KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway.
KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway.
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DOI：
10.18632/oncotarget.10625
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Zhang JH
中科院分区：
文献类型：
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作者：
Liu Y;Wang SQ;Long YH;Chen S;Li YF;Zhang JH
目前尚不清楚转化细胞中突变KRASG 12的信号如何传播到周围的非突变细胞并改变微环境以促进肿瘤形成。我们发现，威廉斯-博伦综合征转录因子（WSTF），一种非分泌性蛋白，与分泌性蛋白-神经调节蛋白-3（NRG-3）复合释放。KRASG 12突变体激活NRG 3的转录。细胞外间隙中的WSTF/NRG 3可以激活携带野生型KRAS的正常结肠细胞中的致癌通路，并赋予它们表达NRG 3和释放WSTF/NRG 3的能力。细胞外WSTF/NRG 3促进结肠肿瘤的形成。阻断细胞外WSTF可以恢复具有突变KRAS的结肠癌细胞对西妥昔单抗的敏感性。血清和尿液中WSTF/NRG 3的出现与携带KRASG 12突变体的结肠肿瘤相关。总之，我们的演示为我们理解复杂疾病的生物学发展提供了一条新途径。
It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams–Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.