Ken Shimada

ANGPTL3 is a novel biomarker as it activates ERK/MAPK pathway in oral cancer

Angiopoietin‐like 3 (ANGPTL3), which is involved in new blood vessel growth and stimulation of mitogen‐activated protein kinase (MAPK), is expressed aberrantly in several types of human cancers. However, little is known about the relevance of ANGPTL3 in the behavior of oral squamous cell carcinoma (OSCC). In this study, we evaluated ANGPTL3 mRNA and protein in OSCC‐derived cell lines (n = 8) and primary OSCCs (n = 109) and assessed the effect of ANGPTL3 on the biology and function of OSCCs in vitro and in vivo. Significant (P < 0.05) ANGPTL3 upregulation was detected in the cell lines and most primary OSCCs (60%) compared with the normal counterparts. The ANGPTL3 expression level was correlated closely (P < 0.05) with tumoral size. In patients with T3/T4 tumors, the overall survival rate with an ANGPTL3‐positive tumor was significantly (P < 0.05) lower than that of ANGPTL3‐negative cases. In vitro, cellular growth in ANGPTL3 knockdown cells significantly (P < 0.05) decreased with inactivated extracellular regulated kinase (ERK) and cell‐cycle arrest at the G1 phase resulting from upregulation of the cyclin‐dependent kinase inhibitors, including p21Cip1 and p27Kip1. We also observed a marked (P < 0.05) reduction in the growth in ANGPTL3 knockdown‐cell xenografts with decreased levels of phosphorylated ERK relative to control‐cell xenografts. The current data indicated that ANGPTL3 may play a role in OSCCs via MAPK signaling cascades, making it a potentially useful diagnostic/therapeutic target for use in patients with OSCC.

Lysophosphatidylcholine Acyltransferase1 Overexpression Promotes Oral Squamous Cell Carcinoma Progression via Enhanced Biosynthesis of Platelet-Activating Factor

Background The relevance of lysophosphatidylcholine acyltransferase1 (LPCAT1), a cytosolic enzyme in the remodeling pathway of phosphatidylcholine metabolism, in oral squamous cell carcinoma (OSCC) is unknown. We investigated LPCAT1 expression and its functional mechanism in OSCCs. Methods We analyzed LPCAT1 mRNA and protein expression levels in OSCC-derived cell lines. Immunohistochemistry was performed to identify correlations between LPCAT1 expression levels and primary OSCCs clinicopathological status. We established LPCAT1 knockdown models of the OSCC-derived cell lines (SAS, Ca9-22) for functional analysis and examined the association between LPCAT1 expression and the platelet-activating factor (PAF) concentration and PAF-receptor (PAFR) expression. Results LPCAT1 mRNA and protein were up-regulated significantly (p<0.05) in OSCC-derived cell lines compared with human normal oral keratinocytes. Immunohistochemistry showed significantly (p<0.05) elevated LPCAT1 expression in primary OSCCs compared with normal counterparts and a strong correlation between LPCAT1-positive OSCCs and tumoral size and regional lymph node metastasis. In LPCAT1 knockdown cells, cellular proliferation and invasiveness decreased significantly (p<0.05); cellular migration was inhibited compared with control cells. Down-regulation of LPCAT1 resulted in a decreased intercellular PAF concentration and PAFR expression. Conclusion LPCAT1 was overexpressed in OSCCs and correlated with cellular invasiveness and migration. LPCAT1 may contribute to tumoral growth and metastasis in oral cancer.

Downregulation of Tumour Suppressor Gene TSLC1 mRNA in Human Oral Squamous Cell Carcinoma

Abstract Objectives: To identify changes in the expression patterns of the TSLC1 (tumour suppressor in lung cancer 1) gene family in oral squamous cell carcinoma. Materials and Methods: DNA microarray was performed to analyse gene expression of the TSLC1 gene family in oral squamous cell carcinoma—derived cell lines (HSC2, HSC3, Ca9-22, and Sa3) when compared with normal oral keratinocytes using high-density Affymetrix U133 plus 2.0 GeneChip arrays containing 54,675 probe sets. Comparison of TSLC1 mRNA expression levels between 30 primary oral squamous cell carcinomas and normal tissues was performed by real-time quantitative reverse transcriptase polymerase chain reaction, which was used to confirm the microarray results. Results: Microarray analysis demonstrated TSLC1 expression levels that were downregulated at least 2-fold or more in 3 of 4 oral squamous cell carcinoma-derived cell lines (75%) compared with normal oral keratinocytes. Significant downregulation of TSLC1 expression levels was shown by real-time quantitative reverse transcriptasepolymerase chain reaction analysis in all oral squamous cell carcinoma—derived cell lines and 23 (77%) of 30 primary oral squamous cell carcinomas (p Conclusions: These results suggest that the TSLC1 gene is frequently altered in oral squamous cell carcinoma. This alteration may contribute to carcinogenesis in oral cancer.