Fig. 8: Hypoxia promotes accumulation of miRNA-targeted mRNAs in clinical tumor specimens.

a, b Analysis of all (a) and top 10 (b) non-difference miRNAs between normal tissues (n = 91) and lung cancer tissues (n = 999) from TCGA lung cancer miRNA-seq data. c The expression levels of the top 10 non-difference miRNA-targeted mRNAs were positively correlated (Pearson r = 0.7718, P value (two tailed) < 0.0001(****)) and the non-miRNA targets were slightly negative correlated (Pearson r = −0.07952, P value (two tailed) = 0.0108(*)) with hypoxia scores from TCGA lung cancer (n = 1028) RNA-Seq data, respectively. d The expression levels of the top 10 non-difference miRNA targets and the non-miRNA targets in high-hypoxia lung cancer tissues were much higher and slightly lower than those in low-hypoxia lung cancer tissues, respectively. Clinical lung cancer samples were divided into two groups, low-hypoxia (hypoxia score < 0, n = 457) and high-hypoxia (hypoxia score > 0, n = 571), according to the hypoxia score. Data were mean ± s.d., and P-values were determined by unpaired two-sided t-test. e Mechanistic model summarizing how hypoxia in the tumor microenvironment was an incentive for mRNA accumulation by inducing AGO2 M1-Ubi. Briefly, Hypoxia induces HOIL-1L transcription and enhances LUBAC interacting with AGO2, thereby catalyzing M1-Ubi of AGO2, which can be conversely removed by OUTLIN. M1-Ubi of AGO2 suppresses miRNA-targeted mRNAs loading to AGO2, thus to inhibit the miRISC activity, consequently augment global-mRNA accumulation.