Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
PLoS One. 2012;7(8):e43236. doi: 10.1371/journal.pone.0043236. Epub 2012 Aug 14.
To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(-) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95%CI 1.2-16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95%CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.
为了确认 NF-κB 和 JNK 蛋白表达在预测接受 5-FU 治疗的患者预后中的临床意义，我们评估了手术切除标本中的蛋白表达。共获得 30 例胃癌和 49 例结直肠癌患者的 79 个标本，这些患者均接受了 R0 切除，术后接受了基于 5-FU 的辅助化疗。组织微阵列（TMA）上的 NF-κB 和 JNK 的免疫组织化学检查显示，在胃（NF-κB(+)，p = 0.0002，HR11.7，95%CI3 3.2-43.4；JNK(-)，p = 0.0302，HR4.4，95%CI 1.2-16.6）和结肠（NF-κB(+)，p = 0.0038，HR36.9，95%CI 3.2-426.0；JNK(-)，p = 0.0098，HR3.2，95%CI 1.3-7.7）癌症中，NF-κB(+)和 JNK(-)亚组的复发时间（TTR）明显缩短。这些蛋白表达模式在胃癌患者的总生存率方面也具有很强的判别能力，表明其具有作为预后或化疗敏感性标志物的潜在应用价值。使用胃癌细胞系检测这些蛋白的基线表达显示 NF-κB 和 JNK 之间存在相反的模式，而这些细胞系对 5-FU 的暴露仅诱导 NF-κB，表明 NF-κB 在对 5-FU 的反应中起主导作用。随后的 siRNA 实验证实，NF-κB 的基因敲低增加了 5-FU 的特异性敏感性，而 JNK 的敲低则不影响化疗敏感性。这些结果表明，这些蛋白的表达可能有助于胃肠道癌症辅助化疗决策。
