Section of Cell and Molecular Biology, The Institute of Cancer Research, London, UK.
J Natl Cancer Inst. 2011 Mar 2;103(5):407-24. doi: 10.1093/jnci/djq569. Epub 2011 Jan 31.
Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC).
We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided.
Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P < .001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P = .037) and invasion (P = .015), whereas SW620+shLOX cells showed reduced proliferation (P = .011) and invasion (P = .013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P = .036) and decreased in SW620+shLOX tumors (P = .048), and metastasis was statistically significantly increased in SW480+LOX tumors (P = .044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal; P = .035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib.
LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These results have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment.
越来越多的证据表明赖氨酰氧化酶（LOX），一种细胞外基质修饰酶，在促进实体瘤转移中起作用。我们研究了 LOX 是否在结直肠癌（CRC）的转移中起重要作用。
我们分析了包含正常结肠黏膜（n=49）、原发性（n=510）和转移性（n=198）组织的患者 CRC 组织微阵列中的 LOX 表达。CRC 细胞系 SW480 中 LOX 过表达（SW480+LOX），并用 LOX 特异性短发夹 RNA（SW620+shLOX）敲低 CRC 细胞系 SW620 中的 LOX 表达。在体外三维细胞增殖和侵袭实验中，研究了 LOX 操作的影响。在皮下肿瘤小鼠模型（每组 3 只小鼠）和脾内转移小鼠模型（每组 3 只小鼠）中研究了 LOX 操作对肿瘤增殖和转移的影响。使用达沙替尼（一种 SRC 激活抑制剂）研究 LOX 介导的通过 v-src 肉瘤（Schmidt-Ruppin A-2）病毒癌基因同源物（avian）（SRC）的效应的机制。所有统计检验均为双侧。
与正常结肠组织（n=49）相比，CRC 患者的肿瘤组织（n=510）中 LOX 表达明显增加（P<0.001），在转移性组织（n=198）中增加更大。SW480+LOX 细胞的三维增殖（P=0.037）和侵袭（P=0.015）明显增加，而 SW620+shLOX 细胞的增殖（P=0.011）和侵袭（P=0.013）明显减少。与对照组相比，SW480+LOX 肿瘤的皮下肿瘤生长明显增加（P=0.036），SW620+shLOX 肿瘤的生长减少（P=0.048），SW480+LOX 肿瘤的转移明显增加（P=0.044），SW620+shLOX 肿瘤的转移减少（SW620 对照 vs SW620+shLOX，平均值为 1.0 发光信号，95%置信区间为 0.3 至 1.7 发光信号，vs 平均值为 0.3 发光信号，95%置信区间为 0.1 至 0.5 发光信号；P=0.035）。LOX 对肿瘤进展的影响与 SRC 激活有关，达沙替尼抑制了这些影响。
LOX 在 CRC 细胞增殖和转移中起重要作用，并且依赖于 SRC 的激活。这些结果有可能确定 SRC 活性高的患者，他们可能受益于达沙替尼治疗。
