Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production

Abstract

Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC). The oral cancer overexpressed 1 (ORAOV1) gene has been identified within this region, but its detailed biological function in human ESCC remains largely unclear. In our clinical samples of stage III ESCC, ORAOV1 amplification was observed in 49 of 94 cases (53%). ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus. Patients with ORAOV1 amplification tended to have a shorter survival period, although the difference was not significant. To investigate the function of ORAOV1, we created ORAOV1-overexpressed ESCC cell lines that exhibited increased cellular proliferation and colony formation, compared with in vitro controls. In vivo, ORAOV1-overexpressed cells exhibited a significantly increased tumorigenicity and a significantly larger tumor volume and poorer differentiation than controls. The peptide mass fingerprinting technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism and reactive oxygen species (ROS) production. Then, ORAOV1-overexpressed cell lines were resistant to stress treatment, which was cancelled by PYCR-knockdown. In addition, the ORAOV1-overexpressed cell line had a higher intracellular proline concentration and a lower ROS level. Our findings indicate that the ORAOV1 gene is frequently amplified in ESCC, enhances tumorigenicity and tumor growth, and is associated with a poorly differentiated tumor histology via proline metabolism and ROS production. ORAOV1 could be a novel target for the treatment of ESCC.

Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients

“…7 These include oncogenes, such as CPT1A , ANO1 , ORAOV1 , CCND1 , FGF3, FGF4, FGF19 , CTTN , and MIR548K ; their contributions to the malignant phenotype of ESCC cells have been verified. 8–11 The genomic material between 11q13.2 and 11q13.3 is nonuniformly increased, with the most recurrent peak spanning CCND1. 12 …”

Identification of candidate target genes of genomic aberrations in esophageal squamous cell carcinoma

“…Togashi et al (7) also reported that oral cancer overexpressed 1 (ORAOV1) located at 11q13 was amplified in 53% of ESCC patients, and its amplification was significantly associated with poor differention status. Overexpression of ORAOV1 could enhance tumorigenicity and tumor growth (7). Thus, the identification of candidate tumor-associated genes is crucial in revealing the mechanism of tumorigenesis of esophageal cancer.…”

Clusterin and Pycr1 alterations associate with strain and model differences in susceptibility to experimental pancreatitis

“…Pycr1 may serve its protective role from oxidative stress and apoptosis possibly through binding with other proteins, such as DJ-1 and ribonucleotide reductase small subunit B [29,31]. Although we did not observed changes in proline levels, other factors such as proline oxidase [32] may be involved. Regardless, the changes reported herein for Pycr1 are novel and the higher Pycr1 levels in FVB/N pancreata correlate with the lower observed caspase-3 activation that we observed.…”