Syk Tyrosine Kinase Is Linked to Cell Motility and Progression in Squamous Cell Carcinomas of the Head and Neck

Abstract

Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase C; (PLC;) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syknegative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLC;1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion. [Cancer Res 2007;67(16):7907-16]

IL-21 Enhances the Activity of the TLR–MyD88–STAT3 Pathway but Not the Classical TLR–MyD88–NF-κB Pathway in Human B Cells To Boost Antibody Production

“…Indeed, a Syk inhibitor abrogated the effect of IL-21 on TLR-induced IgG production but not IL-6 production (7). Although we cannot exclude the possible off-target effect of the Syk inhibitors used in our assay, we consider it most likely that our results are explained by syk inhibition, which is in line with previous studies where the same inhibitors were used (32)(33)(34). Our data indicate that IL-21 enhances IgG production through modulating the TLR-MyD88-Syk-STAT3 pathway but not the TLR-MyD88-NF-kB pathway, which is further confirmed by our finding that stimulation of B cells with IL-21 and TLR agonists resulted in an increased activation of STAT3.…”

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

“…Overexpression of this gene has been associated with resistance to cisplatin [34] and may be a druggable target in HNSCC using metformin [55]. The SYK (spleen tyrosine kinase) gene is a member of the family of non-receptor type tyrosine protein kinases and high SYK expression is believed to play a role in cell migration and invasion and is significantly correlated with worse survival in HNSCC [56,57]. This target may be selectively targeted using GS-9973 [58].…”

Syk Tyrosine Kinase Acts as a Pancreatic Adenocarcinoma Tumor Suppressor by Regulating Cellular Growth and Invasion

“…However, it is important to note that higher levels of syk expression were observed in squamous cell carcinomas of the head and neck and their lymph node metastases than normal tissue (high syk expression correlated significantly with poor survival), and further that syk promoted migration and invasion of squamous cell carci-noma of the head and neck cells in vitro. 20 Indeed, the inappropriate activation of syk in breast epithelial cells contributes to cellular transformation, 21 enhanced nuclear factor-B activation, and resistance to tumor necrosis factor-induced apoptosis in mouse mammary tumor virus-mediated tumorigenesis. 22 These data highlight the complex nature of syk activity in regulating processes associated with tumorigenesis, even within the same tissue (ie, breast epithelium), and thus it is not a foregone conclusion that syk will function as a tumor suppressor in all epithelial cells.…”