Overexpression of LAMP3/TSC403/DC-LAMP promotes metastasis in uterine cervical cancer

LAMP3 （DC-LAMP, TSC403, CD208）最初是作为在肺组织中特异性表达的基因分离出来的。LAMP3位于染色体3q段，在包括子宫癌在内的一些人类癌症中经常被扩增。由于溶酶体膜糖蛋白LAMP家族的另外两个成员LAMP1和LAMP2先前涉及潜在地调节血管内皮细胞和癌细胞的相互作用，我们假设LAMP3也可能在转移中发挥重要作用。为了阐明LAMP3在宫颈癌中的转移潜力，我们将LAMP3表达载体转染到人宫颈癌细胞系TCS中。在体外侵袭实验中，过表达lamp3的TCS细胞的迁移明显高于对照TCS细胞。在体内转移试验中，11只过表达lamp3的tcs细胞注射小鼠中有9只检测到远处转移，而11只对照小鼠中只有1只检测到远处转移。组织学研究表明，过表达lamp3的细胞容易侵入淋巴血管间隙。在临床样本中，定量实时RT-PCR分析显示，与正常子宫颈低水平表达的LAMP3 mRNA相比，47例宫颈癌中有47例（100%）和15例宫颈上皮内瘤变（CINs）中有2例（13%）的LAMP3 mRNA显著上调。有趣的是，高LAMP3表达与I/II期宫颈癌患者的总生存率显著相关。这些发现表明LAMP3过表达与转移潜力增强有关，可能是宫颈癌的预后因素。

LAMP3 (DC-LAMP, TSC403, CD208) was originally isolated as a gene specifically expressed in lung tissues. LAMP3 is located on a chromosome 3q segment that is frequently amplified in some human cancers, including uterine cervical cancer. Because two other members of the LAMP family of lysosomal membrane glycoproteins, LAMP1 and LAMP2,were previously implicated in potentially modulating the interaction of vascular endothelial and cancer cells, we hypothesized that LAMP3 might also play an important part in metastasis.To clarify the metastatic potential of the LAMP3 in cervical cancers, we transfected a LAMP3-expression vector into a human uterine cervical cancer cell line, TCS. In an in vitro invasion assay, the migration of LAMP3-overexpressing TCS cells was significantly higher than in control TCS cells. In an in vivo metastasis assay, distant metastasis was detected in 9 of 11 LAMP3-overexpressing TCS-cell-injected mice and in only 1 of 11 control mice. Histological study showed that LAMP3-overexpressing cells readily invaded into the lymph-vascular space.In clinical samples, quantitative real-time RT-PCR analyses showed that LAMP3 mRNA was significantly up-regulated in 47 of 47 (100%) cervical cancers and in 2 of 15 (13%) cervical intraepithelial neoplasias (CINs), compared to a low level of LAMP3 mRNA expressed in normal uterine cervixes. Interestingly, high LAMP3 expression was significantly correlated with the overall survival of patients with stage I/II cervical cancers.These findings indicate that LAMP3 overexpression is associated with an enhanced metastatic potential, and may be a prognostic factor for cervical cancer.