Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness.
Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness.
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作者：
四种R-spondin（RSPO 1 -4）及其三种相关受体LGR 4、5和6（LGR 4 -6）已成为主要的配体-受体系统，通过调节Wnt信号传导在发育和干细胞存活中发挥关键作用。RSPO 2（与EIF 3E）和RSPO 3（与PTO 3）的复发性表达获得性基因融合发生在人类结直肠癌的一个亚组中。然而，RSPO-LGR系统在肿瘤发生中的确切作用和机制在很大程度上仍然未知。我们发现RSPO 3在大约一半的Keap 1突变的肺腺癌中以高水平异常表达。这种高RSPO 3表达是由其自身启动子区域的去甲基化和Keap 1缺陷的组合驱动的，而不是像结肠癌中那样的基因融合。RSPO 3高肿瘤患者（约9%，36/412）的生存率远低于其余队列（中位生存期为28个月vs. 163个月，对数秩检验p < 0.0001）。在Keap 1缺陷和RSPO 3-LGR 4高表达的肺癌细胞系中，RSPO 3、LGR 4或其信号传导介质IQGAP 1的敲低导致细胞增殖和迁移的减少，并且LGR 4或IQGAP 1的敲低导致体内肿瘤生长和转移的减少。这些发现表明，异常RSPO 3-LGR 4信号可能作为Keap 1缺陷型肺腺癌侵袭性的驱动机制。
The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of the Keap1-mutated lung adenocarcinomas. This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohorts (median survival of 28 vs. 163 months, logrank test p < 0.0001). Knockdown of RSPO3, LGR4, or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and knockdown of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung adenocarcinomas.
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影响因子：
5.4
作者：
Gattelli, Albana;Zimberlin, Marfa N.;Kordon, Edith C.
通讯作者：
Kordon, Edith C.
DOI：
10.1038/jid.2008.445
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chien AJ;Conrad WH;Moon RT
通讯作者：
Moon RT
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
14.9
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
通讯作者：
Biswal S
影响因子：
--
作者：
Kato, Shigeki;Matsubara, Mitsunobu;Nishimori, Katsuhiko
通讯作者：
Nishimori, Katsuhiko