癌症是台灣近30年來造成死亡的重要影響因素。90-95% 的尿路上皮癌發生在膀胱，5-10% 發生在上泌尿道 (腎盂及輸尿管）。膀胱癌的分級(grading)及分期(staging)仍是影響此類病人預後最重要的因素。但是，要能夠精準的篩選需要新輔助性療法之病人，必須找尋更多的預後指標。我們之前的研究證實，病人尿液中可以達到的大豆異黃酮化合物(genistein，daidzein及biochanin-A)濃度，具有不同的抗癌功效。在找尋被大豆異黃酮影響的基因群研究中，EMP2基因是會被大豆異黃酮誘發的其中一個基因。另外，上尿路上皮癌細胞株（如RT-112, KU-19-19, CRL-7930）等可以偵測到染色體19q13的過度表現。而EMP3恰巧落在染色體19q13.3的位置。因此，我們希望研究EMP2 和EMP3在尿路上皮致癌的重要性。在尿路上皮癌模式中，大豆異黃酮可以正相調控EMP2基因的表現。過度表現EMP2會抑制癌細胞株的集落形成及細胞的非貼附性生長，並抑制動物模式中的腫瘤生長。我們也證實，EMP2和整合素V及β3之間有緊密地關係，進一步影響到細胞爬行及貼附能力。以病人檢體的臨床研究發現，EMP2的高度表現會減緩疾病進展，並提高上泌尿道尿路上皮癌病患的存活率。另外，EMP3基因會在ErbB2基因高度表現的尿路上皮癌細胞株(TCC-SUP-N5)中被偵測到。給予trastuzumab藥物進一步確認EMP3會受ErbB2所調控。當EMP3基因在TSGH8301細胞高度表現時，可以經由PI3K/AKT的路徑而有意義的增加細胞生長，並促進癌細胞之爬行能力。但是，EMP3基因高度表現會降低癌細胞與細胞外間質的貼附能力。EMP3也會調控整合素（integrins）的表現，並活化FAK/Src蛋白後，正向調控下游的RhoA/ROCK通路，增加細胞的生物功能。以上尿路上皮癌臨床檢體的研究證實，當ErbB2以及EMP3共同表現時，會促進患者的疾病進展以及轉移進展，並降低患者的存活率。本研究證實，在上尿路上皮癌中EMP2基因扮演抑癌基因的功能，影響整合素之表現，以及細胞的功能。本研究亦釐清，EMP3基因在上尿路上皮癌中扮演致癌基因 (proto-oncogenes)。EMP3與致癌基因ErbB2在上尿路上皮癌有緊密地調控關係。未來可針對EMP2與整合素或EMP3與ErbB2兩者為目標，尋找可能的新治療策略。

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.

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