Oral squamous cel1 carcinoma(OSCC) is the most common malignancy of head neck region. Typically OSCC cells s how persist ent invasion that frequently leads to local recurrence and distant lymphatic metastasls However, molecular mechanisms of invasion of OSCC remain poorly understood. Her e we identifi ed periostin, interferon induced transmembrane protein l (IF1TM1) and wingless-type MMTV integration site family, member 5B(WNT5B) , as invasion promoting molecules in OSCC by comparing gene expression profiles between a parent OSCC cell line(MSCC-l) and its highly invasive clone(MSCC-1nvl). Overexpression of periostin, IFITMl and WNT5B mRNAs were confirmed in MSCC-1nvl by RT-PCR. Transfection of these molecules promoted invasion of OSCC cells Moreover , siRNA t r eatment of these molecules suppressed invasion of cancer cells in vitro I nter estingly, Periostin, 1F1TMl and WNT5B were highly expressed in OSCCs in comparison with nonnal tissues. 1n an orthotopic mouse model of OSCC, periostin-overexpressing cells metas tasized spontaneously to cervical lymph nodes and t o t he lung through their aggressive invasiveness. These findings suggest that peri ostin, IFITMl and WNT5B play important roles for invasion and of OSCC and can be prognostic markers and therapeutic t argets of OSCC.