The significance of EMP2 and EMP3 genes on human urothelial cacinoma

Abstract

Human cancer is the most important cause of death in Taiwan over the past 30 years Most of the urothelial carcinoma (UC) (90% to 95%) occurs in the urinary bladder with lower incidence (5% to 10%) in the upper urinary tract (renal pelvis and ureter UUT-UC) The prognosis of UC patients is related to tumor stage and histological grading; however more indicators are mandatory in the design of neoadjuvant or adjuvant therapy We showed that genistein daidzein and biochanin-A demonstrate differential anticancer effects in the range of human urine excretion In a molecular profiling experiment to search for genes modulated by isoflavones epithelial membrane protein 2 (EMP2) is one of the up-regulated candidate genes In addition amplification of 19q13 was detected in UC cell lines (RT-112 KU-19-19 CRL-7930) and EMP3 is localized within this chromosomal region This study was designed to investigate the biological significance of EMP2 and EMP3 in the pathogenesis of UC and their prognostic implication EMP2 was upregulated by isoflavones at both transcriptional and translational levels EMP2 overexpression suppressed foci formation anchorage-independent growth in vitro and tumorigenicity in SCID mice (all P <0 05) In addition a crosstalk between EMP2 and integrins ?V and β3 was demonstrated in regulation of cell adhesion and migration Higher EMP2 expression was associated with a better progression-free survival (P = 0 008) and cancer-related death (P <0 001) In terms of EMP3 we showed a functional crosstalk between ErbB2 and EMP3 in vitro EMP3 overexpression promoted the proliferation and migration of cancer cells but suppressed cell adhesion in vitro EMP3 activated the ErbB2-PI3K-AKT pathway to increase cell growth in vitro Kaplan-Meier survival estimates of clinical cohort showed that co-expression of ErbB2 and EMP3 is the most important indicator of progression-free (P = 0 018 log-rank test) and metastasis-free survival (P = 0 04; log-rank test) for patients with UUT-UC EMP2 was identified as a tumor suppressor gene in UC and may be an innovative co-targeting candidate for designing integrin-based cancer therapy On the contrary EMP3 is an important prognostic indicator in the selection of patients with UUT-UC for more intensive therapy EMP3 is an innovative co-targeting candidate for designing ErbB2-based cancer therapy

Date of Award	2014 Apr 8
Original language	English
Supervisor	Nan-Haw Chow (Supervisor)