Rab8 和 Rabin8 介导的肿瘤形成，通过 FGFR 信号传导的超活化 EGFR 信号传导,International Journal of Molecular Sciences

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Rab8 和 Rabin8 介导的肿瘤形成，通过 FGFR 信号传导的超活化 EGFR 信号传导
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2020-10-20 , DOI: 10.3390/ijms21207770
Junghwa Choi ₁ , Jee Young Sung ₁ , Saerom Lee ₁ , Jungyoen Yoo ₁ , Christopher Rongo ₂ , Yong-Nyun Kim ₁ , Jaegal Shim ₁

Affiliation

表皮生长因子受体 (EGFR) 信号传导对于正常发育很重要，例如秀丽隐杆线虫的外阴发育，并且 EGFR 的过度活化通常与癌症发展有关。我们之前的报告通过使用抗 TKI 的人类 EGFR T790-L858 突变体设计 LET-23/EGFR 证明了多外阴 (Muv) 表型，这是一种秀丽隐杆线虫 (jgIs25 菌株) 的肿瘤模型。因为 Rab 蛋白调节囊泡转运，这对受体信号传导很重要，所以我们筛选了 jgIs25 菌株中的 RNAi，以找到对 Muv 形成至关重要的 Rab。在这里，我们展示了 rab-8 RNAi 和 rab-8 (-/-) 突变有效地减少了 Muv 的形成。我们证明了 RABN-8，Rabin8 的直系同源物，被称为 Rab8 的 GEF，通过促进外阴前体细胞分泌 EGL-17/FGF 也是 Muv 形成所必需的。此外，FGFR 抑制剂减少了突变 EGFR 介导的 Muv 形成。我们的数据表明，在 EGFR-TKI 抗性线虫模型中，Rab8 和 Rabin8 通过 FGF 分泌介导 Muv 形成。此外，FGFR-TKI 在 H1975（EGFR T790M-L858R；EGFR-TKI 耐药）中比 H522（野生型 EGFR）和 H1650（EGFR 外显子 19 缺失；EGFR-TKI 敏感）更有效地抑制肺癌细胞系的生长) 细胞，表明 FGFR-TKI 可用于控制具有 EGFR-TKI 抗性突变的癌症。

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Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling

The epidermal growth factor receptor (EGFR) signaling is important for normal development, such as vulval development in Caenorhabditis elegans, and hyperactivation of the EGFR is often associated with cancer development. Our previous report demonstrated the multivulva (Muv) phenotype, a tumor model in C. elegans (jgIs25 strain) by engineering LET-23/EGFR with a TKI-resistant human EGFR T790-L858 mutant. Because Rab proteins regulate vesicle transport, which is important for receptor signaling, we screened the RNAi in the jgIs25 strain to find the Rabs critical for Muv formation. Herein, we show that rab-8 RNAi and the rab-8 (-/-) mutation effectively reduce Muv formation. We demonstrate that RABN-8, an ortholog of Rabin8, known as a GEF for Rab8, is also required for Muv formation by promoting the secretion of EGL-17/FGF from vulval precursor cells. In addition, FGFR inhibitors decreased Muv formation mediated by mutant EGFR. Our data suggest that Rab8 and Rabin8 mediate Muv formation through FGF secretion in the EGFR-TKI-resistant nematode model. Furthermore, FGFR-TKIs more effectively inhibit the growth of lung cancer cell lines in H1975 (EGFR T790M-L858R; EGFR-TKI-resistant) than H522 (wild-type EGFR) and H1650 (EGFR exon 19 deletion; EGFR-TKI-sensitive) cells, suggesting that FGFR-TKIs could be used to control cancers with EGFR-TKI-resistant mutations.

更新日期：2020-10-20

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