Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
PLoS One. 2013 Apr 8;8(4):e60715. doi: 10.1371/journal.pone.0060715. Print 2013.
The role of peroxisome proliferator--activated receptor- δ (PPAR δ) gene in colon carcinogenesis remains highly controversial. Here, we established nude mice xenograft model using a human colon cancer cell line KM12C either with PPAR δ silenced or normal. The xenografts in PPAR δ-silenced group grew significantly larger and heavier with less differentiation, promoted cell proliferation, increased expression of vascular endothelial growth factor (VEGF) and similar apoptosis index compared with those of PPAR δ-normal group. After treated with the specific VEGF inhibitor bevacizumab, the capacities of growth and proliferation of xenografts were decreased in both groups while still significantly higher in PPAR δ-silenced group than in PPAR δ-normal group. Administration of PPAR δ agonist significantly decreased VEGF expression in PPAR δ-normal KM12C cells but not in PPAR δ-silenced cells. These findings demonstrate that, knockdown of PPAR δ promotes the growth of colon cancer by inducing less differentiation, accelerating the proliferation and VEGF expression of tumor cells in vivo, and reduces tumor sensitivity to bevacizumab. This study indicates that PPAR δ attenuates colon carcinogenesis.
过氧化物酶体增殖物激活受体-δ（PPAR δ）基因在结肠癌发生中的作用仍存在很大争议。在这里，我们建立了裸鼠异种移植模型，使用沉默或正常的人结肠癌细胞系 KM12C。与 PPAR δ-正常组相比，PPAR δ 沉默组的异种移植物生长显著增大且重量增加，分化减少，促进细胞增殖，血管内皮生长因子（VEGF）表达增加，凋亡指数相似。用特异性 VEGF 抑制剂贝伐单抗处理后，两组的生长和增殖能力均下降，但 PPAR δ-沉默组仍明显高于 PPAR δ-正常组。PPAR δ 激动剂显著降低了 PPAR δ-正常 KM12C 细胞中 VEGF 的表达，但对 PPAR δ 沉默细胞没有作用。这些发现表明，敲低 PPAR δ 通过诱导分化减少、加速体内肿瘤细胞的增殖和 VEGF 表达来促进结肠癌的生长，并降低肿瘤对贝伐单抗的敏感性。本研究表明 PPAR δ 可抑制结肠癌的发生。
