MEG3 is associated with gsp oncogene regulation of growth hormone hypersecretion, proliferation and invasiveness of human GH‑secreting adenomas

Abstract

Overactivation of the Gs-mediated pathway by mutations of the G-protein α subunit (Gsα), a gsp oncogene, results in increased growth hormone (GH) hypersecretion and reduced tumor volume in patients with GH-secreting pituitary tumors. However, the mechanism underlying the clinical characteristics of gsp oncogene requires further investigation. Cyclic adenosine monophosphate-responsive element binding (CREB), as a downstream target gene of gsp oncogene, is implicated in activating maternally expressed gene 3 (MEG3). The present study proposes that gsp oncogene mediates MEG3-regulating GH hypersecretion, resulting in the small tumor size of GH-secreting tumors. Therefore, the present study detected Gsα mutations by polymerase chain reaction in GH-secreting tumors, and revealed that Gsα mutations were observed in 7/25 (28%) GH-secreting tumors. Gsp-positive tumors indicated significantly increased levels of phosphorylated p-CREB (P<0.0001) and MEG3 (P=0.039), compared with gsp-negative tumors. The results indicated that MEG3 levels were positively correlated with GH and IGF-1 levels, and negatively correlated with the tumor volume of GH-secreting tumors. The group with gsp-positive or with high MEG3 expression indicated a significantly reduced proportion of invasiveness and lower Ki-67 index, compared with the gsp-negative or low MEG3 expression group. In conclusion, gsp oncogene may mediate MEG3 by promoting GH hypersecretion, resulting in smaller tumors, as well as suppressing proliferation and invasiveness of GH-secreting pituitary tumors.

GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer

“…In particular, the study by Mezzomo et al highlighted a higher expression of MEG3 in GH-secreting pituitary adenomas with respect to nonfunctioning pituitary adenomas, where the expression was lost in most samples (70). Consistently, the study by Tang et al reported that MEG3 levels were increased in GH-secreting pituitary tumors with respect to non-functioning pituitary tumors (71). Moreover, the authors reported that MEG3 levels were positively correlated with GH and IGF1 serum levels, whilst they were negatively correlated with tumor size.…”

“…The proposed mechanism involves Gsp which enhances MEG3 expression by means of phospho-CREB overexpression leading to a reduction in cell proliferation and invasiveness. Indeed, a cAMP responsive element is located at the MEG3 proximal promoter region and is critical for MEG3 activity (71). This study reveals a new possible pivotal gene in the development of pituitary tumors, and this could be useful in the development of novel therapeutic strategies against pituitary adenomas.…”

“…Two studies have reported the involvement of the lncRNA MEG3 in the development of GH-secreting pituitary adenomas (70,71). LncRNA MEG3 is encoded by a maternally imprinted gene and suppresses cell proliferation (117).…”

Research Progress on lncRNA Functions and Mechanisms in Pituitary Adenomas

“…Therefore, PCNA and MEG3 are negatively correlated. According to Tang et al [36], MEG3 levels in GHPAs (Growth hormone-secreting pituitary adenomas) are directly proportional to GH and IGF1 (Insulin-like growth factor 1) levels, but inversely proportional to GHPAs volume. Moreover, the invasive ratio in GSP positive or MEG3 high expression groups is significantly lower than that in other groups.…”

“…▶table 1 lncRNAs in PAs. As a tumor suppressor, it was negatively correlated with the development and invasiveness of NFPAs[28,[33][34][35][36] …”