Ng G, Winder D, Muralidhar B, Gooding E, Roberts I, Pett M, Mukherjee G, Huang J, Coleman N
Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
J Pathol. 2007 Jul;212(3):325-34. doi: 10.1002/path.2184.
For many oncogenes, increased expression resulting from copy number gain confers a selective advantage to cells that consequently make up the tumour bulk. To identify oncogenes of potential biological significance in cervical squamous cell carcinoma (SCC), 36 primary samples and ten cell lines were screened by array comparative genomic hybridization (CGH). The most commonly occurring regions of copy number gain that also showed amplification were 5p15.2-14.3 (59%), 5p13.3 (65%), and 5p13.2-13.1 (63%). Gene copy numbers were significantly associated with expression levels for three candidate oncogenes at these loci: OSMR (oncostatin M receptor) (p=0.03), PDZK3 (PDZ domain containing protein 3) (p=0.04), and TRIO (triple functional domain) (p=0.03). Further examination by fluorescence in situ hybridization on a tissue microarray of 110 primary cervical SCC samples revealed copy number gain frequencies of 60.9%, 57.3%, and 54.5% for OSMR, PDZK3, and TRIO, respectively, with OSMR adversely influencing overall patient survival independently of tumour stage (p=0.046). By array CGH, copy number gain of OSMR was not seen in any of 40 microdissected precursor cervical squamous intraepithelial lesions (SILs). Moreover, global mRNA expression analysis, using Affymetrix U133A 2.0 Arrays, showed no overexpression of OSMR in SILs, suggesting that OSMR gain and overexpression are relatively late steps in cervical carcinogenesis. In the cervical SCC cell lines CaSki and SW756, exogenous OSM activated downstream-signalling elements of OSMR including STAT3, p44/42 MAPK, and S6 ribosomal protein, and induced transcription of the angiogenic factor VEGF, effects that were reduced by OSMR depletion using RNA interference. We conclude that copy number gain of OSMR is frequently found in cervical SCC and is associated with adverse clinical outcome. As well as being a potential prognostic marker, OSMR is a candidate cell surface therapeutic target.
对于许多癌基因而言，拷贝数增加导致的表达增加赋予了细胞选择性优势，这些细胞进而构成了肿瘤主体。为了鉴定宫颈鳞状细胞癌（SCC）中具有潜在生物学意义的癌基因，通过阵列比较基因组杂交（CGH）对36份原发性样本和10个细胞系进行了筛查。拷贝数增加且同时显示扩增的最常见区域为5p15.2 - 14.3（59%）、5p13.3（65%）和5p13.2 - 13.1（63%）。在这些位点，三个候选癌基因的基因拷贝数与表达水平显著相关：OSMR（抑瘤素M受体）（p = 0.03）、PDZK3（含PDZ结构域蛋白3）（p = 0.04）和TRIO（三功能结构域）（p = 0.03）。通过对110份原发性宫颈SCC样本的组织微阵列进行荧光原位杂交进一步检测发现，OSMR、PDZK3和TRIO的拷贝数增加频率分别为60.9%、57.3%和54.5%，其中OSMR独立于肿瘤分期对患者总体生存产生不利影响（p = 0.046）。通过阵列CGH，在40份显微切割的宫颈鳞状上皮内瘤变（SIL）前体病变样本中均未发现OSMR的拷贝数增加。此外，使用Affymetrix U133A 2.0阵列进行的全基因组mRNA表达分析显示，SIL中OSMR无过表达，这表明OSMR的拷贝数增加和过表达是宫颈癌发生过程中相对较晚的步骤。在宫颈SCC细胞系CaSki和SW756中，外源性OSM激活了OSMR的下游信号元件，包括STAT3、p44/42 MAPK和S6核糖体蛋白，并诱导血管生成因子VEGF的转录，而使用RNA干扰使OSMR缺失则可减弱这些效应。我们得出结论，OSMR的拷贝数增加在宫颈SCC中经常出现，并与不良临床结局相关。OSMR不仅是一个潜在的预后标志物，还是一个候选的细胞表面治疗靶点。
