A NOVEL VARIANT OF HUMAN GRB7 IS ASSOCIATED WITH INVASIVE ESOPHAGEAL-CARCINOMA

The cDNAs of a putative growth factor-bound (Grb) 7 signal transductio n molecule and Grb7V novel splice variant were isolated from an invasi ve human esophageal carcinoma. Although both Grb7 isoforms share homol ogy with the Mig-10 cell migration gene, the Grb7V isoform lacks 88 ba se pairs in the C terminus; the resultant frame shift leads to substit ution of an SH2 domain with a short hydrophobic sequence. The wild-typ e Grb7 protein, but not the Grb7V isoform, is rapidly tyrosyl phosphor ylated in response to EGF stimulation in esophageal carcinoma cells. A nalysis of human esophageal tumor tissues and regional lymph nodes wit h metastases revealed that Grb7V was expressed in 40% of Grb7-positive esophageal carcinomas. More importantly, Grb7V expression was enhance d after metastatic spread to lymph nodes as compared to the original t umor tissues. Finally, transfection of an antisense Grb7 RNA expressio n construct lowered endogenous Grb7 protein levels and suppressed the invasive phenotype exhibited by esophageal carcinoma cells. These find ings suggest that Grb7 isoforms are involved in cell invasion and meta static progression of human esophageal carcinomas.