Role of NF-κB activation in hormone-refractory prostate cancer

采用前列腺癌细胞系和成骨细胞系建立异种移植模型采用LNCaP、MDA-PCa2b和LNCaP混合mc3t3 - e1细胞在裸鼠背部皮下病变处建立异种移植模型。免疫组化研究NF-κB、雄激素受体和SRC-3的表达采用异种移植标本和激素初治或激素难治性前列腺癌患者的临床前列腺标本进行免疫组化分析。NF-κB主要在异种移植物和临床前列腺癌任何阶段的细胞质表达。在这些样本中，只有不到20%的癌细胞表达核NF-κB。gleason分级越高的肿瘤核NF-κB阳性表达率越高。雄激素受体与SRC-3在临床前列腺癌中的表达水平存在相关性。从LNCaP、DU145、PC3和MDA PCa2b细胞中提取粗条件培养基（CM）可增强mc3t3 - e1细胞中NF-κB配体受体激活因子（RANKL）的mRNA表达。然而，这些CM不影响mc3t3 - e1细胞中骨保护素（OPG） mRNA的表达。来自LNCaP、DU145细胞的CM也促进了破骨细胞前体细胞的成熟（Cancer letter, in press）。激素难治性前列腺癌患者血清IL-6、TGF-β1、il - 8和VEGF水平进展后，血清IL-6水平显著升高，而血清TGF-β1水平显著下降。血清IL-6水平升高与预后不良有显著相关性，而血清TGF-β1水平升高与预后不良无显著相关性。疾病进展后，血清IL-8和VEGF水平略有升高。NF-κB抑制剂MG132对前列腺癌生长的影响蛋白体抑制剂MG132可抑制NF-κB的活化。MG132在体外对LNCaP、DU145和PC3细胞的生长有明显抑制作用。

Establishment of xenograft models using prostate cancer cell lines and osteblastic cell linesXenograft models using LNCaP, MDA-PCa2b and LNCaP mixed with MC3T3-E1cells were established on dorsal subcutaneous lesion of nude mice.Assessment of the expression of NF-κB, androgen receptor, and SRC-3 by immunohistochemical studyXenograft samples and clinical prostate samples obtained from patients with hormone-naive or hormone-refractory prostate cancer were used for immunohistochemical analysis. NF-κB mainly showed cytoplasmic expression in both xenografts and any stage of clinical prostate cancer. Less than 20% of cancer cells showed nuclear NF-κB expression in these samples. Higher gleason grade tumors had higher percentage of positivity of nuclear NF-κB expression.Expression levels of androgen receptor and SRC-3 in clinical prostate cancer were correlated.The effect of prostate cancer on oeteoclastgenesisCrude conditioned medium (CM) from LNCaP, DU145, PC3 and MDA PCa2b cells enhanced mRNA for receptor activator of NF-κB ligand (RANKL) in MC3T3-E1cells. However, these CM did not affect osteoprotegerin (OPG) mRNA expression in MC3T3-E1cells. CM from LNCaP, DU145 cells also enhanced maturation of osteoclast precursor cells (Cancer letter, in press).Serum levels of IL-6, TGF-β1, IL8 and VEGF in patients with hormone-refractory prostate cancerAfter disease progression, serum IL-6 levels significantly elevated, whereas serum TGF-β1 levels significantly declined. Higher serum IL-6 levels had significant association with poor prognosis, whereas higher serum TGF-β1 levels did not. After disease progression, serum IL-8 and VEGF levels increased marginally.The effect of NF-κB inhibitor, MG132, on prostate cancer growthA proteosomal inhibitor, MG132, inhibits the activation of NF-κB. MG132 inhibited the growth of LNCaP, DU145 and PC3 cells significantly in vitro.