High mobility group AT-hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma.
High mobility group AT-hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma.
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作者：
Liau SS;Rocha F;Matros E;Redston M;Whang E
高迁移率族AT-钩1（HMGA 1）蛋白是胰腺癌过度表达的结构性转录因子。作者假设肿瘤HMGA 1状态代表胰腺癌的一种新的预后标志物。他们还测试了HMGA 1促进锚定非依赖性细胞增殖和体内致瘤性的假设。通过免疫组化分析89例连续胰腺癌切除患者的组织，检测肿瘤HMGA 1表达。使用短发夹RNA（shRNA）介导的RNA干扰来沉默MiaPaCa 2和PANC 1胰腺癌细胞中的HMGA 1表达。锚定非依赖性增殖通过使用软琼脂测定进行评估。利用特异性抑制剂和腺病毒显性失活/激活Akt构建体研究了磷脂酰肌醇3-激酶（PI 3-K）/Akt和细胞外信号调节激酶（ERK）信号转导的作用。通过使用裸鼠异种移植模型评估体内致瘤性。在93%的胰腺癌患者中检测到肿瘤HMGA 1表达。在单变量分析（P = 0.0028）和多变量分析（P<0.05）中，HMGA 1阴性肿瘤患者的中位生存期显著长于HMGA 1表达癌症患者。shRNA介导的HMGA 1沉默导致软琼脂中锚定非依赖性增殖显著减少。强制HMGA 1过表达通过依赖于PI 3-K/Akt激活的信号而非丝裂原活化蛋白激酶（MEK）/ERK信号的过程促进软琼脂中的增殖。靶向沉默HMGA 1通过降低增殖（Ki-67指数）和增加凋亡（末端脱氧核苷酸转移酶切口末端标记）降低体内肿瘤生长。目前的研究结果表明，HMGA 1是胰腺癌患者术后生存率差的独立预测因子。此外，HMGA 1通过PI 3-K/Akt依赖性机制促进致瘤性。HMGA 1作为胰腺癌的预后标志物和治疗靶点值得进一步评价。
High mobility group AT-hook 1 (HMGA1) proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. The authors hypothesized that tumor HMGA1 status represents a novel prognostic marker in pancreatic adenocarcinoma. They also tested the hypothesis that HMGA1 promotes anchorage-independent cellular proliferation and in vivo tumorigenicity. Tumor HMGA1 expression was examined by immunohistochemical analysis of tissues from 89 consecutive patients who underwent resection for pancreatic adenocarcinoma. Short-hairpin RNA (shRNA)-mediated RNA interference was used to silence HMGA1 expression in MiaPaCa2 and PANC1 pancreatic cancer cells. Anchorage-independent proliferation was assessed by using soft agar assays. The roles of phosphatidylinositol 3-kinase (PI3-K)/Akt and extracellular signal-regulated kinase (ERK) signaling were investigated by using specific inhibitors and adenoviral dominant-negative/active Akt constructs. In vivo tumorigenicity was assessed by using a nude mouse xenograft model. Tumor HMGA1 expression was detected in 93% of patients with pancreatic adenocarcinoma. Patients with HMGA1-negative tumors had a significantly longer median survival than patients with HMGA1-expressing cancers in univariate analysis (P = .0028) and in multivariate analysis (P<.05). shRNA-mediated HMGA1 silencing resulted in significant reductions in anchorage-independent proliferation in soft agar. Forced HMGA1 overexpression promoted proliferation in soft agar through a process that was dependent on PI3-K/Akt-activited signaling, but not on mitogen-activated protein kinase (MEK)/ERK signaling. Targeted silencing of HMGA1 reduced tumor growth in vivo through reduced proliferation (Ki-67 index) and increased apoptosis (terminal deoxynucleotidyl transferase nick-end labeling). The current findings suggested that HMGA1 is an independent predictor of poor postoperative survival in patients with pancreatic adenocarcinoma. Furthermore, HMGA1 promotes tumorigenicity through a PI3-K/Akt-dependent mechanism. HMGA1 warrants further evaluation as a prognostic marker and therapeutic target in pancreatic cancer.
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影响因子：
11.5
作者：
Chiappetta, G;Botti, G;Fusco, A
通讯作者：
Fusco, A
影响因子：
3.7
作者：
Dement, Gregory A.;Maloney, Scott C.;Reeves, Raymond
通讯作者：
Reeves, Raymond
影响因子：
11.2
作者：
Liau, Siong-Seng;Jazag, Amarsanaa;Whang, Edward E.
通讯作者：
Whang, Edward E.
影响因子：
14.9
作者：
FRIEDMANN, M;HOLTH, LT;REEVES, R
通讯作者：
REEVES, R
DOI：
10.1083/jcb.124.4.619
发表时间：
1994-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Frisch SM;Francis H
通讯作者：
Francis H