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LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment.

ABSTRACT: Metastasis to distant organs is a particularly ominous feature of malignant cancer. LKB1 (also known as STK11) has been identified as a tumor suppressor in several types of cancers. Here, we show that LKB1 is at low levels and is negatively associated with poor clinical outcomes in pancreatic cancer (PC). LKB1 is inversely correlated with Snail protein in PC, in which the loss of LKB1 facilitates metastasis through elevating Snail protein level. Furthermore, LKB1 boosts Snail's interaction with E3 ligase FBXL14, leading to increasing ubiquitin-mediated Snail degradation. Notably, metformin could increase Snail protein ubiquitination via augmenting the location of LKB1 at cytoplasm as well as increasing LKB1 expression. Altogether, our data established that LKB1 impedes invasion and metastasis by decreasing the Snail protein level in PC. Targeting the LKB1/FBXL14/Snail axis may represent a promising therapeutic strategy and metformin might be beneficial for PC therapy through activating the LKB1-mediated Snail ubiquitination pathway.

SUBMITTER: Song L

PROVIDER: S-EPMC5980291 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment.

Song Lele L Guo Jingyu J Chang Renxu R Peng Xiaobo X Li Jie J Xu Xiaorong X Zhan Xianbao X Zhan Lixing L

Cancer science 20180501 5

Metastasis to distant organs is a particularly ominous feature of malignant cancer. LKB1 (also known as STK11) has been identified as a tumor suppressor in several types of cancers. Here, we show that LKB1 is at low levels and is negatively associated with poor clinical outcomes in pancreatic cancer (PC). LKB1 is inversely correlated with Snail protein in PC, in which the loss of LKB1 facilitates metastasis through elevating Snail protein level. Furthermore, LKB1 boosts Snail's interaction with ...[more]

PMID: 29601127

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Project description:BACKGROUND:Recent evidence indicates that metformin inhibits mammalian cancer growth and metastasis through the regulation of microRNAs. Metformin regulates miR-381 stability, which plays a vital role in tumor progression. Moreover, increased YAP expression and activity induce non-small cell lung cancer (NSCLC) tumor growth and metastasis. However, the molecular mechanism underpinning how metformin-induced upregulation of miR-381 directly targets YAP or its interactions with the epithelial-mesenchymal transition (EMT) marker protein Snail in NSCLC is still unknown. METHODS:Levels of RNA and protein were analyzed using qPCR, western blotting and immunofluorescence staining. Cellular proliferation was detected using a CCK8 assay. Cell migration and invasion were analyzed using wound healing and transwell assays. Promoter activity and transcription were investigated using the luciferase reporter assay. Chromatin immunoprecipitation was used to detect the binding of YAP to the promoter of Snail. The interaction between miR-381 and the 3'UTR of YAP mRNA was analyzed using the MS2 expression system and co-immunoprecipitation with biotin. RESULTS:We observed that miR-381 expression is negatively correlated with YAP expression and plays an opposite role to YAP in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. The miR-381 function as a tumor suppressor was significantly downregulated in lung cancer tissue specimens and cell lines, which decreased the expression of its direct target YAP. In addition, metformin decreased cell growth, migration, invasion, and EMT via up-regulation of miR-381. Moreover, YAP, which functions as a co-transcription factor, enhanced NSCLC progression and metastasis by upregulation of Snail. Snail knockdown downregulated the mesenchymal marker vimentin and upregulated the epithelial marker E-cadherin in lung cancer cells. Furthermore, miR-381, YAP, and Snail constitute the miR-381-YAP-Snail signal axis, which is repressed by metformin, and enhances cancer cell invasiveness by directly regulating EMT. CONCLUSIONS:Metformin-induced repression of miR-381-YAP-Snail axis activity disrupts NSCLC growth and metastasis. Thus, we believe that the miR-381-YAP-Snail signal axis may be a suitable diagnostic marker and a potential therapeutic target for lung cancer.

Dataset Information

LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment.

Publications

LKB1 obliterates Snail stability and inhibits pancreatic cancer metastasis in response to metformin treatment.

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