LincRNA-p21 promotes p21-mediated cell cycle arrest in benzene-induced hematotoxicity by sponging miRNA-17-5p

Benzene is widely employed in manufacturing and causes hematotoxic effects and leukemia in humans. A long intergenic noncoding RNA (lincRNA)-microRNA (miRNA)-mRNA coexpression and competing endogenous RNA (ceRNA) regulatory network was constructed by bioinformatics analysis based on a benzene-induced aplastic anemia (BIAA) mouse model. In this population-based study, we observed a trend consistent with that in the BIAA mice: lincRNA-p21 and p21 were upregulated, while miRNA-17-5p expression was downregulated in benzene-exposed workers. Moreover, multiple linear regressions indicated that lincRNA-p21 was negatively associated with white blood cell (WBC) counts. Predictive thresholds of hematotoxicity were identified by ROC curve analysis with S-phenylmercapturic acid (SPMA) and lincRNA-p21 showing a better predictive ability than the other parameters and the combination of SPMA and lincRNA-p21 exhibiting the highest predictive value for hematotoxicity. LincRNA-p21 was predominantly present in the cytoplasm of bone marrow cells (BMCs) and K562 cells as assessed by fluorescence in situ hybridization (FISH). Upon exploring the underlying mechanism by which lincRNA-p21 mediates benzene-induced hematotoxicity, we observed that the negative regulation of 1,4-benzoquinone (1,4-BQ) on cell cycle arrest and inhibition of K562 cell proliferation was partially relieved by lincRNA-p21 knockdown, which can inhibit the expression of P21 and thereby suppress the toxic effects of 1,4-BQ. Finally, dual-luciferase reporter gene and RIP assay showed that, by acting as a sponge, lincRNA-p21 reduced the activity of miRNA-17-5p and consequently increased the expression of p21. In conclusion, our research suggested that benzene induces hematotoxicity via the lincRNA-p21/miRNA-17-5p/p21 signaling which might contribute to the underlying mechanism of lincRNA-p21 in benzene-induced hematotoxicity. Therefore, lincRNA-p21 can serve as a potential biomarker for the early detection of hematopoiesis inhibition in individuals with long-term exposure to low-dose benzene.