Regazzo Daniela, Bertazza Loris, Galletta Eva, Barollo Susi, Mondin Alberto, Zovato Stefania, Iacobone Maurizio, Zilio Eleonora, Scaroni Carla, Radu Claudia Maria, di Benedetto Giulietta, Mian Caterina, Lefkimmiatis Konstantinos, Occhi Gianluca
Department of Medicine - Endocrinology Unit, Padova University Hospital, Padova, Italy.
Department of Biology, University of Padova, Padova, Italy.
Endocr Relat Cancer. 2022 Apr 29;29(5):273-284. doi: 10.1530/ERC-21-0258.
The improper expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GIP/GIPR axis activation has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. A high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in humans' and in rats' medullary thyroid cancer (MTC), suggesting a direct link between the neoplastic transformation and the mechanism of receptor overexpression. In this study, we evaluated the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC patients by correlating GIPR mRNA steady-state levels to clinical phenotypes. The molecular effect of GIP/GIPR axis stimulation in MTC-derived cells was also determined. We detected GIPR expression in ~80% of tumor specimens, especially in sporadic, larger, advanced-stage cancers with higher Ki-67 values. GIPR stimulation induced cAMP elevation in MTC-derived cells and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. On the contrary, the effects on PI3K-Akt and MAPK-ERK1/2 signaling pathways were marginal. To conclude, our data confirm the high T/N GIPR ratio in MTC tumors and suggest that it may represent an index for the degree of advancement of the malignant process. We have also observed a functional coupling between GIP/GIPR axis and calcitonin secretion in MTC models. However, the molecular mechanisms underlying this process and the possible implication of GIP/GIPR axis activation in MTC diagnosis and prognosis need further evaluation.
葡萄糖依赖性促胰岛素多肽受体（GIPR）的异常表达以及GIP/GIPR轴激活在内分泌肿瘤中日益受到关注，具有潜在的诊断和预后价值。据报道，在人类和大鼠的甲状腺髓样癌（MTC）中，GIPR的肿瘤与正常组织比率（T/N比率）都很高，这表明肿瘤转化与受体过表达机制之间存在直接联系。在本研究中，我们通过将GIPR mRNA稳态水平与临床表型相关联，评估了GIPR表达在一大群MTC患者中的潜在诊断和预后意义。我们还确定了GIP/GIPR轴刺激对MTC来源细胞的分子效应。我们在约80%的肿瘤标本中检测到GIPR表达，特别是在散发性、较大、晚期癌症且Ki-67值较高的标本中。GIPR刺激导致MTC来源细胞中的cAMP升高以及Ca2+有小但显著的波动，两者可能都与降钙素分泌增加有关。相反，对PI3K-Akt和MAPK-ERK1/2信号通路的影响很小。总之，我们的数据证实了MTC肿瘤中GIPR的高T/N比率，并表明它可能代表恶性进程的进展程度指标。我们还在MTC模型中观察到GIP/GIPR轴与降钙素分泌之间的功能偶联。然而，这一过程的分子机制以及GIP/GIPR轴激活在MTC诊断和预后中的可能意义需要进一步评估。
