The absence of PRDM2 involved the tumorigenesis of somatotroph adenomas through regulating c-Myc.

Somatotroph adenoma is the main cause of acromegaly which have peripheral signs with growth of soft tissues and multiple comorbidities. Surgery and adjuvant therapy with somatostatin analogs (SSA) fail in more than 25% of patients. PRDM2, a tumor suppressor, plays an important role in cancer and obesity, including pituitary adenomas. In this study, we analyze the correlation of PRDM2 and oncogene c-Myc in 70 somatotroph adenomas according immunohistochemical staining, furthermore, we probed that whether PRDM2 participates in c-Myc signaling pathway in vitro experiment. 70 somatotroph adenomas patients were divided into low patients and high patients according to median of H-score of PRDM2 or c-Myc. Low PRDM2 patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than high PRDM2 group (P = 0.015, P = 0.031, P = 0.017). High c-Myc patients had higher risk of invasive behavior, larger tumor volume and recurrence chance than low c-Myc group (P = 0.012, P = 0.002, P = 0.015). It was a negative correlation between H-score of PRDM2 and c-Myc (PRDM2 = -0.163 × c-Myc + 67.11, r = -0.407). The ability of cell proliferation was declined in a time dependent manner after overexpression of PRDM2 (PRDM2 group) compared to that in control GH3 cells (P < 0.05). Through flow cytometry assay, PRDM2 could induce the apoptosis and G2/M arrest in GH3 cell (both p < 0.05). Transwell experiment proved less trans-membrane cells in PRDM2 group than those in control group (415 ± 76 vs 145 ± 37, P < 0.01). RT-PCR and western blot both proved PRDM2 could inhibit the level c-Myc and elevate the levels of CDKN1A and CDKN1B. Combined with c-Myc inhibitor 10058-F4, PRDM2 further inhibited cell proliferation and induced more apoptosis in GH3 cell. Taken together, we found that PRDM2 negatively regulated the expression of c-Myc in somatotroph adenomas, and testified the synergism between PRDM2 gene therapy and c-Myc inhibitor in vitro experiment.

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