HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma
HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma
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DOI：
10.1158/0008-5472.can-06-1460
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发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Whang, Edward E.
中科院分区：
文献类型：
--
作者：
Liau, Siong-Seng;Jazag, Amarsanaa;Whang, Edward E.
HMGA 1蛋白是一种结构性转录因子，在一系列人类恶性肿瘤（包括胰腺癌）中过表达。我们假设HMGA 1表达是胰腺癌细胞侵袭和转移的决定因素。通过转染短发夹RNA生成载体实现MiaPaCa 2和PANC 1胰腺癌细胞中HMGA 1的稳定沉默。此外，在MiaPaCa 2细胞中实现了HMGA 1的稳定过表达（特征在于低水平的固有HMGA 1表达）。HMGA 1沉默导致通过基质胶的细胞侵袭力显著降低;细胞基质金属蛋白酶-9（MMP-9）活性、mRNA水平和基因启动子活性显著降低;以及Ser（473）处Akt磷酸化显著降低。相反，HMGA 1过度表达导致细胞侵袭性、细胞MMP-9活性、mRNA水平和启动子活性以及Akt丝氨酸磷酸化水平显著增加（473）。HMGA 1过表达诱导的侵袭性增加是MMP-9依赖性的。磷脂酰肌醇-3激酶（PI 3 K）/Akt在介导HMGA 1依赖性侵袭中的作用通过特异性PI 3 K抑制剂（LY 294002）和组成性活性和显性阴性Akt腺病毒构建体来阐明。MMP-9活性的Akt依赖性调节显著促进HMGA 1过表达诱导的侵袭能力增加。此外，HMGA 1沉默导致体内转移潜能和肿瘤生长以及肿瘤MMP-9活性降低。我们的研究结果表明，HMGA 1可能是一个新的分子决定因素的侵袭和转移，以及一个潜在的治疗靶点，在胰腺癌。
HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNA-generating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser(473). Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels and promoter activity: and in Akt phosphorylation at Ser(473). HMGA1 overexpression-induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpression-induced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma.