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Background/Aims: The pathogenic mechanisms underlying pituitary adenoma formation, progression, and invasion are poorly understood. To identify candidate tumor suppressor genes, we selected somatotroph adenomas as representative of pituitary adenomas. Methods/ Results: We used genome-wide differential expression analysis in 15 invasive and 12 noninvasive somatotroph adenomas. HEPN1 reduction was more frequent in the invasive group, and this result was confirmed by qRT-PCR. To understand the function of HEPN1, the pituitary adenoma cell lines, GH3 and GT1.1, were stably transfected with short hairpin RNA (shRNA) targeting HEPN1 or ectogenic HEPN1 by lentivirus-mediated transfection. We found that HEPN1 overexpression in GH3 and GT1.1 cells inhibited cell proliferation, induced apoptosis, and attenuated invasive capacity, whereas HEPN1 silencing enhanced cell proliferation and invasion accompanied by decreased apoptosis. Western blot analysis revealed that HEPN1 overexpression decreased MMP-2, MMP-9, and Bcl-2 expression, but increased BAX, p53, and caspase-3 expression. In contrast, HEPN1 silencing increased MMP-2, MMP-9, and Bcl-2 expression, but decreased BAX, p53, and caspase-3 expression. Conclusion: Taken together, our results suggest that reduction of HEPN1 may play an important role in the progression of pituitary somatotroph adenomas. HEPN1 may thus be a candidate as a prognostic predictor or an anticancer therapeutic target for patients with somatotroph adenoma. [ABSTRACT FROM AUTHOR]