Background: Cancer-specific oncoproteins are expected to be useful for the development of novel biomarkers and therapeutic targets for oral cancers. Methods: We screened candidate oncoproteins as follows: i) Identification of up-regulated genes in oral cancers by gene microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cells by siRNA/small molecule compounds, iv) Elucidation of their tumor promoting effects by enforced gene expression. Results: Using above mentioned approach, we identified URST1 (Up-regulated solid tumor 1) as a candidate. Immunohistochemical staining showed that URST1 protein expression was observed in 110 (71.0%) of 155 oral cancers that had undergone curative surgery. In addition, high level of URST1 expression was associated with poor prognosis for oral cancer patients (P = 0.0021, by log-rank test) and it was an independent prognostic factor. Reduction of URST1 expression by siRNA specific for URST1 significantly suppressed the growth of oral cancer cell lines and induced G2/M arrest as detected by flowcytometry and time lapse imaging. In contrast, enforced expression of URST1 enhanced the growth of oral cancer cells. The growth of oral cancer cells were inhibited by the URST1 inhibitor. Microarray analysis coupled with siRNAs for URST1 suggested various URST1-related oncogenic pathways in oral cancer cells. Conclusions: URST1 is a possible prognostic biomarker and therapeutic target for oral cancer.