J Cancer 2018; 9(18):3326-3333. doi:10.7150/jca.25666

Research Paper

Overexpression of Translocation Associated Membrane Protein 2 Leading to Cancer-Associated Matrix Metalloproteinase Activation as a Putative Metastatic Factor for Human Oral Cancer

Reo Fukushima1, Atsushi Kasamatsu2✉, Dai Nakashima2, Morihiro Higo2, Kazuaki Fushimi3, Hiroki Kasama3, Yosuke Endo-Sakamoto2, Masashi Shiiba4, Hideki Tanzawa1,2, Katsuhiro Uzawa1,2✉

1. Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
2. Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
3. Department of Dentistry and Oral-Maxillofacial Surgery, Eastern Chiba Medical Center, 3-6-2 Okayamadai, Togane, Chiba 283-8686, Japan
4. Department of Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan

Abstract

Translocation associated membrane protein 2 (TRAM2) has been characterized as a component of the translocon that is a gated channel at the endoplasmic reticulum (ER) membrane. TRAM2 is expressed in a wide variety of human organs. To date, no information is available regarding TRAM2 function in the genesis of human cancer. The purpose of this study was to investigate the status of the TRAM2 gene in oral squamous cell carcinoma (OSCC) cells and clinical OSCC samples. Using real-time quantitative reverse transcriptase-polymerase chain reaction, Western blotting analysis, and immunohistochemistry, we detected accelerated TRAM2 mRNA and protein expression levels both in OSCC-derived cell lines and primary tumors. Moreover, TRAM2-positive OSCC tissues were correlated closely (P<0.05) with metastasis to regional lymph nodes and vascular invasiveness. Of note, knockdown of TRAM2 inhibited metastatic phenotypes, including siTRAM2 cellular migration, invasiveness, and transendothelial migration activities with a significant (P<0.05) decrease in protein kinase RNA(PKR) - like ER kinase (PERK) and matrix metalloproteinases (MMPs) (MT1-MMP, MMP2, and MMP9). Taken together, our results suggested that TRAM2 might play a pivotal role in OSCC cellular metastasis by controlling major MMPs. This molecule might be a putative therapeutic target for OSCC.

Keywords: Oral squamous cell carcinoma, Translocation associated membrane protein 2, Tumor metastasis, Tumor invasion, Matrix metalloproteinase

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How to cite this article:
Fukushima R, Kasamatsu A, Nakashima D, Higo M, Fushimi K, Kasama H, Endo-Sakamoto Y, Shiiba M, Tanzawa H, Uzawa K. Overexpression of Translocation Associated Membrane Protein 2 Leading to Cancer-Associated Matrix Metalloproteinase Activation as a Putative Metastatic Factor for Human Oral Cancer. J Cancer 2018; 9(18):3326-3333. doi:10.7150/jca.25666. Available from http://www.jcancer.org/v09p3326.htm