Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
J Clin Endocrinol Metab. 2013 Mar;98(3):E586-94. doi: 10.1210/jc.2012-3490. Epub 2013 Feb 5.
KLLN is a newly identified gene with unknown function and shares a bidirectional promoter with PTEN.
The objective of the study was to analyze the relationship between KILLIN (KLLN) expression and prostate cancer and the potential tumor suppressive effect.
We conducted an in silico analysis to compare KLLN expression in normal prostate and matched primary carcinoma tissues. We subsequently used immunohistochemistry to examine KLLN expression and association with Gleason grade and score in 109 prostatectomy samples. KLLN's tumor-suppressive effect was studied in androgen-dependent and androgen-independent cell models.
Patients were diagnosed with peripheral zone prostate carcinomas without metastasis at the time of prostatectomy. Each patient's primary tumor comprised at least 2 tumoral regions with different Gleason grades.
KLLN expression decreased from normal prostate tissue to primary carcinomas (P < .0001). The loss of epithelial and stromal KLLN expression is associated with poor differentiation and high Gleason scores (P < .0001), consistent with our in vitro observation that KLLN inhibits tumor cell proliferation and invasiveness. KLLN decreases prostate-specific antigen levels and suppresses androgen-mediated cell growth by inhibiting androgen receptor (AR) transcription. As an androgen receptor-regulated target, KLLN also functions as a transcriptional activator, directly promoting the expression of TP53 and TP73, with consequent elevated apoptosis, regardless of AR status.
Our observations suggest that KLLN is a transcription factor directly regulating AR, TP53, and TP73 expression, with a role in prostate carcinogenesis. Loss of KLLN associates with high Gleason scores, suggesting that KLLN might be used as a potential prognostic marker for risk management and as a novel therapy target for advanced prostate carcinomas.
KLLN 是一个新鉴定的基因，其功能未知，与 PTEN 共享双向启动子。
本研究旨在分析 KILLIN（KLLN）表达与前列腺癌的关系及其潜在的肿瘤抑制作用。
我们进行了一项计算机分析，比较了正常前列腺组织和匹配的原发性癌组织中 KLLN 的表达。随后，我们使用免疫组织化学方法检测了 109 例前列腺切除术样本中 KLLN 的表达及其与 Gleason 分级和评分的关系。在雄激素依赖性和雄激素非依赖性细胞模型中研究了 KLLN 的肿瘤抑制作用。
患者在前列腺切除术时被诊断为无转移的外周区前列腺癌。每位患者的原发性肿瘤至少包括 2 个具有不同 Gleason 分级的肿瘤区域。
从正常前列腺组织到原发性癌，KLLN 的表达降低（P<0.0001）。上皮和基质 KLLN 表达的丧失与分化不良和高 Gleason 评分相关（P<0.0001），与我们的体外观察结果一致，即 KLLN 抑制肿瘤细胞增殖和侵袭性。KLLN 降低前列腺特异性抗原水平，并通过抑制雄激素受体（AR）转录抑制雄激素介导的细胞生长。作为雄激素受体调节的靶标，KLLN 还作为转录激活因子起作用，直接促进 TP53 和 TP73 的表达，导致细胞凋亡增加，而与 AR 状态无关。
我们的观察结果表明，KLLN 是直接调节 AR、TP53 和 TP73 表达的转录因子，在前列腺癌发生中起作用。KLLN 的缺失与高 Gleason 评分相关，提示 KLLN 可能作为风险管理的潜在预后标志物，并作为晚期前列腺癌的新治疗靶点。
