Xie Yi, Chan Hiuman, Fan Jianqing, Chen Yongxiong, Young Joseph, Li Wen, Miao Xiaoping, Yuan Zhengwei, Wang Huanmin, Tam Paul K H, Ren Yi
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Carcinogenesis. 2007 Oct;28(10):2122-30. doi: 10.1093/carcin/bgm147. Epub 2007 Jul 5.
Tumor growth and metastasis require that tumor cells must have either the potential to shift genetically or epigenetically between proliferative and invasive phenotypes or both phenotypes simultaneously. In the present study, we demonstrated that neuroblastoma growth and invasion were distinct processes that were carried out by proliferative and invasive phenotypes of tumor cells, respectively. Two subpopulations from human neuroblastoma cell line were isolated: highly invasive (HI) cells and low-invasive (LI) cells. HI and LI cells had different proliferative rate and metastatic ability in vitro and in vivo. In addition, they had distinct activated signal pathways and sensitivities to chemotherapy drugs. Affymetrix microarray and quantitative reverse transcriptase-polymerase chain reaction revealed that visinin-like protein-1 (VSNL-1) mRNA in HI cells was significantly higher than that in LI cells. We also observed that VSNL-1 was over-expressed in tumor specimens from patients with distant organ metastases compared with those without metastases. Furthermore, the invasive and proliferative phenotypes of neuroblastoma cells could be exchanged by regulation of VSNL-1 expression in vitro and in vivo. Up-regulation of VSNL-1 potentiated the anoikis-resistant ability of neuroblastoma cell. The expression of anoikis inhibitor TrkB, intracellular adhesion molecule 1, major histocompatibility complex class I, CD44 and CD44v6 was associated with VSNL-1 level. These results suggested that distinct roles of proliferative and invasive phenotypes contributed to neuroblastoma progression and strongly demonstrated that VSNL-1 played a very important role in neuroblastoma metastasis.
肿瘤的生长和转移要求肿瘤细胞必须具备在增殖和侵袭表型之间发生遗传或表观遗传转变的潜力，或者同时具备这两种表型。在本研究中，我们证明神经母细胞瘤的生长和侵袭是不同的过程，分别由肿瘤细胞的增殖和侵袭表型执行。从人神经母细胞瘤细胞系中分离出两个亚群：高侵袭性（HI）细胞和低侵袭性（LI）细胞。HI细胞和LI细胞在体外和体内具有不同的增殖率和转移能力。此外，它们具有不同的激活信号通路以及对化疗药物的敏感性。Affymetrix微阵列和定量逆转录聚合酶链反应显示，HI细胞中的视宁蛋白样蛋白-1（VSNL-1）mRNA显著高于LI细胞。我们还观察到，与无远处器官转移的患者相比，有远处器官转移的患者肿瘤标本中VSNL-1过表达。此外，在体外和体内通过调节VSNL-1表达可交换神经母细胞瘤细胞的侵袭和增殖表型。VSNL-1的上调增强了神经母细胞瘤细胞的失巢凋亡抵抗能力。失巢凋亡抑制剂TrkB、细胞间黏附分子1、主要组织相容性复合体I类、CD44和CD44v6的表达与VSNL-1水平相关。这些结果表明，增殖和侵袭表型的不同作用促成了神经母细胞瘤的进展，并有力地证明VSNL-1在神经母细胞瘤转移中发挥了非常重要的作用。
