A High Level of TM4SF5 Is Associated with Human Esophageal Cancer Progression and Poor Patient Survival

Purpose We investigated expression of TM4SF5 and its involvement in human esophageal cancer (HEC). Methods We analyzed TM4SF5 expression in normal esophageal epithelial cells (HEEC), in four HEC cell lines, and in 20 HEC clinical tissue samples and matched nontumor samples. The effect of TM4SF5 on HEC cell proliferation and metastasis and invasion was assessed, and the relationship between TM4SF5 and integrin beta 1 was determined. Finally, TM4SF5 and integrin beta 1 expression were further examined by use of immunohistochemistry (IHC) and tissue microarray analysis, and the prognostic use of TM4SF5 and integrin beta 1 in HEC was evaluated. Results TM4SF5 was more highly expressed in HEC cells and in HEC tissues than in HEEC and matched nontumor tissues. Down-regulation of TM4SF5 in KYSE150 cells reduced cell proliferation and metastasis and invasion whereas metastasis and invasion by KYSE510 increased after TM4SF5 cDNA transfection. In HEC cells, TM4SF5 formed a complex with integrin beta 1, and interference with integrin beta 1 in KYSE510-TM4SF5 cells markedly inhibited cell invasion on laminin 5. Our findings also showed that TM4SF5 and integrin beta 1 overexpression correlated with low differentiation and high stage (p < 0.05, respectively). Postoperative 5-year overall survival of patients with TM4SF5(low) and/or integrin beta 1(low) was higher than for patients with TM4SF5(high) and/or integrin beta 1(high). Multivariate analysis demonstrated that TM4SF5 and integrin beta 1 co-overexpression was an independent prognostic marker for HEC. Conclusion TM4SF5 is positively associated with HEC invasiveness. The combination of TM4SF5 with integrin beta 1 could potentially serve as a novel marker for predicting HEC prognosis.