Abstract
The hypoxic microenvironment is beneficial to the metastasis but not to the proliferation of cancer cells. However, the mechanisms regarding to hypoxia differentially regulating cancer metastasis and proliferation are largely unknown. In this study, we revealed that hypoxia induced the expression of LIN28A at mRNA level but segregated LIN28A mRNAs in the P-bodies and thus inhibits the production of LIN28A protein. This unexpected finding suggests that there may be non-coding role for LIN28A mRNA in the progression of colon cancer. We further showed that the non-coding LIN28A mRNA promotes the metastasis but not proliferation of colon cancer cells in vitro and in vivo. Mechanistically, we revealed that methionyl aminopeptidase 2 (METAP2) is one of the up-regulated metastasis regulators upon over-expression of non-coding LIN28A identified by mass spectrum, and confirmed that it is non-coding LIN28A mRNA instead of LIN28A protein promotes the expression of METAP2. Moreover, we demonstrated that knockdown of DICER abolished the promotional effects of non-coding LIN28A on the metastasis and METAP2 expression. Conclusively, we showed that hypoxia induces the production of LIN28A mRNAs but segregated them into the P-bodies together with miRNAs targeting both LIN28A and METAP2, and then promotes the metastasis by positively regulating the expression of METAP2. This study uncovered a distinctive role of hypoxia in manipulating the metastasis and proliferation by differently regulating the expression of LIN28A at mRNA and protein level.
Highlights
Recent studies demonstrated that hypoxia is a common characteristic of solid malignant tumors and the hypoxic microenvironment is beneficial to cancer metastasis (Dhani et al, 2015)
Detected by Western Blot, the expression of LIN28A protein was not altered or even decreased under both hypoxia models (Figures 1C,D). These results indicate that hypoxia induces LIN28A expression at the mRNA level rather than the protein level in colon cancer cells
We demonstrated that hypoxia-inducible factor 1 alpha (HIF1α) binds to LIN28A in the colon cancer cells by Chromatin Immunoprecipitation (ChIP) assay (Figure 1G)
Summary
Recent studies demonstrated that hypoxia is a common characteristic of solid malignant tumors and the hypoxic microenvironment is beneficial to cancer metastasis (Dhani et al, 2015). The RNA-binding protein LIN28A has been reported to be associated with poor prognosis and often up-regulated in a variety of malignant tumors (Viswanathan et al, 2009; Salmena et al, 2011; Li et al, 2012b; Wang et al, 2016a) and facilitate cancer metastasis (Wang et al, 2016b). Hypoxia and other cellular stresses induce the accumulation of the mRNA-processing bodies (P-bodies) in the cytoplasm, the cytoplasmic granules containing nontranslating mRNAs toward degradation or translation repression (Andrei et al, 2005; Ferraiuolo et al, 2005; Liu et al, 2005; Teixeira et al, 2005) It is undetected if the expression of LIN28A gene at the mRNA level and the protein level is parallel in cancer cells under hypoxia
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
