Overexpression of CDC25B and LAMC2 mRNA and protein in esophageal squamous cell carcinomas and premalignant lesions in subjects from a high-risk population in China
Overexpression of CDC25B and LAMC2 mRNA and protein in esophageal squamous cell carcinomas and premalignant lesions in subjects from a high-risk population in China
复制标题
DOI：
10.1158/1055-9965.epi-06-0666
复制
发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Taylor, Philip R.
中科院分区：
文献类型：
--
作者：
Shou, Jian-Zhong;Hu, Nan;Taylor, Philip R.
与食道鳞状细胞癌(ESCC)发生和发展相关的分子事件仍然知之甚少，但可能是这种几乎总是致命的癌症早期有效检测方法的关键。CDC25B和LAMC2是新的食管癌分子研究中出现的两个有希望的早期检测候选基因。为了进一步阐明这两个基因在食道癌发生中的作用，我们进行了一系列研究，以(A)证实RNA的过度表达，(B)确定蛋白质过度表达的流行率，(C)蛋白质过度表达与生存的关系，以及(D)探索它们作为早期检测生物标志物的可能性。这些研究结果表明，在73例食管鳞癌患者中，CDC25BmRNA的过度表达(肿瘤组织中CDC25BmRNA的过度表达是正常组织的2倍)，而LAMC2mRNA的过度表达占89%。在肿瘤组织芯片上，CDC25B蛋白表达阳性者占59%(144/243)，而LAMC2蛋白表达非阴性者占82%(225/275)。多变量调整的比例风险回归模型显示CDC25B蛋白表达得分与死亡风险之间没有关联[表达得分每增加一个单位的危险比(HR)为1.00；P=0.90]；然而，几种LAMC2蛋白表达模式强烈地预测了生存。以细胞质模式(死亡率最低的模式)为参照，弥漫型患者的死亡风险增加254%(HR，3.52；P=0.007)，无LAMC2表达的患者死亡风险增加169%(HR，2.69；P=0.009)，周边型患者的死亡风险增加130%(HR，2.3；P=0.02)。CDC25B蛋白在正常(n=35)、异型增生(n=23)和食管鳞癌(n=32)患者中的表达随着组织形态的发展而显著升高。对于LAMC2，所有正常和发育异常的患者都有连续的蛋白表达模式，而所有的ESCC都表现出不连续的替代模式。这一系列研究表明，CDC25B和LAMC2在绝大多数ESCC病例中都过表达RNA和蛋白质。LAMC2蛋白表达模式与生存期密切相关，提示其在预后中有一定作用，而CDC25B与肿瘤形态进展的相关性则提示其作为早期检测标志物的潜在作用。
Molecular events associated with the initiation and progression of esophageal squamous cell carcinoma (ESCC) remain poorly understood but likely hold the key to effective early detection approaches for this almost invariably fatal cancer. CDC25B and LAMC2 are two promising early detection candidates emerging from new molecular studies of ESCC. To further elucidate the role of these two genes in esophageal carcinogenesis, we did a series of studies to (a) confirm RNA overexpression, (b) establish the prevalence of protein overexpression, (c) relate protein overexpression to survival, and (d) explore their potential as early detection biomarkers. Results of these studies indicated that CDC25B mRNA was overexpressed (>= 2-fold overexpression in tumor compared with normal) in 64% of the 73 ESCC cases evaluated, whereas LAMC2 mRNA was overexpressed in 89% of cases. CDC25B protein expression was categorized as positive in 59% (144 of 243) of ESCC cases on a tumor tissue microarray, and nonnegative LAMC2 patterns of protein expression were observed in 82% (225 of 275) of cases. Multivariate-adjusted proportional hazard regression models showed no association between CDC25B protein expression score and risk of death [hazard ratio (HR) for each unit increase in expression score, 1.00; P = 0.90]; however, several of the LAMC2 protein expression patterns strongly predicted survival. Using the cytoplasmic pattern as the reference (the pattern with the lowest mortality), cases with a diffuse pattern had a 254% increased risk of death (HR, 3.52; P = 0.007), cases with no LAMC2 expression had a 169% increased risk of death (HR, 2.69; P = 0.009), and cases with a peripheral pattern had a 130% greater risk of death (HR, 2.30; P = 0.02). CDC25B protein expression scores in subjects with esophageal biopsies diagnosed as normal (n = 35), dysplastic (n = 23), or ESCC (n = 32) increased significantly with morphologic progression. For LAMC2, all normal and dysplastic patients had a continuous pattern of protein expression, whereas all ESCCs showed alternative, noncontinuous patterns. This series of studies showed that both CDC25B and LAMC2 overexpress RNA and protein in a significant majority of ESCC cases. The strong relation of LAMC2 pattern of protein expression to survival suggests a role in prognosis, whereas the association of CDC25B with morphologic progression indicates a potential role as an early detection marker.