Cellular and Molecular Department, Stefan S. Nicolau Institute of Virology, Mihai Bravu 285 Ave, 030304, Bucharest, Romania.
Nicolae Cajal Institute, Titu Maiorescu University, Bucharest, Romania.
Gastric Cancer. 2017 Nov;20(6):948-959. doi: 10.1007/s10120-017-0712-y. Epub 2017 Mar 15.
Keratin 17 (KRT17) was shown to be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of various cancer types. Our previous studies identified KRT17 as a possible biomarker for gastric cancer by gene microarray, with an elevated expression that occurred early during tumorigenesis and increased during tumor progression. Based on these findings, we aimed to investigate KRT17 biological functions in gastric adenocarcinoma and its possible use as a rational molecular target for anticancer therapy.
We used RNA interference-mediated knockdown of KRT17 expression and analyzed the effects on cell proliferation, cell migration, and signal transduction in two gastric cell lines (AGS and NCI-N87) in vitro and on xenograft growth in vivo.
The functional analysis of KRT17 knockdown cell lines showed a decreased cell proliferation (with 42.36% ± 3.2%) and migration ability (with 37.2% ± 6.2%) relative to scrambled siRNA control. The in vivo tumorigenicity on nude mice exhibited a significant decrease in tumor weight with 69.14% in xenografts obtained from AGS cells and 84.43% in xeno-NCI-N87 tumors. The analysis on KRT17 knockdown outcome on intracellular signaling identifies AKT/mTOR as the main affected pathway that sustains proliferation and survival, and also the AMPKα1/CREB pathway that was recently shown to induce organ protection and antiinflammatory response.
Our results highlight KRT17 as a possible biomarker in gastric cancer promoting tumor growth, motility, and invasion, and suggest that KRT17 can be a valuable molecular target for development of anti-gastric cancer-specific therapies.
角蛋白 17（KRT17）被证明是预测各种癌症类型的癌变、进展和预后的重要分子标志物。我们之前的研究通过基因微阵列发现 KRT17 是胃癌的一个潜在生物标志物，其表达在肿瘤发生早期升高，并在肿瘤进展过程中增加。基于这些发现，我们旨在研究 KRT17 在胃腺癌中的生物学功能及其作为抗癌治疗合理分子靶点的可能性。
我们使用 RNA 干扰介导的 KRT17 表达敲低，并分析了其对体外两种胃细胞系（AGS 和 NCI-N87）中的细胞增殖、细胞迁移和信号转导的影响，以及体内异种移植生长的影响。
KRT17 敲低细胞系的功能分析显示，与对照 scrambled siRNA 相比，细胞增殖（减少 42.36%±3.2%）和迁移能力（减少 37.2%±6.2%）降低。裸鼠体内肿瘤发生显示，AGS 细胞来源的异种移植肿瘤重量显著减少 69.14%，NCI-N87 肿瘤的异种移植肿瘤重量减少 84.43%。对 KRT17 敲低后细胞内信号的分析表明，AKT/mTOR 是维持增殖和存活的主要受影响途径，而 AMPKα1/CREB 途径最近被证明可诱导器官保护和抗炎反应。
我们的研究结果强调 KRT17 是促进胃癌肿瘤生长、迁移和侵袭的潜在生物标志物，并表明 KRT17 可能是开发抗胃癌特异性治疗的有价值的分子靶点。
