LMNA Reduced Acquired Resistance to Erlotinib in NSCLC by Reversing the Epithelial-Mesenchymal Transition via the FGFR/MAPK/c-fos Signaling Pathway.
LMNA Reduced Acquired Resistance to Erlotinib in NSCLC by Reversing the Epithelial-Mesenchymal Transition via the FGFR/MAPK/c-fos Signaling Pathway.
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LMNA通过通过FGFR/MAPK/C-FOS信号通路逆转上皮 - 间质转变，从而降低了NSCLC中获得的erlotinib。
DOI：
10.3390/ijms232113237
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发表时间：
2022-10-31
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
对于表皮生长因子受体（EGFR）突变激活的非小细胞肺癌（NSCLC）患者，表皮生长因子受体酪氨酸激酶抑制剂（EGFR- tkis）是一线治疗方法。然而，大多数最初对EGFR-TKIs有反应的患者最终发展为获得性耐药，限制了治疗的有效性。人们早就知道上皮-间质转化（EMT）导致NSCLC对EGFR-TKIs的获得性耐药。然而，依赖于EMT的耐药机制尚不清楚。本研究旨在揭示LMNA在EMT对NSCLC获得性厄洛替尼耐药调控中的作用。厄洛替尼敏感的HCC827细胞通过逐渐增加厄洛替尼浓度诱导获得性厄洛替尼耐药细胞（HCC827/ER）。我们进行了RNA测序和生物信息学分析，以揭示LMNA在诱导对厄洛替尼获得性耐药性的EMT过程中的作用。通过克隆形成、创面愈合和transwell实验分别检测LMNA对细胞增殖和迁移的影响。免疫荧光法检测emt相关蛋白、细胞核形状和体积、细胞骨架变化。Western blot检测了LMNA调控EMT的潜在分子机制。获得性厄洛替尼耐药的HCC827/ER细胞进行EMT，与亲代敏感细胞相比，LMNA表达较低。LMNA负向调控EMT标志物的表达；HCC827/ER细胞间充质标志物CDH2、SNAI2、VIM、ZEB1、TWIST1表达显著上调。LMNA在HCC827/ER细胞中过表达显著抑制EMT和细胞增殖，且在2.5 μM厄洛替尼的作用下，LMNA的抑制作用增强。此外，LMNA表达的减少导致核变形能力增强和细胞骨架变化。在HCC827/ER细胞中，AKT、FGFR、ERK1/2和c-fos磷酸化水平高于HCC827细胞；此外，在HCC827/ER细胞中，LMNA的过表达降低了AKT、ERK1/2、c-fos和FGFR的磷酸化。总之，我们的研究结果首次证明了LMNA的下调促进EMT在EGFR突变的NSCLC中获得性EGFR- tki耐药。LMNA通过抑制FGFR/MAPK/c-fos信号通路抑制厄洛替尼耐药细胞的增殖和迁移。这些发现表明LMNA是对厄洛替尼获得性耐药的驱动因素，并为EGFR突变的NSCLC患者对厄洛替尼治疗耐药的发展提供了重要信息。
For patients exhibiting non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a first-line treatment. However, most patients who initially responded to EGFR-TKIs eventually developed acquired resistance, limiting the effectiveness of therapy. It has long been known that epithelial–mesenchymal transition (EMT) leads to acquired resistance to EGFR-TKIs in NSCLC. However, the mechanisms underlying the resistance dependent on EMT are unknown. This research aimed to reveal the effects of LMNA in the regulation of acquired resistance to erlotinib by EMT in NSCLC. The acquired erlotinib-resistant cells (HCC827/ER) were induced by gradual increase of concentrations of erlotinib in erlotinib-sensitive HCC827 cells. RNA sequencing and bioinformatics analysis were performed to uncover the involvement of LMNA in the EMT process that induced acquired resistance to erlotinib. The effect of LMNA on cell proliferation and migration was measured by clone-formation, wound-healing, and transwell assays, respectively. The EMT-related protein, nuclear shape and volume, and cytoskeleton changes were examined by immunofluorescence. Western blot was used to identify the underlying molecular mechanism of LMNA regulation of EMT. HCC827/ER cells with acquired resistance to erlotinib underwent EMT and exhibited lower LMNA expression compared to parental sensitive cells. LMNA negatively regulated the expression of EMT markers; HCC827/ER cells showed a significant up-regulation of mesenchymal markers, such as CDH2, SNAI2, VIM, ZEB1, and TWIST1. The overexpression of LMNA in HCC827/ER cells significantly inhibited EMT and cell proliferation, and this inhibitory effect of LMNA was enhanced in the presence of 2.5 μM erlotinib. Furthermore, a decrease in LMNA expression resulted in a higher nuclear deformability and cytoskeletal changes. In HCC827/ER cells, AKT, FGFR, ERK1/2, and c-fos phosphorylation levels were higher than those in HCC827 cells; Furthermore, overexpression of LMNA in HCC827/ER cells reduced the phosphorylation of AKT, ERK1/2, c-fos, and FGFR. In conclusion, our findings first demonstrated that downregulation of LMNA promotes acquired EGFR-TKI resistance in NSCLC with EGFR mutations by EMT. LMNA inhibits cell proliferation and migration of erlotinib-resistant cells via inhibition of the FGFR/MAPK/c-fos signaling pathway. These findings indicated LMNA as a driver of acquired resistance to erlotinib and provided important information about the development of resistance to erlotinib treatment in NSCLC patients with EGFR mutations.
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影响因子：
17.1
作者：
Nilsson MB;Sun H;Diao L;Tong P;Liu D;Li L;Fan Y;Poteete A;Lim SO;Howells K;Haddad V;Gomez D;Tran H;Pena GA;Sequist LV;Yang JC;Wang J;Kim ES;Herbst R;Lee JJ;Hong WK;Wistuba I;Hung MC;Sood AK;Heymach JV
通讯作者：
Heymach JV
影响因子：
12.3
作者：
Grigoryan A;Guidi N;Senger K;Liehr T;Soller K;Marka G;Vollmer A;Markaki Y;Leonhardt H;Buske C;Lipka DB;Plass C;Zheng Y;Mulaw MA;Geiger H;Florian MC
通讯作者：
Florian MC
影响因子：
5.2
作者：
Koulouris, Andreas;Tsagkaris, Christos;Corriero, Anna Chiara;Metro, Giulio;Mountzios, Giannis
通讯作者：
Mountzios, Giannis
影响因子：
4
作者：
Clement MS;Gammelgaard KR;Nielsen AL;Sorensen BS
通讯作者：
Sorensen BS
影响因子：
82.9
作者：
Liu, BH;Wang, JM;Zhou, ZJ
通讯作者：
Zhou, ZJ