Rychahou Piotr G, Jackson Lindsey N, Silva Scott R, Rajaraman Srinivasan, Evers B Mark
Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA.
Ann Surg. 2006 Jun;243(6):833-42; discussion 843-4. doi: 10.1097/01.sla.0000220040.66012.a9.
The phosphatidylinositol 3-kinase (PI3K) pathway promotes cancer cell proliferation and survival. The authors determined the pattern of distribution of PI3K pathway components (ie, the p85alpha regulatory subunit, p110alpha catalytic subunit, Akt1, Akt2, and the tumor suppressor PTEN) in human colorectal cancer. In addition, inhibition of in vitro proliferation and in vivo liver metastasis by p85alpha or p110alpha siRNA treatment was analyzed.
Small interfering RNA (siRNA) molecules suppress expression of target genes and may have therapeutic applications as target-specific therapies for cancer. Therefore, the purpose of this study was 2-fold: 1) to analyze the distribution pattern of PI3K pathway components in human normal colorectal cancers, and 2) to determine whether targeted inhibition of PI3K inhibits colon cancer growth in vitro and suppresses metastatic growth in vivo.
Immunohistochemical analysis was performed on colorectal adenocarcinomas and adjacent normal mucosa for PI3K pathway components, including p85alpha, p110alpha, Akt1, Akt2, and the tumor suppressor PTEN, which inhibits PI3K. HT29 and KM20 human colon cancer cells were treated with siRNA directed to p85alpha or p110alpha, and cell viability and apoptosis assessed. HT29 cells, transfected with a plasmid containing green fluorescent protein (GFP), were injected into the spleen of athymic nude mice to establish liver metastases; mice were randomized to receive either nontargeting control (NTC), p85alpha or p110alpha siRNA.
PI3K pathway components p85alpha and Akt2 were highly expressed in glandular elements of colon cancers, with a correlation between staining intensity and clinical stage; PTEN expression was decreased in the colon cancers of all stages. PI3K-specific siRNA treatment decreased cell viability in vitro and suppressed metastatic tumor growth in vivo.
Selective targeting of PI3K pathway components may enhance the effects of standard chemotherapeutic agents and provide novel adjuvant treatment of selected colorectal cancers.
磷脂酰肌醇3-激酶（PI3K）通路可促进癌细胞增殖与存活。作者确定了PI3K通路组分（即p85α调节亚基、p110α催化亚基、Akt1、Akt2以及肿瘤抑制因子PTEN）在人大肠癌中的分布模式。此外，分析了用p85α或p110α小干扰RNA（siRNA）处理对体外增殖及体内肝转移的抑制作用。
小干扰RNA（siRNA）分子可抑制靶基因表达，作为癌症的靶向特异性疗法可能具有治疗应用价值。因此，本研究目的有两个：1）分析PI3K通路组分在人正常大肠癌中的分布模式，2）确定PI3K的靶向抑制是否在体外抑制结肠癌生长并在体内抑制转移瘤生长。
对大肠腺癌及相邻正常黏膜进行免疫组织化学分析，检测PI3K通路组分，包括p85α、p110α、Akt1、Akt2以及抑制PI3K的肿瘤抑制因子PTEN。用针对p85α或p110α的siRNA处理HT29和KM20人结肠癌细胞，并评估细胞活力和凋亡情况。将转染了含绿色荧光蛋白（GFP）质粒的HT29细胞注入无胸腺裸鼠脾脏以建立肝转移模型；小鼠随机接受非靶向对照（NTC）、p85α或p110α siRNA。
PI3K通路组分p85α和Akt2在结肠癌腺管成分中高表达，染色强度与临床分期相关；各期结肠癌中PTEN表达均降低。PI3K特异性siRNA处理在体外降低细胞活力，在体内抑制转移瘤生长。
选择性靶向PI3K通路组分可能增强标准化疗药物的疗效，并为特定的大肠癌提供新的辅助治疗方法。
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