Leptin, insulin-like growth factor-1, and insulin-like growth factor-2 are Mitogens in ApcMin/+ but not Apc+/+ colonic epithelial cell lines
Leptin, insulin-like growth factor-1, and insulin-like growth factor-2 are Mitogens in ApcMin/+ but not Apc+/+ colonic epithelial cell lines
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DOI：
10.1158/1055-9965.epi-04-0916
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发表时间：
2005-07-01
影响因子：
3.8
通讯作者：
Hursting, SD
中科院分区：
文献类型：
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作者：
Fenton, JI;Hord, NG;Hursting, SD
肥胖状态与胰岛素、胰岛素样生长因子（IGF）和瘦素的循环水平升高有关。关于这些升高的生长因子在结肠癌风险中的作用，研究是矛盾的。我们假设，当暴露于这些生长因子时，Apc缺陷（Apcm（Min/+））但不表达野生型Apc（Ape（+/+））的结肠上皮细胞将经历过度增殖和抗凋亡表型。使用两种具有不同Apc基因型的非致瘤性小鼠结肠上皮细胞系：Apc（+/+）YAMC细胞和Apc（Min/+）IMCE细胞来解决这一假设。用不同浓度的瘦素（0.001-50 ng/mL）、IGF-1（0.1-200 ng/mL）或IGF-2（0.1-600 ng/mL）处理细胞48小时。在YAMC细胞中，瘦素通过诱导caspase活性和细胞凋亡，使细胞增殖能力显著降低（P < 0.01）。与此相反，在IMCE细胞中，瘦素诱导细胞增殖比对照组增加75%（P < 0.0001）。与对照组相比，IGF-1和IGF-2也诱导IMCE细胞增殖增加50%（P < 0.001）。IGF-1或IGF-2与瘦素共同处理IMCE细胞比单独使用生长因子诱导更大的增殖（P < 0.0001）。单纯瘦素治疗引起的IMCE细胞增殖与p42/44丝裂原活化蛋白激酶（MAPK）、P38 MAPK和核因子-κ B核转位的激活有关，但与MAPK激酶或Janus活化激酶/信号转导和转录激活因子的激活无关。这些数据提供了第一个证据，瘦素可能与IGFs相互作用，以促进结肠上皮细胞的生存和扩张，是Apc缺陷（Apc（Min/+）），但不是那些表达野生型Apc（Apc（+/+））。
The obese state is associated with elevated circulating levels of insulin, insulin-like growth factors (IGF), and leptin. Research is contradictory regarding the role of these elevated growth factors in colon cancer risk. We hypothesized that colonic epithelial cells that were Apc deficient (Apcm(Min/+)) but not those expressing wild-type Apc (Ape(+/+)) would experience a hyperproliferative and antiapoptotic phenotype when exposed to these growth factors. This hypothesis was addressed using two nontumorigenic murine colonic epithelial cell lines with distinct Apc genotypes: Apc(+/+) YAMC cells and Apc(Min/+) IMCE cells. Cells were treated for 48 hours with various concentrations of leptin (0.001-50 ng/mL), IGF-1 (0.1-200 ng/mL), or IGF-2 (0.1-600 ng/mL). In YAMC cells, leptin caused a significant decrease in cell proliferation (P < 0.01) compared with controls due to induction of caspase activity and apoptosis. In contrast, in the IMCE cells, leptin induced a 75% increase in cell proliferation compared with controls (P < 0.0001). IGF-1 and IGF-2 also induced 50% greater proliferation in the IMCE cells (P < 0.001) compared with controls. Cotreatment of IMCE cells with leptin and either IGF-1 or IGF-2 induced greater proliferation than either growth factor alone (P < 0.0001). IMCE cell proliferation caused by leptin only treatment was associated with activation of p42/44 mitogen-activated protein kinase (MAPK), P38 MAPK, and nuclear factor-kappa B nuclear translocation but not with MAPK kinase or Janus-activated kinase/ signal transducers and activators of transcription activation. These data provide the first evidence that leptin may interact with IGFs to promote survival and expansion of colonic epithelial cells that were Apc deficient (Apc(Min/+)) but not those expressing wild-type Apc (Apc(+/+)).