Department of Pathology, Stanford University, Stanford, California, United States of America.
PLoS One. 2011;6(8):e23924. doi: 10.1371/journal.pone.0023924. Epub 2011 Aug 22.
Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy.
胰腺癌是一种致命的疾病，迫切需要新的治疗靶点。我们之前在胰腺癌细胞系中发现了 7q21-q22 处的 DNA 扩增。现在，通过对人类胰腺癌细胞系和人类肿瘤（在免疫缺陷小鼠中移植以富集癌细胞上皮部分）的高分辨率基因组分析，我们定义了一个跨越 SMURF1 的 325 Kb 最小扩增子，SMURF1 是一种 E3 泛素连接酶，也是转化生长因子 β（TGFβ）生长抑制信号的已知负调节剂。通过荧光原位杂交（FISH）在原发性人胰腺癌中证实了 SMURF1 的扩增，95 例中的 4 例（4.2%）存在扩增。通过 RNA 干扰（RNAi），在具有局灶性扩增的人胰腺癌细胞系（AsPC-1）中敲低 SMURF1 不会改变细胞生长，但会导致细胞侵袭和非锚定依赖性生长减少。有趣的是，这种作用不是通过改变 TGFβ 信号转导来介导的，通过转录报告进行了测定。最后，SMURF1 的过表达（但不是催化突变体）导致 NIH-3T3 小鼠胚胎成纤维细胞失去接触抑制。总之，这些发现确定 SMURF1 是驱动胰腺癌多种致瘤表型的扩增癌基因，并为分子靶向治疗提供了一个新的可用药靶。
