Tian Yu-Feng, Chen Tzu-Ju, Lin Ching-Yih, Chen Li-Tzong, Lin Li-Ching, Hsing Chung-Hsi, Lee Sung-Wei, Sheu Ming-Jen, Lee Hao-Hsien, Shiue Yow-Ling, Huang Hsuan-Ying, Pan Hsin-Yi, Li Chien-Feng, Chen Shang-Hung
Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan.
Tumour Biol. 2013 Apr;34(2):1107-17. doi: 10.1007/s13277-013-0652-z. Epub 2013 Jan 18.
The S-phase kinase-associated protein 2 (SKP2) oncoprotein is an E3 ubiquitin ligase. Overexpression of SKP2 was found in various human cancers, including colorectal cancers, but its potential role as a prognostic marker after neoadjuvant chemoradiotherapy (CRT) and for therapeutic intervention in rectal cancers is unknown. This study examined the correlation of SKP2 expression in the prognosis of rectal cancer patients and the viability of colorectal cancer cells treated with CRT. SKP2 immunoexpression was retrospectively assessed in pretreatment biopsies of 172 rectal cancer patients treated with neoadjuvant CRT followed by surgery. Results were correlated with clinicopathological features, therapeutic responses, and patient survival. Pharmacologic assays were used to evaluate the therapeutic relevance of Bortezomib in two colorectal cancer cell lines (HT-29 and SW480). High expression of SKP2 was correlated with the advanced Post-Tx nodal status (p = 0.002), Post-Tx International Union for Cancer Control stage (p = 0.002), and a lower-degree tumor regression grade (p < 0.001). Moreover, high expression of SKP2 (p = 0.027, hazard ratio 3.21) was an independent prognostic factor for local recurrence-free survival. In vitro, Bortezomib downregulated SKP2 expression, induced caspase activation, and decreased the viability of colorectal cancer cells with or without a combination with fluorouracil. Bortezomib also promoted caspase activation and gamma-H2AX formation in colorectal cancer cells concurrently treated with CRT. High expression of SKP2 was associated with a poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CRT. In the presence of chemotherapy with or without radiotherapy, the promoted sensitivity of colorectal cancer cells to Bortezomib with an SKP2-repressing effect indicated that it is a potential therapeutic target.
S期激酶相关蛋白2（SKP2）癌蛋白是一种E3泛素连接酶。在包括结直肠癌在内的多种人类癌症中均发现SKP2过表达，但其作为新辅助放化疗（CRT）后预后标志物以及在直肠癌治疗干预中的潜在作用尚不清楚。本研究检测了SKP2表达与直肠癌患者预后以及CRT处理的结肠癌细胞活力之间的相关性。对172例行新辅助CRT后手术的直肠癌患者的预处理活检组织进行回顾性评估SKP2免疫表达情况。结果与临床病理特征、治疗反应和患者生存情况相关。采用药理学分析评估硼替佐米在两种结肠癌细胞系（HT-29和SW480）中的治疗相关性。SKP2高表达与Tx后晚期淋巴结状态（p = 0.002）、Tx后国际癌症控制联盟分期（p = 0.002）以及较低程度的肿瘤退缩分级（p < 0.001）相关。此外，SKP2高表达（p = 0.027，风险比3.21）是无局部复发生存的独立预后因素。在体外，硼替佐米下调SKP2表达，诱导半胱天冬酶激活，并降低了无论是否联合氟尿嘧啶的结肠癌细胞活力。硼替佐米还在与CRT同时处理的结肠癌细胞中促进半胱天冬酶激活和γ-H2AX形成。SKP2高表达与接受新辅助CRT的直肠癌患者的治疗反应差和不良结局相关。在有或无放疗的化疗存在的情况下，结肠癌细胞对具有SKP2抑制作用的硼替佐米的敏感性增加表明它是一个潜在的治疗靶点。
