Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.
Ludwig Institute for Cancer Research Melbourne-Austin Branch and Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
Clin Cancer Res. 2015 Aug 15;21(16):3695-704. doi: 10.1158/1078-0432.CCR-14-2457. Epub 2015 May 5.
The clinical management of colorectal cancer patients has significantly improved because of the identification of novel therapeutic targets such as EGFR and VEGF. Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify novel candidate therapeutic targets.
The doubling time of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. We then investigated the potential of genes highly expressed in cancer cells with faster growth as new therapeutic targets.
Faster proliferation rates were associated with microsatellite instability and poorly differentiated histology. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing, and protein transport. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPOX) were shown to have higher expression in faster growing cell lines and primary tumors. Pharmacologic or siRNA-based inhibition of GAPDH or PPOX reduced the growth of colon cancer cells in vitro. Moreover, using a mouse xenograft model, we show that treatment with the specific PPOX inhibitor acifluorfen significantly reduced the growth of three of the seven (42.8%) colon cancer lines investigated.
We have characterized at the transcriptomic level the differences between colorectal cancer cells that vary in their growth rates, and identified novel candidate chemotherapeutic targets for the treatment of colorectal cancer.
由于鉴定出了新的治疗靶点，如 EGFR 和 VEGF，结直肠癌患者的临床治疗得到了显著改善。由于肿瘤的快速增殖与患者预后不良有关，因此，我们试图鉴定新的候选治疗靶点，对快速增殖的结直肠癌细胞的转录特征进行了研究。
确定了 52 种结直肠癌细胞系的倍增时间，并通过微阵列分析评估了其中一部分细胞系的全基因组表达谱。然后，我们研究了在生长较快的癌细胞中高表达的基因是否有可能成为新的治疗靶点。
较快的增殖速度与微卫星不稳定性和组织学分化不良有关。1290 个基因的表达与结直肠癌细胞的生长速度显著相关。这些基因包括参与细胞周期、RNA 加工/剪接和蛋白质转运的基因。甘油醛-3-磷酸脱氢酶（GAPDH）和原卟啉原氧化酶（PPOX）在生长较快的细胞系和原发性肿瘤中表达较高。用 GAPDH 或 PPOX 的药理学或 siRNA 抑制可减少体外结肠癌细胞的生长。此外，通过使用小鼠异种移植模型，我们表明，特异性 PPOX 抑制剂 acifluorfen 的治疗可显著减少所研究的七种结肠癌系中的三种（42.8%）的生长。
我们从转录组水平上描述了在生长速度上存在差异的结直肠癌细胞之间的差异，并鉴定出了治疗结直肠癌的新的候选化疗靶点。
