Berrout Jonathan, Kyriakopoulou Eleni, Moparthi Lavanya, Hogea Alexandra S, Berrout Liza, Ivan Cristina, Lorger Mihaela, Boyle John, Peers Chris, Muench Stephen, Gomez Jacobo Elies, Hu Xin, Hurst Carolyn, Hall Thomas, Umamaheswaran Sujanitha, Wesley Laura, Gagea Mihai, Shires Michael, Manfield Iain, Knowles Margaret A, Davies Simon, Suhling Klaus, Gonzalez Yurema Teijeiro, Carragher Neil, Macleod Kenneth, Abbott N Joan, Calin George A, Gamper Nikita, Zygmunt Peter M, Timsah Zahra
School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK.
Division of Clinical Chemistry and Pharmacology, Lund University, 221 85, Lund, Sweden.
Nat Commun. 2017 Oct 16;8(1):947. doi: 10.1038/s41467-017-00983-w.
Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.
最近的证据表明，离子通道TRPA1与肺腺癌（LUAD）有关，但其作用和作用机制尚不清楚。我们之前已经证实，膜受体FGFR2通过其富含脯氨酸的C末端基序介导的异常蛋白质-蛋白质相互作用驱动LUAD进展。在此我们报告，TRPA1的N末端锚蛋白重复序列直接与FGFR2的富含脯氨酸的C末端基序结合，诱导受体的组成性激活，从而促进LUAD的进展和转移。此外，我们发现，在转移至脑时，TRPA1会耗竭，这是由脑星形胶质细胞向癌细胞转移靶向TRPA1的外泌体微小RNA（miRNA-142-3p）所触发的效应。这种下调反过来会抑制TRPA1介导的FGFR2激活，阻碍转移过程。我们的研究揭示了一种直接结合事件，并阐明了TRPA1锚蛋白重复序列在调节FGFR2驱动的致癌过程中的作用；这一机制会受到miRNA-142-3p的阻碍。据报道，TRPA1与肺腺癌（LUAD）有关，但其机制尚不清楚。在此，作者提出TRPA1/FGFR2相互作用在LUAD中具有功能，并表明星形胶质细胞通过外泌体传递的miRNA-142-3p介导TRPA1的下调，从而对抗脑转移。
