Reciprocal androgen receptor/interleukin‐6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis

Abstract

Oesophageal squamous cell carcinoma (ESCC), a leading lethal malignancy of the digestive tract, is characterized by marked gender disparity. Clarifying the roles of the function and regulatory pathway of the androgen receptor (AR) will improve our understanding of oesophageal cancer progression, thereby facilitating the personalized management of ESCC. Here we report evidence to show that AR is a key mediator of inflammatory signals in ESCC cancer progression. High AR expression was associated with poor overall survival in tobacco-using ESCC patients but not in ESCC patients not using tobacco. A gain and loss of AR function enhanced and repressed ESCC cell growth, respectively, by altering cell cycle progression. In mice bearing human ESCC xenografts, silencing AR expression attenuated tumour growth, whereas AR overexpression promoted tumour growth in mice of different androgen statuses (male, female, and castrated male). Array assays revealed that the inflammatory cytokine interleukin-6 (IL6) is a prominent AR target gene in ESCC. By directly binding to the IL6 promoter, AR enhances IL6 transcription, and IL6 can in turn activate AR expression, thus forming a reciprocal regulatory circuit to sustain STAT3 oncogenic signalling in ESCC. Moreover, high expression levels of both AR and IL6 in human ESCC predict poor clinical outcome in tobacco users. Together, these data establish that AR promotes ESCC growth and is associated with poor patient prognosis. The discovery of a positive feedback loop between IL6 and AR bridges the knowledge gaps among lifestyle factor-associated inflammation, gender disparity, and oesophageal carcinoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The oncogenic roles of nuclear receptor coactivator 1 in human esophageal carcinoma

“…Given the marked gender disparity in incidence and clinical outcomes of human ESCC, one intriguing question is how sex steroid signaling pathways are involved in the regulation of ESCC oncogenesis and progression . We and others have previously shown that AR and ERβ signaling pathways play important roles in tumorigenesis and progression of esophageal carcinoma.…”

“…The cylindrical tumor cores were punched and transferred to the recipient block using a 2.0‐mm diameter precision punch. Blocks of the tissue microarray (TMA) were cut into 4‐μm sections and processed for IHC as described previously . TMA slides were incubated with anti‐NCOA1 antibody (sc‐8995, Santa Cruz) at room temperature for 1 hour followed by incubation with the HRP‐conjugated secondary antibody at room temperature for 30 minutes.…”

“…Blocks of the tissue microarray (TMA) were cut into 4-μm sections and processed for IHC as described previously. [42][43][44][45] TMA slides were incubated with anti-NCOA1 antibody (sc-8995, Santa Cruz) at room temperature for 1 hour followed by incubation with the HRP-conjugated secondary antibody at room temperature for 30 minutes. Immunostaining was visualized by 3, 3′-diaminobenzidine (DAB), and the cell nuclei were counterstained by hematoxylin.…”

“…jsp). 42,44 2.11 | Statistical analysis SPSS 13.0 (SPSS Inc, Chicago, IL) was used to analyze the data. The correlation between the expression of NCOA1 and clinic-pathological features of ESCC patients was examined by chi-square test.…”

Regulation of sex hormone receptors in sexual dimorphism of human cancers

“…In esophageal adenocarcinoma, AR-dependent androgen signaling suppressed cell proliferation [81] whereas estrogen signaling (through both ERα and ERβ) promoted the cell growth [82, 83]. In contrast, in esophageal squamous cell carcinoma, AR-dependent androgen signaling promoted the cell growth and migration [84–86] whereas whether estrogen signaling suppressed the cell growth through ERα or ERβ was under the debate [85, 87–91]. These studies have been mainly conducted in human esophageal cancer cell lines.…”