Long noncoding RNAs (lncRNAs) are implicated in human cancer, but their mechanisms of action are largely unknown. In this study, we investigated lncRNA alterations that contribute to colorectal cancer (CRC) through microarray expression profiling in CRC patient samples. Here, we report that the CRC-associated lncRNA PVT1-214 is a key regulator of CRC development and progression; patients with high PVT1-214 expression had a shorter survival and poorer prognosis. In vitro and in vivo investigation of the role of PVT1-214 revealed a complex integrated phenotype affecting cell growth, stem-like properties, migration, and invasion. Furthermore, using RNA pull-down and mass spectrometry, we found that Lin28 (also known as Lin28A), a highly conserved RNA-binding protein, is associated with PVT1-214. Strikingly, we found that PVT1-214 not only upregulated Lin28 protein expression in CRC cells by stabilizing Lin28, but also participated in crosstalk with Lin28 mRNA through competition for miR-128 binding, imposing an additional level of post-transcriptional regulation. In addition, we further show that PVT1-214 repressed expression of let-7 family miRNAs, which was abrogated by Lin28 knockdown. Taken together, our findings support a model in which the PVT1-214/Lin28/let-7 axis serves as a critical regulator of CRC pathogenesis, which may simulate a new direction for CRC therapeutic development.
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This work was supported by grants from the National Natural Science Foundation of China (Grant no. 8187101464, 81600654 and 81600862); the Guangdong Natural Science Foundation (Grant no. 2017A030311035, 2016A030313490 and 2016A030310227); the Fundamental Research Funds for the Central Universities (Grant no. XZYXD2175080); and the Guangdong Provincial Department of Science and Technology (Grant no. 2017A020215146); Guangzhou Science Technology and Innovation Commission (Grant no. 201805010003); and US National Institutes of Health (NIH) grant R01 HL136507.
Conflict of interest
The authors declare that they have no conflict of interest.
Accession numbers: Microarray data have been deposited in the Gene Expression Omnibus database (accession number GSE109454).
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He, F., Song, Z., Chen, H. et al. Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene 38, 164–179 (2019). https://doi.org/10.1038/s41388-018-0432-8
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