<p>Prognostic and Therapeutic Significance of Androgen Receptor in Patients with Gastric Cancer</p>

Abstract

Purpose The clinical studies carried out in the last few decades unequivocally introduced activated androgen receptor (AR) as a pathogenic feature of human malignancies which not only endows cancer cells with survival advantage, but also may be exploited for anticancer interventions. Patients and Methods In this study, we have investigated the expression profile of AR and EMT-related genes in fresh gastric cancer (GC), adjacent nontumor and normal gastric tissues, as well as the effect and molecular mechanisms of AR inhibition in GC cell lines. Results Amongst 60 GC patients, 66.7% overexpressed AR that was remarkably correlated with the overexpression of Snail, β-catenin, Twist1, and STAT3 . AR overexpression was also remarkably associated with unfavorable outcome (HR=3.478, P =0.001); however, multivariate Cox regression analysis indicated that it was not an independent prognostic factor (HR=2.089, P =0.056). This study has investigated simultaneous assessment of AR and EMT-related genes expression and indicated that concurrent overexpression of AR and Snail is an independent unfavorable factor for GC overall survival after adjustment with other variables (HR=2.382, P =0.021). Interestingly, the inhibition of AR signaling by potent AR antagonist enzalutamide suppressed cell growth, migration and invasion of GC cells via regulation of apoptosis-, cell cycle-, and EMT-related gene expressions. Conclusion Our findings have clinical importance proposing AR as an important prognostic factor involved in GC progression and metastasis, and submit AR inhibition as an appealing therapeutic approach for GC patients, either as a single agent or in a combined-modal strategy.

Network pharmacological analysis for the identification of the molecular mechanism ofLilium brownii(Baihe) against gastric cancer: 3-Demethylcolchicine targeting androgen receptor

“…Aberrant AR expression is a major factor in the development and progression of gastric cancer 36 . According to epidemiological studies, men and women experience GC at a ratio of approximately 2:1 regardless of the etiology, which is related to how AR affects this disease 37 38,39 . By regulating the expression and protein activity of oncogene and antioncogene, AR can substantially affect the complex mechanism that causes and promotes the occurrence and advancement of GC [40][41][42][43][44][45] (Table 2).…”

Role of the Androgen Receptor in Gender-Related Cancers

“…In gastric cancer, whose incidence is twice higher in males than in females [123], the AR upregulates the gene that codifies metalloprotease 9 (MMP 9), thus promoting cell invasion [125]. Furthermore, by using the antagonist ENZ, it has been demonstrated how the AR correlates with cell proliferation and survival [123].…”

“…For these reasons, there is a need to investigate new prognostic markers as well as more successful therapies for severe GC. Different reports have indicated that the incidence of GC is significantly higher in men than in women, with a ratio of 2:1 [123], and this will be similar in 2023 [45]. In the 1990s, Wu and colleagues demonstrated for the first time the significant presence of ARs in GC [124], so later reports have since focused on studying the prognostic and therapeutic role of this receptor in GC.…”

“…Tang and colleagues confirmed that AR activity promotes migration, invasiveness, and EMT of cultured GC-derived cells through the upregulation of proteins directly responsible for these processes, such as β-catenin, snail, slug, and alpha smooth muscle actin (α-SMA, [126]). Fard and his research team focused, instead, on the analysis of the effect of AR inhibitors such ENZ on cell proliferation and the EMT in GC [123]. They found that the AR is expressed at a higher level in GC with an advanced TNM stage and its expression is positively correlated to β-catenin and negatively to E-cadherin, while they observed a moderate positive correlation between AR and other EMT markers such as snail, twist1, and STAT3.…”

“…EZN was also able to reduce EMT, reducing the β-catenin, snail, twist1, and STAT3 levels and increasing the E-cadherin level. In addition, the authors observed that the addition of ENZ to 5-fluorouracil (5-FU), an effective chemotherapeutic drug used in GC therapy, increased the effectiveness and the cytotoxicity of 5-FU [123].…”