FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein.

The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC.

Zhang Y ，Zhang X ，Ye M ，Jing P ，Xiong J ，Han Z ，Kong J ，Li M ，Lai X ，Chang N ，Zhang J ，Zhang J ... -  《-》

MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the Met gene.

The microRNA miR-182, belonging to the miR-183 family, is one of the most frequently studied cancer-related oncogenic miRNAs that is dysregulated in various cancer tissues, and it plays a crucial role in tumorigenesis and tumor progression. Studies revealed that miR-182 might function as an oncogenic or tumor suppressor miRNA in different tissues. However, the role of miR-182 in the development of lung cancer remains largely unknown. miR-182 expression in tumor samples from 58 patients, normal lung tissue samples, and lung cancer cell lines were evaluated by qRT-PCR. Survival curves were analyzed using the Kaplan-Meier method and compared with a log-rank test. Our study demonstrated that miR-182 is frequently downregulated in metastatic NSCLC cells compared with primary tumor tissues. Over-expression of miR-182 significantly inhibited the migration and invasion of lung cancer cells and promoted the expression of the epithelial marker (E-cadherin) in addition to reducing the levels of Snail in lung cancer cells. Further studies demonstrated that miR-182 negatively regulated Met via direct binding to the Met 3'-untranslated region (3'-UTR). Furthermore, we found that miR-182 suppressed the phosphorylation of AKT and the nuclear accumulation of Snail, a transcription factor that promotes the epidermal to mesenchymal transition (EMT). Moreover, miR-182 could repress cell migration, invasion, and EMT of lung cancer cells induced by hepatocyte growth factor (HGF). miR-182 might suppress the EMT and metastasis via inactivation of Met/AKT/Snail in non-small cell lung cancer (NSCLC) cells, which implicates miR-182 may be useful as a new therapeutic target in NSCLC.

Li Y ，Zhang H ，Li Y ，Zhao C ，Fan Y ，Liu J ，Li X ，Liu H ，Chen J ... -  《-》

Silencing Snail suppresses tumor cell proliferation and invasion by reversing epithelial-to-mesenchymal transition and arresting G2/M phase in non-small cell lung cancer.

Yang X ，Han M ，Han H ，Wang B ，Li S ，Zhang Z ，Zhao W ... -  《-》

FBW7 upregulation enhances cisplatin cytotoxicity in non- small cell lung cancer cells.

Yu HG ，Wei W ，Xia LH ，Han WL ，Zhao P ，Wu SJ ，Li WD ，Chen W ... -  《-》

Knockdown of long non-coding RNA linc-ITGB1 inhibits cancer stemness and epithelial-mesenchymal transition by reducing the expression of Snail in non-small cell lung cancer.

The main cause of death in patients with non-small cell lung cancer (NSCLC) is the progression of cancer metastasis, which can be attributed to multiple factors, such as cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) play important roles in the regulation of the cell cycle, cell proliferation, immune responses, and metastasis in cancers, but the potential roles and mechanisms of lincRNAs in CSC-like properties of cancer have not yet been elucidated. Human NSCLC cell lines (A549 and H1299), highly metastatic cell lines (L9981 and 95D), and their corresponding low-metastatic cell lines (NL9980 and 95C) were subject to quantitative real-time PCR and Western blot, transwell invasion, colony formation, and wound healing assays. Linc-ITGB1 was greatly upregulated in CSC spheres. Linc-ITGB1 knockdown markedly inhibited CSC formation and the expression of stemness-associated genes, such as Sox2, Nanog, Oct-4, c-Myc, and CD133. Depletion of linc-ITGB1 expression also inhibited the in vitro invasive and migratory potential of cells, and further analysis indicated that linc-ITGB1 knockdown increased the expression of the epithelial marker E-cadherin and downregulated the mesenchymal markers vimentin and fibronectin. The EMT-related transcription factor Snail mediated these effects of linc-ITGB1 in NSCLC, and overexpression of Snail significantly reversed the inhibitory effects of linc-ITGB1 depletion. Overall, our study demonstrated that linc-ITGB1 promoted NSCLC cell EMT and cancer stemness by regulating Snail expression.

Guo L ，Sun C ，Xu S ，Xu Y ，Dong Q ，Zhang L ，Li W ，Wang X ，Ying G ，Guo F ... -  《-》