Stock Peggy, Monga Dulabh, Tan Xinping, Micsenyi Amanda, Loizos Nick, Monga Satdarshan P S
Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, S421-BST Pittsburgh, PA 15213, USA.
Mol Cancer Ther. 2007 Jul;6(7):1932-41. doi: 10.1158/1535-7163.MCT-06-0720. Epub 2007 Jun 29.
Hepatocellular cancer (HCC) is a disease of poor prognosis. Identifying novel molecular aberrations might present opportunities to identify new therapeutic targets. Due to the similarities between the processes of development and cancer, we used early developing livers to identify genes that might play a primary role in HCC. Platelet-derived growth factor receptor-alpha (PDGFRalpha) was identified from microarray using early developing mouse livers. Expression of PDGFRalpha and its upstream effectors, PDGF-AA and PDGF-CC, were examined in HCC tissues (n = 43) by Western blot, real-time PCR, and immunohistochemistry. Finally, effect of anti-PDGFRalpha antibody (mAb 3G3, ImClone Systems, Inc.) was examined on human hepatoma cells. A high expression of PDGFRalpha was observed during early liver development. HCCs (17 of 21) revealed cytoplasmic PDGFRalpha and activated PDGFRalpha (phospho-Tyr(754)) by immunohistochemistry. Additional HCCs (14 of 22) showed elevated PDGFRalpha levels when compared with the adjacent normal livers by Western blots. Of these 14 patients, 3 showed increased PDGFRalpha gene expression, 3 showed elevated PDGF-AA, and 4 had higher PDGF-CC levels in the tumors compared with adjacent livers. Multiple hepatoma cell lines, when treated with mAb 3G3, showed significant decreases in cell proliferation and survival (P < 0.05). In conclusion, approximately 70% of HCC tissues had elevated PDGFRalpha levels due to diverse mechanisms. PDGFRalpha inhibition in hepatoma cells led to diminution of tumor cell survival and proliferation and thus might be of therapeutic significance.
肝细胞癌（HCC）是一种预后较差的疾病。识别新的分子异常可能为确定新的治疗靶点提供机会。由于发育过程与癌症之间存在相似性，我们利用早期发育的肝脏来识别可能在HCC中起主要作用的基因。通过使用早期发育的小鼠肝脏，从微阵列中鉴定出血小板衍生生长因子受体α（PDGFRα）。通过蛋白质免疫印迹法、实时定量PCR和免疫组织化学检测了43例HCC组织中PDGFRα及其上游效应分子PDGF-AA和PDGF-CC的表达。最后，检测了抗PDGFRα抗体（mAb 3G3，ImClone Systems公司）对人肝癌细胞的作用。在肝脏早期发育过程中观察到PDGFRα的高表达。通过免疫组织化学，21例HCC中有17例显示细胞质PDGFRα和活化的PDGFRα（磷酸化Tyr(754)）。另外22例HCC中，通过蛋白质免疫印迹法检测发现，与相邻正常肝脏相比，14例HCC的PDGFRα水平升高。在这14例患者中，与相邻肝脏相比，3例患者的肿瘤中PDGFRα基因表达增加，3例患者的肿瘤中PDGF-AA升高，4例患者的肿瘤中PDGF-CC水平更高。多种肝癌细胞系在用mAb 3G3处理后，细胞增殖和存活率显著降低（P<0.05）。总之，约70%的HCC组织由于多种机制导致PDGFRα水平升高。抑制肝癌细胞中的PDGFRα可导致肿瘤细胞存活率和增殖能力降低，因此可能具有治疗意义。
