfu Sun, Department lating various cell signaling pathways. It was reported that the of Oral and Maxillofacial Surgery, School of Stomatology, China tyrosine phosphorylation of the members of the Janus family Medical University, 117 Nanjing Bei Jie, Heping, Shenyang, of kinases, including Jak1, Jak2, Jak3 and tyrosine kinase Liaoning 110002, P.R. China 2 (Tyk2), may be involved in the occurrence and develop- E-mail: [email protected] ment of prostate and breast cancer (9). Specifically, it has E-mail: [email protected] been demonstrated that Jak3 is involved in dendritic cell * maturation and migration via the CCR7-mediated signaling Contributed equally pathway (10,11). However, whether Jak3 was able to be tyro- Abbreviations: SCCHN, squamous cell carcinoma of the head and sine phosphorylated upon stimulation with chemokine ligand neck; Jak3, Janus activated kinase-3; CCR7, chemokine receptor 7 19 (CCL19) in SCCHN cells, and the specific role of Jak3 activation in the migration and invasion of SCCHN cells, Key words: chemokine receptor 7, squamous cell carcinoma of the remains unknown. head and neck, Janus activated kinase-3 In the present study, the role of Jak3 in SCCHN migra- tion and invasion was evaluated. The appropriate dose and duration of CCL19 (a CCR7 ligand) treatment to activate 3192 ZHANG et al: Jak3 IS INVOLVED IN CCR7-DEPENDENT MIGRATION AND INVASION IN SCCHN Jak3 phosphorylation through the CCR7 signaling pathway 30 min at room temperature. For antigen retrieval, sections was investigated. Furthermore, diverse methodologies were were put in a jar filled with 10 mM sodium citrate buffer applied to examine the role of Jak3 activation on the biological and heated for 10 min at 95˚C using a microwave oven, and behavior of SCCHN cells, including invasion and migra- subsequently cooled to room temperature. Subsequently, tion. In addition, the association between the expression of sections were blocked via incubation with normal goat serum phospho-Jak3, lymphatic metastasis and clinical stage was (cat. no. KIT-9706, Fuzhou Maixin Biotech Co., Ltd., Fuzhou, investigated. The present study observed that the activation of China) for 10 min at room temperature and incubated with Jak3, through the interaction of chemokine receptor CCR7 and rabbit polyclonal anti-phospho-Jak3 antibody (dilution, its ligand, is significantly involved in the invasion and migra- 1:100) overnight at 4˚C. The sections were washed and then tion of metastatic SCCHN. These results demonstrate the role incubated with 50 µl undiluted biotinylated labeled secondary of CCR7 signaling in metastatic SCCHN and provide new antibody (cat. no. KIT-9706, Fuzhou Maixin Biotech Co., therapeutic targets for SCCHN. Ltd.) for 1 h at room temperature, subsequent to the incuba- tion of primary antibody. Then, following washing three times Materials and methods with PBS, sections were further incubated with a complex of avidin/streptavidin-peroxidase for 10 min at room tempera- Human tumor samples and cell lines. In total, 70 SCCHN ture. Following diaminobenzidine development, the sections specimens with the adjacent metastatic (or normal) lymph were then counterstained with hematoxylin for histology. nodes and 10 normal human oral mucosal tissue were obtained Negative controls were conducted by exchange of primary from the Head and Neck Tumor Center, School of Stomatology, antibody for PBS. Images were captured of the stained slides China Medical University (Shenyang, China). SCCHN clas- and they were analyzed by microscopy (Nikon Eclipse 80i; sification, including primary tumors (T), regional lymph nodes Nikon Corporation, Tokyo, Japan) at a magnification of x100. (N), distant metastasis (M) and clinical stage, was determined Tumors were classified according to the percentage of posi- according to the rules of the International Union Against Cancer tive cells: Negative (‑), ≤10% or no staining; weakly positive for Head and Neck Cancer (Tumor node metastasis, TNM (+), 11-50%; positive (++), 51-75%; or strongly positive (+++), classification, 1997) (12). All procedures were performed in >75%. For each experimental condition, ≥5 randomly selected accordance with the provisions of the Declaration of Helsinki fields were analyzed. and approved by the Ethics Committee of the China Medical University. All the specimens were obtained with the consent Western blot assay. To explore whether Jak3 is phosphory- of the patients prior to surgery and in accordance with Health lated by CCL19, the protein expression of phospho-Jak3 and Insurance Portability. Written informed consent was received Jak3 was determined using western blot analysis. PCI-37B from all individuals. cells were exposed to CCL19 at a concentration of 200 ng/ml PCI-37B, a metastatic SCCHN cell line expressing for 0, 0.25, 1, 5, 10, 15 and 30 min. The cells were lysed with CCR7, was donated by the University of Pittsburgh Cancer ice-cold RIPA lysis buffer (Beijing Dingguo Changsheng Institute (Pittsburgh, PA, USA). The cells were cultured in Biotechnology Co., Ltd., Beijing, China) and centrifuged at Dulbecco's modified Eagle's medium (DMEM) containing 13,400 x g at 4˚C, for 30 min. Using a BCA Protein assay 10% fetal bovine serum, penicillin, and streptomycin in an kit, the protein concentration of the supernatants was deter- atmosphere of 5% CO2 and 95% air at 37˚C. The ZM39923 mined. The supernatant in the aliquots, which contained inhibitor treatment at the dose used did not affect the viability equal amounts of total protein (20 µg) were denatured and as determined using the Cell Counting Kit-8 (CCK8; cat. no. electrophoresed by 10% SDS-PAGE. Separated proteins C0038; Beyotime Institute of Biotechnology, Haimen, China) were transferred to nitrocellulose filters. The membrane according to the manufacturer's protocol. was blocked for 1 h at room temperature with 5% non-fat dried milk and subsequently incubated with rabbit polyclonal Reagents and antibodies. CCL19 and monoclonal anti-human anti-Jak3 and anti-phospho-Jak3 antibody (both dilutions, CCR7 antibody (10 µg/ml; cat. no. MAB197) were purchased 1:500) at 4˚C overnight. The primary antibodies were labeled from R&D Systems (Minneapolis,
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