PTBP1-mediated regulation of AXL mRNA stability plays a role in lung tumorigenesis

Chun Yu Cho, Shih Ying Chung, Shankung Lin, Jhy Shrian Huang, Yen Lin Chen, Shih Sheng Jiang, Li Chun Cheng, Tsu Hsiang Kuo, Jong Ding Lay, Ya Yu Yang, Gi Ming Lai, Shuang En Chuang

研究成果: 雜誌貢獻文章

3 引文 斯高帕斯(Scopus)

摘要

AXL is expressed in many types of cancer and promotes cancer cell survival, metastasis and drug resistance. Here, we focus on identifying modulators that regulate AXL at the mRNA level. We have previously observed that the AXL promoter activity is inversely correlated with the AXL expression levels, suggesting that post-transcriptional mechanisms exist that down-regulate the expression of AXL mRNA. Here we show that the RNA binding protein PTBP1 (polypyrimidine tract-binding protein) directly targets the 5′-UTR of AXL mRNA in vitro and in vivo. Moreover, we also demonstrate that PTBP1, but not PTBP2, inhibits the expression of AXL mRNA and the RNA recognition motif 1 (RRM1) of PTBP1 is crucial for this interaction. To clarify how PTBP1 regulates AXL expression at the mRNA level, we found that, while the transcription rate of AXL was not significantly different, PTBP1 decreased the stability of AXL mRNA. In addition, over-expression of AXL may counteract the PTBP1-mediated apoptosis. Knock-down of PTBP1 expression could enhance tumor growth in animal models. Finally, PTBP1 was found to be negatively correlated with AXL expression in lung tumor tissues in Oncomine datasets and in tissue micro-array (TMA) analysis. In conclusion, we have identified a molecular mechanism of AXL expression regulation by PTBP1 through controlling the AXL mRNA stability. These findings may represent new thoughts alternative to current approaches that directly inhibit AXL signaling and may eventually help to develop novel therapeutics to avoid cancer metastasis and drug resistance.

原文英語
文章編號16922
期刊Scientific Reports
9
發行號1
DOIs
出版狀態已發佈 - 十二月 1 2019

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    Cho, C. Y., Chung, S. Y., Lin, S., Huang, J. S., Chen, Y. L., Jiang, S. S., Cheng, L. C., Kuo, T. H., Lay, J. D., Yang, Y. Y., Lai, G. M., & Chuang, S. E. (2019). PTBP1-mediated regulation of AXL mRNA stability plays a role in lung tumorigenesis. Scientific Reports, 9(1), [16922]. https://doi.org/10.1038/s41598-019-53097-2