Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the Kras^LSL-G12D/+; Trp53^flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.

中文翻译：

---

miR-200缺乏通过激活癌症相关成纤维细胞中的Notch信号促进肺癌转移

肺腺癌是最普遍的肺癌亚型，其特征在于其高转移倾向。尽管转移在肺癌死亡率中的重要性，其潜在的细胞和分子机制仍然很大程度上难以捉摸。在这里，我们将miR-200 miRNA 鉴定为肺腺癌转移的有效抑制因子。miR-200 的表达在小鼠转移性肺腺癌中受到特异性抑制，而miR-200 的降低与患者存活率低密切相关。一致地，删除Kras ^LSL-G12D/+中的mir - 200c / 141；Trp53 ^flox/flox肺腺癌小鼠模型显着促进了转移，产生了一种非常容易让人联想到转移性人肺癌的促纤维增生性肿瘤基质。肺癌细胞中miR - 200的缺乏会促进邻近癌症相关成纤维细胞 (CAF) 的增殖和活化，进而提高癌细胞的转移潜能。miR-200至少部分通过靶向癌细胞中的 Notch 配体 Jagged1 和 Jagged2 并诱导相邻 CAF 中的 Notch 激活来调节癌细胞和 CAF 之间的功能相互作用。因此，癌细胞和CAFs之间的相互作用构成了促进转移潜能的重要机制。