Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Gastroenterology. 2011 Oct;141(4):1371-80, 1380.e1-2. doi: 10.1053/j.gastro.2011.06.071. Epub 2011 Jul 8.
BACKGROUND & AIMS: Protein tyrosine kinase 6 (PTK6) is expressed throughout the gastrointestinal tract and is a negative regulator of proliferation that promotes differentiation and DNA-damage-induced apoptosis in the small intestine. PTK6 is not expressed in normal mammary gland, but is induced in most human breast tumors. Signal transducer and activator of transcription 3 (STAT3) mediates pathogenesis of colon cancer and is a substrate of PTK6. We investigated the role of PTK6 in colon tumorigenesis.
Ptk6+/+ and Ptk6-/- mice were injected with azoxymethane alone or in combination with dextran sodium sulfate; formation of aberrant crypt foci and colon tumors was examined. Effects of disruption of Ptk6 on proliferation, apoptosis, and STAT3 activation were examined by immunoblot and immunohistochemical analyses. Regulation of STAT3 activation was examined in the HCT116 colon cancer cell line and young adult mouse colon cells.
Ptk6-/- mice developed fewer azoxymethane-induced aberrant crypt foci and tumors. Induction of PTK6 increased apoptosis, proliferation, and STAT3 activation in Ptk6+/+ mice injected with azoxymethane. Disruption of Ptk6 impaired STAT3 activation following azoxymethane injection, and reduced active STAT3 levels in Ptk6-/- tumors. Stable knockdown of PTK6 reduced basal levels of active STAT3, as well as activation of STAT3 by epidermal growth factor in HCT116 cells. Disruption of Ptk6 reduced activity of STAT3 in young adult mouse colon cells.
PTK6 promotes STAT3 activation in the colon following injection of the carcinogen azoxymethane and regulates STAT3 activity in mouse colon tumors and in the HCT116 and young adult mouse colon cell lines. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice.
蛋白酪氨酸激酶 6（PTK6）在整个胃肠道中表达，是增殖的负调节剂，可促进小肠的分化和 DNA 损伤诱导的细胞凋亡。PTK6 在正常乳腺中不表达，但在大多数人类乳腺癌中诱导表达。信号转导和转录激活因子 3（STAT3）介导结肠癌的发病机制，是 PTK6 的底物。我们研究了 PTK6 在结肠癌发生中的作用。
单独或联合给予葡聚糖硫酸钠，向 Ptk6+/+和 Ptk6-/-小鼠注射氧化偶氮甲烷；检测异常隐窝病灶和结肠肿瘤的形成。通过免疫印迹和免疫组织化学分析检测 Ptk6 缺失对增殖、凋亡和 STAT3 激活的影响。在 HCT116 结肠癌细胞系和成年小鼠结肠细胞中检测 STAT3 激活的调节。
Ptk6-/- 小鼠形成的氧化偶氮甲烷诱导的异常隐窝病灶和肿瘤较少。在注射氧化偶氮甲烷的 Ptk6+/+小鼠中诱导 PTK6 可增加细胞凋亡、增殖和 STAT3 激活。氧化偶氮甲烷注射后，Ptk6 缺失可损害 STAT3 激活，并降低 Ptk6-/-肿瘤中的活性 STAT3 水平。PTK6 的稳定敲低降低了 HCT116 细胞中基础水平的活性 STAT3 以及表皮生长因子对 STAT3 的激活。Ptk6 缺失降低了成年小鼠结肠细胞中 STAT3 的活性。
PTK6 在注射致癌剂氧化偶氮甲烷后促进结肠中 STAT3 的激活，并调节小鼠结肠肿瘤以及 HCT116 和成年小鼠结肠细胞系中的 STAT3 活性。Ptk6 缺失可减少小鼠氧化偶氮甲烷诱导的结肠癌发生。
