Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Clin Cancer Res. 2016 Nov 1;22(21):5277-5286. doi: 10.1158/1078-0432.CCR-15-1945. Epub 2016 May 10.
One of the main reasons for cancer treatment resistance is the existence of cancer stem-like cells (CSCs). Here, we elucidated the relationship between low proteasome activity cells (LPACs) and CSCs.
The human colorectal cancer cell lines HCT116, SW480, DLD1, and KM12SM were engineered to stably express a green fluorescent molecule fused to the degron of ornithine decarboxylase, resulting in an accumulation of the fluorescence in LPACs. LPACs were isolated by flow cytometry. Treatment resistance (radio- and chemotherapy) and the capacity of LPACs to act as CSCs were analyzed. Microarray analysis was performed to reveal genes related to treatment resistance. The prognostic impact of potent genes was examined in 190 patients with colorectal cancer.
LPACs had a significantly increased capacity for radioresistance and chemoresistance (5-fluorouracil and oxaliplatin), significantly lower reactive oxygen species activity, and significantly increased sphere formation capacity compared with non-LPACs. The number of cells in the G-G phase was significantly higher among LPACs. Subcutaneous injection of as few as 20 LPACs led to tumor formation in immunologically incompetent mice. Microarray analysis revealed that the expression of EP300-interacting inhibitor of differentiation 3 (EID3) was significantly increased in LPACs. In vitro assay revealed that EID3 positively controlled cell proliferation and treatment resistance. The high expression of EID3 was an adverse prognostic indicator in patients with colorectal cancer (P = 0.0400).
LPACs have characteristic treatment resistance and act as CSCs in colorectal cancer. In addition, EID3 is one of the potential regulators of treatment resistance in colorectal cancer and may be a potential therapeutic target. Clin Cancer Res; 22(21); 5277-86. ©2016 AACR.
癌症治疗抵抗的主要原因之一是癌症干细胞样细胞（CSCs）的存在。在这里，我们阐明了低蛋白酶体活性细胞（LPACs）与 CSCs 之间的关系。
将人结直肠癌细胞系 HCT116、SW480、DLD1 和 KM12SM 工程化，使其稳定表达绿色荧光分子与鸟氨酸脱羧酶降解结构域融合，导致 LPACs 中荧光积累。通过流式细胞术分离 LPACs。分析 LPACs 的治疗抵抗（放射和化学疗法）和作为 CSCs 的能力。进行微阵列分析以揭示与治疗抵抗相关的基因。在 190 名结直肠癌患者中检查了有效基因的预后影响。
与非 LPACs 相比，LPACs 的放射抗性和化学抗性（5-氟尿嘧啶和奥沙利铂）、活性氧物种活性显著降低、球体形成能力显著提高。LPACs 中 G1-G0 期细胞的数量显著增加。在免疫功能不全的小鼠中，仅注射 20 个 LPACs 就导致肿瘤形成。微阵列分析显示，LPACs 中 EP300 相互作用的分化抑制剂 3（EID3）的表达显著增加。体外试验显示，EID3 可正向控制细胞增殖和治疗抵抗。EID3 的高表达是结直肠癌患者的不良预后指标（P=0.0400）。
LPACs 具有特征性的治疗抵抗性，并在结直肠癌中充当 CSCs。此外，EID3 是结直肠癌治疗抵抗的潜在调节剂之一，可能是潜在的治疗靶点。Clin Cancer Res; 22(21); 5277-86. ©2016 AACR.
