Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer.
Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer.
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激活素 A 受体 IB 型基因的纯合缺失与胰腺癌的侵袭性癌症表型相关。
DOI：
10.1186/1476-4598-13-126
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发表时间：
2014-05-27
期刊：
影响因子：
37.3
通讯作者：
Nishio K
中科院分区：
文献类型：
--
作者：
Togashi Y;Sakamoto H;Hayashi H;Terashima M;de Velasco MA;Fujita Y;Kodera Y;Sakai K;Tomida S;Kitano M;Ito A;Kudo M;Nishio K
转化生长因子β (TGFB)信号被认为是一种基于胰腺癌（PC）中SMAD4基因频繁基因组缺失的肿瘤抑制途径；然而;激活素信号也属于TGFB超家族，其作用在很大程度上仍不清楚。利用阵列比较基因组杂交技术，我们在8株PC细胞系中发现2株激活素a受体IB型（ACVR1B）基因的纯合缺失，并在这2株细胞系中证实了ACVR1B mRNA和蛋白的缺失。激活素A刺激可抑制细胞生长，提高SMAD2的磷酸化水平和p21CIP1/WAF1的表达水平（野生型ACVR1B和SMAD4基因），但在Sui68细胞系中无此作用（ACVR1B基因纯合缺失）。使用短发夹RNA稳定敲除acvr1b可消除激活素A对PC细胞系细胞生长的影响。此外，与对照组相比，acvr1b敲低显著增强了细胞生长和集落形成能力。在一项异种移植研究中，与对照组相比，acvr1b基因敲低导致肿瘤发生水平显著升高，肿瘤体积更大。此外，在临床样本中，29个PC样本中有6个（20.7%）携带ACVR1B基因缺失，29个样本中有10个（34.5%）携带SMAD4基因缺失。值得注意的是，6个缺失ACVR1B基因的样本中有5个也缺失了SMAD4基因。我们在PC细胞系和临床样本中发现了ACVR1B基因的纯合缺失，并提出ACVR1B基因的缺失可能介导了PC的侵袭性癌症表型。我们的发现为激活素信号在PC中的作用提供了新的见解。
Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.
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影响因子：
11.2
作者：
Burdette, JE;Jeruss, JS;Woodruff, TK
通讯作者：
Woodruff, TK
影响因子：
8.8
作者：
Harder J;Ihorst G;Heinemann V;Hofheinz R;Moehler M;Buechler P;Kloeppel G;Röcken C;Bitzer M;Boeck S;Endlicher E;Reinacher-Schick A;Schmoor C;Geissler M
通讯作者：
Geissler M
影响因子：
8.8
作者：
Kaneda, H.;Arao, T.;Matsumoto, K.;De Velasco, M. A.;Tamura, D.;Aomatsu, K.;Kudo, K.;Sakai, K.;Nagai, T.;Fujita, Y.;Tanaka, K.;Yanagihara, K.;Yamada, Y.;Okamoto, I.;Nakagawa, K.;Nishio, K.
通讯作者：
Nishio, K.
影响因子：
45.3
作者：
Moore, Malcolm J.;Goldstein, David;Parulekar, Wendy
通讯作者：
Parulekar, Wendy
影响因子：
3.3
作者：
Day, JD;Digiuseppe, JA;Hruban, RH
通讯作者：
Hruban, RH