Spleen tyrosine kinase as a novel candidate tumor suppressor gene for human oral squamous cell carcinoma

Abstract

We analyzed the mutational and methylation status of the spleen tyrosine kinase (Syk) gene and both mRNA and protein levels in primary oral squamous cell carcinoma (OSCC) and OSCCderived cell lines and examined the function of the Syk gene in OSCC-derived cell lines in vitro. Using quantitative real-time reverse transcription polymerase chain reaction, Western blotting and immunofluorescence on 7 OSCC-derived cell lines and normal oral keratinocytes (NOKs), Syk mRNA and protein expression were commonly downregulated in all cell lines compared to the NOKs. Although no sequence variation in the coding region of the Syk gene was identified in these cell lines, we found frequent hypermethylation in the CpG island region. Syk expression was restored by experimental demethylation. In addition, using a wound healing assay and in vitro invasion assay, we performed functional analysis using Syk transfected into the OSCC-derived cell lines, and they showed significant inhibition of motility and invasiveness. In clinical samples, high frequencies of Syk downregulation were detected by immunohistochemistry (33 of 53 [62%]). Furthermore, the Syk expression status was correlated significantly (p 5 0.047) with tumor metastasis to cervical lymph nodes. These results suggest that the Syk gene is frequently inactivated during oral carcinogenesis and that an epigenetic mechanism may regulate loss of expression possibly leading to metastasis.

CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma

“…While its major structural domains are preserved (2 tandem SH2 domains and a kinase domain), SYK(S) is characterized by biologic functions that are different from those of SYK(L). Overexpression of SYK(L), but not SYK(S), has been shown to lead to reduced proliferation and invasiveness, indicating that SYK(L) may be a tumor suppressor (15,17). Indeed, the loss of SYK(L) has been recently shown to be associated with tumorigenesis in multiple cancer types.…”

Associations between polymorphisms in the SYK promoter and susceptibility to sporadic colorectal cancer in a Southern Han Chinese population - a short report

“…Accordingly, other studies have shown that observed decreases in SYK protein expression were not due to gene loss in breast cancer, melanoma, pancreatic adenocarcinoma, oral squamous cell carcinoma and CRC (including metastasis) [2,[7][8][9][10][11], whereas additional evidence has shown that nuclear SYK may act as a repressor of oncogene transcription [8]. Together, these findings suggest that decrease or loss of SYK expression may be regulated at the transcriptional level, and that SYK may act as a tumor suppressor.…”

Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis

“…Recently, SYK expression has been demonstrated in numerous nonhematopoietic cells, and its downregulation has been shown to be involved in tumor formation and progression. [3][4][5][6] The transfection of SYK into an SYK-negative cancer cell line dramatically inhibited its cell growth, migration, and invasion. [3][4][5][6] Conversely, the knockdown of SYK in SYK-positive breast cancer cells increased proliferation and invasion.…”

“…[3][4][5][6] The transfection of SYK into an SYK-negative cancer cell line dramatically inhibited its cell growth, migration, and invasion. [3][4][5][6] Conversely, the knockdown of SYK in SYK-positive breast cancer cells increased proliferation and invasion. 7 Several researchers have also reported that the loss of SYK expression correlates with poor survival and tumor metastasis in patients with breast, 8 bladder, 9 liver, 10 pancreas, 5 or stomach cancer.…”

“…11 Epigenetic silencing through hypermethylation of promoter CpG islands has been proposed to be involved in the loss of SYK expression in these tumors. [3][4][5][6] Although SYK was shown to affect cell proliferation, motility, and invasion in several types of cancers, in HCC, its tumor suppressive activity and the molecular mechanisms of its effects remain to be clarified.…”