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

LAMP3(DC-LAMP，TSC403，CD208)最初是作为一个在肺组织中特异表达的基因被分离出来的。LAMP3位于染色体3Q片段上，该片段在包括宫颈癌在内的一些人类癌症中经常被扩增。由于LAMP家族的另外两个成员LAMP1和LAMP2先前被认为可能参与调节血管内皮细胞和癌细胞之间的相互作用，因此我们推测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表达载体导入人宫颈癌细胞系TCS。在体外侵袭实验中，过表达LAMP3的TCS细胞的迁移能力显著高于对照TCS细胞。在体内转移试验中，在11只高表达LAMP3的TCS细胞注射的小鼠中有9只检测到远处转移，而在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，LAMP3过表达的细胞容易侵入淋巴血管间隙。在临床标本中，实时定量RT-PCR分析显示，在47例宫颈癌(100%)和15例宫颈上皮内瘤变(CIN)中，47例(100%)和2例(13%)LAMP3mRNA表达显著上调，而正常宫颈组织中LAMP3mRNA表达水平较低。有趣的是，LAMP3的高表达与I/II期宫颈癌患者的总生存期显著相关。这些发现表明，LAMP3的过度表达与宫颈癌转移潜能的增强有关，并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.