LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
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LRIG1 是前列腺癌中的多效性雄激素受体调节反馈肿瘤抑制因子
DOI：
10.1038/s41467-019-13532-4
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发表时间：
2019-12-02
影响因子：
16.6
通讯作者：
Tang, Dean G.
中科院分区：
文献类型：
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作者：
Li, Qiuhui;Liu, Bigang;Tang, Dean G.
据报道，LRIG1在胃肠道和表皮中是一种肿瘤抑制因子。然而，对于LRIG1在前列腺癌（PCa）中的表达、调控和生物学功能知之甚少。我们发现LRIG1在PCa中过表达，但其表达与患者更好的生存相关。功能研究表明，LRIG1在雄激素受体（AR）阳性和AR阴性的异种移植模型中均具有强大的肿瘤抑制功能，并且LRIG1的转基因表达在Hi - Myc和TRAMP模型中抑制肿瘤发展。LRIG1还抑制去势抵抗性前列腺癌，并在已形成的肿瘤中显示出治疗效果。我们进一步表明：1）AR通过与LRIG1基因座中的几个AR结合位点结合直接反式激活LRIG1；2）LRIG1以细胞类型依赖的方式抑制ERBB表达，并抑制ERBB2驱动的肿瘤生长。总之，我们的研究表明，LRIG1是一种多效性的受AR调控的反馈性肿瘤抑制因子，其作用是限制来自AR、Myc、ERBBs以及可能其他致癌驱动因子的致癌信号传导。
LRIG1 has been reported to be a tumor suppressor in gastrointestinal tract and epidermis. However, little is known about the expression, regulation and biological functions of LRIG1 in prostate cancer (PCa). We find that LRIG1 is overexpressed in PCa, but its expression correlates with better patient survival. Functional studies reveal strong tumor-suppressive functions of LRIG1 in both AR+and AR−xenograft models, and transgenic expression of LRIG1 inhibits tumor development in Hi-Myc and TRAMP models. LRIG1 also inhibits castration-resistant PCa and exhibits therapeutic efficacy in pre-established tumors. We further show that 1) AR directly transactivates LRIG1 through binding to several AR-binding sites inLRIG1locus, and 2) LRIG1 dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth. Collectively, our study indicates that LRIG1 represents a pleiotropic AR-regulated feedback tumor suppressor that functions to restrict oncogenic signaling from AR, Myc, ERBBs, and, likely, other oncogenic drivers.