Kim-Fuchs Corina, Winterhalder Sebastian, Winter Annja, Malinka Thomas, Born Diana, Schäfer Stephan, Stroka Deborah, Gloor Beat, Candinas Daniel, Angst Eliane
Department of Visceral Surgery and Medicine, Inselspital University of Bern, Bern, Switzerland.
Dig Surg. 2014;31(2):135-42. doi: 10.1159/000363065. Epub 2014 Jun 20.
The understanding of molecular mechanisms leading to poor prognosis in pancreatic cancer may help develop treatment options. N-myc downstream-regulated gene-1 (NDRG1) has been correlated to better prognosis in pancreatic cancer. Therefore, we thought to analyze how the loss of NDRG1 affects progression in an orthotopic xenograft animal model of recurrence.
Capan-1 cells were silenced for NDRG1 (C(sil)) or transfected with scrambled shRNA (C(scr)) and compared for anchorage-dependent and anchorage-independent growth, invasion and tube formation in vitro. In an orthotopic xenograft model of recurrence tumors were grown in the pancreatic tail. The effect of NDRG1 silencing was evaluated on tumor size and metastasis.
The silencing of NDRG1 in Capan-1 cells leads to more aggressive tumor growth and metastasis. We found faster cell growth, double count of invaded cells and 1.8-fold increase in tube formation in vitro. In vivo local tumors were 5.9-fold larger (p = 0.006) and the number of metastases was higher in animals with tumors silenced for NDRG1 primarily (3 vs. 1.1; p = 0.005) and at recurrence (3.3 vs. 0.9; p = 0.015).
NDRG1 may be an interesting therapeutic target as its silencing in human pancreatic cancer cells leads to a phenotype with more aggressive tumor growth and metastasis.
了解导致胰腺癌预后不良的分子机制可能有助于开发治疗方案。N- myc下游调控基因1（NDRG1）与胰腺癌较好的预后相关。因此，我们想分析NDRG1的缺失如何影响原位异种移植复发动物模型中的肿瘤进展。
对Capan - 1细胞进行NDRG1基因沉默（C(sil)）或用乱序短发夹RNA转染（C(scr)），并比较它们在体外的贴壁依赖性和非贴壁依赖性生长、侵袭及管腔形成能力。在原位异种移植复发模型中，肿瘤在胰尾生长。评估NDRG1基因沉默对肿瘤大小和转移的影响。
Capan - 1细胞中NDRG1的沉默导致肿瘤生长和转移更具侵袭性。我们发现体外细胞生长更快，侵袭细胞数量翻倍，管腔形成增加1.8倍。在体内，主要在NDRG1基因沉默的动物中，局部肿瘤大5.9倍（p = 0.006），转移灶数量更多（初次时为3个对1.1个；p = 0.005），复发时为3.3个对0.9个；p = 0.015）。
NDRG1可能是一个有吸引力的治疗靶点，因为其在人胰腺癌细胞中的沉默会导致肿瘤生长和转移更具侵袭性的表型。
