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Patients with germline  AIP  mutations or low AIP protein expression have large, invasive somatotroph adenomas and poor response to somatostatin analogues (SSA).    Methods  To study the mechanism of low AIP protein expression 31 sporadic somatotropinomas with low (n = 13) or high (n = 18) AIP protein expression were analyzed for expression of  AIP  messenger RNA (mRNA) and 11 microRNAs (miRNAs) predicted to bind the 3’UTR of  AIP . Luciferase reporter assays of wild-type and deletion constructs of  AIP -3’UTR were used to study the effect of the selected miRNAs in GH3 cells. Endogenous AIP protein and mRNA levels were measured after miRNA over- and underexpression in HEK293 and GH3 cells.    Results  No significant difference was observed in  AIP  mRNA expression between tumors with low or high AIP protein expression suggesting post-transcriptional regulation. miR-34a was highly expressed in low AIP protein samples compared high AIP protein adenomas and miR-34a levels were inversely correlated with response to SSA therapy. miR-34a inhibited the luciferase- AIP -3’UTR construct, suggesting that miR-34a binds to  AIP -3’UTR. Deletion mutants of the 3 different predicted binding sites in  AIP -3’UTR identified the c.*6–30 site to be involved in miR-34a’s activity. miR-34a overexpression in HEK293 and GH3 cells resulted in inhibition of endogenous AIP protein expression.    Conclusion  Low AIP protein expression is associated with high miR-34a expression. miR-34a can down-regulate AIP-protein but not RNA expression  in vitro . miR-34a is a negative regulator of AIP-protein expression and could be responsible for the low AIP expression observed in somatotropinomas with an invasive phenotype and resistance to SSA.

Regulation of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Protein Expression by MiR-34a in Sporadic Somatotropinomas