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

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.

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

“…It is now recognized that angiogenesis plays a crucial role in the establishment of cancer and is the rate-determining step in tumor progression (7,8). Numerous studies have demonstrated the key participation of MMPs along with EMT to promote angiogenesis, infiltration by cancer cells, and metastasis (9)(10)(11)(12)(13). MMPs are a family of zinc-binding metalloproteinases that participate in the degradation of ECM components, including the basement membrane and the tumor surface, resulting in tumor cell migration into the near tissue.…”

Glycosylated Nanoparticles for Cancer-Targeted Drug Delivery

“…Changes in the intrinsic glycosylation of cell surface adhesion molecules, such as selectin ligands, integrins, and mucins, have been implicated in changes in the tumor microenvironment that can contribute to drug resistance and pH acidification (29), which lead to more aggressive cancer cell phenotypes; thus, their implications in the design of glycan-based therapies should be investigated (30). Therefore, glycans, glycoproteins, glycan-binding proteins, and proteoglycans are mechanistically implicated in cancer hallmarks (31,32). For instance, lowered tumor extracellular pH (pHe) and upregulation of the membrane protein matrix metalloproteinase 2 (MMP2) in the tumor microenvironment has been exploited as a strategy to improve the selectivity of plasmid DNA release.…”

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

“…In chronic myeloid leukemia, eIF2α is constitutively phosphorylated and enhances invasive ability of tumor cells but also tumor associated stromal fibroblasts by modulating ECM remodeling through cathepsin and MMPs expression via the induction of ATF4 [154]. Interestingly, TRAM2 (for translocation associated membrane protein 2), a component of the SEC61 translocation channel located at ER, is highly expressed in oral squamous cell carcinoma and has a main role in metastasis by controlling PERK activation and the expression of MT1-MMP, MMP2, and MMP9 [155]. Breast cancer cell lines exhibit increased secretion of ECM proteins that perturbs ER morphology due to the overload in secretory proteins and show a constitutively activated PERK/eIF2α/ATF4 axis [156].…”