MIB1 upregulates IQGAP1 and promotes pancreatic cancer progression by inducing ST7 degradation.

Abstract

Despite recent progress in cancer treatment, the prognosis of patients with pancreatic cancer still remains poor. Pancreatic tumors are reported to display high molecular heterogeneity. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient treatment and survival. The overexpression of E3 ubiquitin ligase mind bomb 1 (MIB1) was previously described in pancreatic cancer cells, where it enhanced tumor cell proliferation. However, the role of MIB1 in pancreatic cancer progression remains elusive. In the present study, we confirmed that MIB1 expression is elevated in pancreatic cancer tissues and that high levels of MIB associate with unfavorable prognosis. Overexpression of MIB1 enhanced proliferation and invasion of pancreatic cancer cells both in vitro and in vivo. We further investigated the molecular mechanisms downstream of MIB1 and observed for the first time that MIB1 targets suppressor of tumorigenicity 7 protein (ST7), previously described as suppressor of tumorigenicity, for proteasomal degradation. Furthermore, we found that ST7 suppressed tumor growth by downregulating IQ motif containing GTPase activating protein 1 (IQGAP1) in pancreatic tumor cells. Thus, these data show that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation followed by downregulation of IQGAP1 in pancreatic cancer cells. In conclusion, our research shows that the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may serve as a novel therapeutic strategy in patients with pancreatic cancer.