Rahman M M, Qian Z R, Wang E L, Sultana R, Kudo E, Nakasono M, Hayashi T, Kakiuchi S, Sano T
Department of Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Br J Cancer. 2009 Feb 10;100(3):501-10. doi: 10.1038/sj.bjc.6604883. Epub 2009 Jan 20.
The molecular pathogenesis of gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) remains to be elucidated. High-mobility group A (HMGA) proteins play important roles in the regulation of transcription, differentiation, and neoplastic transformation. In this study, the expression of HMGA1 and HMGA2 was studied in 55 GEP NETs. Overexpression of HMGA1 and 2 was frequently detected in GEP NETs compared with normal tissues. Nuclear immunostaining of HMGA1 and 2 was observed in GEP NETs (38 of 55, 69%; 40 of 55, 73%, respectively). High-mobility group A2 expression increased from well-differentiated NET (WNET) to well-differentiated neuroendocrine carcinoma (WNEC) and poorly differentiated NEC (PNEC) (P<0.005) and showed the highest level in stage IV tumours (P<0.01). In WNECs, the expression of HMGA1 and 2 was significantly higher in metastatic tumours than those without metastasis (P<0.05). Gastroenteropancreatic NETs in foregut showed the highest level of HMGA1 and 2 expressions. MIB-1 labelling index (MIB-1 LI) correlated with HMGA1 and 2 overexpression (R=0.28, P<0.05; R=0.434, P<0.001; respectively) and progressively increased from WNETs to WNECs and PNECs (P<0.001). Let-7 expression was addressed in 6 normal organs, 30 tumour samples, and 24 tumour margin non-tumour tissues. Compared with normal tissues, let-7 downregulation was frequent in NETs (19 of 30, 63%). Higher expression of HMGA1 and 2 was frequently observed in tumours with let-7 significant reduction (53, 42%, respectively). The reverse correlation could be detected between HMGA1 and let-7 (P<0.05). Our findings suggested that HMGA1 and 2 overexpression and let-7 downregulation might relate to pathogenesis of GEP NETs.
胃肠胰（GEP）神经内分泌肿瘤（NETs）的分子发病机制仍有待阐明。高迁移率族A（HMGA）蛋白在转录、分化和肿瘤转化的调控中发挥重要作用。在本研究中，对55例GEP NETs中HMGA1和HMGA2的表达进行了研究。与正常组织相比，GEP NETs中经常检测到HMGA1和2的过表达。在GEP NETs中观察到HMGA1和2的核免疫染色（分别为55例中的38例，69%；55例中的40例，73%）。高迁移率族A2表达从高分化NET（WNET）到高分化神经内分泌癌（WNEC）和低分化NEC（PNEC）逐渐增加（P<0.005），并在IV期肿瘤中显示出最高水平（P<0.01）。在WNECs中，HMGA1和2在转移瘤中的表达明显高于无转移瘤（P<0.05）。前肠的胃肠胰NETs显示出最高水平的HMGA1和2表达。MIB-1标记指数（MIB-1 LI）与HMGA1和2的过表达相关（分别为R=0.28，P<0.05；R=0.434，P<0.001），并从WNETs到WNECs和PNECs逐渐增加（P<0.001）。在6个正常器官、30个肿瘤样本和24个肿瘤边缘非肿瘤组织中检测了Let-7表达。与正常组织相比，NETs中Let-7下调很常见（30例中的19例，63%）。在Let-7显著降低的肿瘤中，经常观察到较高的HMGA1和2表达（分别为53%，42%）。在HMGA1和Let-7之间可检测到负相关（P<0.05）。我们的研究结果表明，HMGA1和2的过表达以及Let-7的下调可能与GEP NETs的发病机制有关。
