Overexpression of Bromodomain and Extraterminal Domain is Associated with Progression, Metastasis and Unfavorable Outcomes: Highlighting Prognostic and Therapeutic Value of the BET Protein Family in Gastric Cancer.

BACKGROUND: As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer. METHODS: In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines. RESULTS: Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex. CONCLUSIONS: Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

Investigation of the Correlation between Androgen Receptor and ZEB1 and its Value in Progression of Gastric Cancer.

BACKGROUND: Zinc-finger Enhancer Binding protein (ZEB1) acts as a transcription factor to promote cancer progression through regulating Epithelial to Mesenchymal Transition (EMT). It is well-known that ZEB1 mRNA expression is directly induced by both Estrogen Receptor (ER) and Progesterone Receptor (PR). Moreover, Androgen Receptor (AR) and PR could bind to the same regulatory element. Since it has been shown that AR overexpresses in Gastric Cancer (GC) as a male-predominant tumor, the goal of this study was to evaluate whether AR could regulate ZEB1 expression in GC. METHODS: The expression profile of ZEB1 in 60 fresh GC and adjacent non-tumor tissues and 50 normal gastric specimens was assessed by qRT-PCR, and the association of ZEB1 expression with clinicopathological features was investigated. Furthermore, possible correlation between ZEB1 and AR was evaluated to elucidate a novel prognostic marker using Kaplan-Meier method and Cox regression model. Finally, molecular interaction of ZEB1 and AR was assessed using a potent AR antagonist in GC cells. RESULTS: Among GC patients, 70.2% (40/57) overexpressed ZEB1 and 64.91% (37/57) overexpressed AR relative to normal gastric tissues. ZEB1 overexpression was significantly correlated with the AR overexpression in GC patients. Moreover, ZEB1 overexpression was remarkably associated with lower overall survival; however, it was not an independent prognostic factor. Evidence shows that simultaneous evaluation of ZEB1 and AR expression could independently predict survival of GC patients (HR= 2.193, p=0.047). CONCLUSION: These findings have clinical importance suggesting simultaneous evaluation of ZEB1 and AR expression as a potential prognostic marker. Moreover, AR may regulate ZEB1 expression in GC cells proposing a possible promising targeted therapy for GC patients.

The Correlation between EGFR and Androgen Receptor Pathways: A Novel Potential Prognostic Marker in Gastric Cancer.

BACKGROUND: Despite worthy biologic rationale and numerous studies introducing therapeutic strategies targeting Epidermal Growth Factor Receptor (EGFR), phase III clinical trials have claimed that these current anti-EGFR agents did not significantly improve overall survival of Gastric Cancer (GC) patients. Therefore, to discover flawless candidates of anti-EGFR therapy and ideal prognostic markers, innovative studies are warranted. METHODS: The aim of this study was to assess the expression profile of EGFR in GC, adjacent non-tumor and normal gastric tissues by qRT-PCR, investigating the association of EGFR expression with clinicopathological features, evaluating possible molecular interaction between EGFR and Androgen Receptor (AR), and elucidating novel prognostic marker using Cox regression model. RESULTS: Among 60 GC patients, 70% (42/60) overexpressed EGFR relative to normal gastric tissues. EGFR overexpression was significantly correlated with the AR overexpression in GC patients. Although EGFR overexpression was remarkably associated with unfavorable outcomes (HR= 4.067, 95% CI= 1.228-13.467, p= 0.022), it was not an independent prognostic factor adjusted for other variables. However, we provided evidences that simultaneous evaluation of EGFR and AR expression, could independently predict the outcome of GC patients and could use as a precise prognostic marker. Moreover, it was revealed that induction or inhibition of AR signaling could alter the mRNA expression of EGFR in GC cell lines. CONCLUSION: By targeting AR and EGFR using a potent AR inhibitor such as Enzalutamide, we postulate the possible crosstalk between EGFR and AR pathways in GC. Moreover, our study provided evidences elucidating a novel promising marker, simultaneous evaluation of EGFR and AR expression, which could properly predict prognosis of gastric cancer patients.