Upregulation of LAPTM4B-35 Promotes Malignant Transformation and Tumorigenesis in L02 Human Liver Cell Line
Upregulation of LAPTM4B-35 Promotes Malignant Transformation and Tumorigenesis in L02 Human Liver Cell Line
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DOI：
10.1002/ar.21421
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发表时间：
2011-07-01
影响因子：
2
通讯作者：
Zhou, Rou-Li
中科院分区：
文献类型：
--
作者：
Li, Li;Shan, Yi;Zhou, Rou-Li
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一，也是中国癌症死亡的第二大原因。我们之前已经证明，由溶酶体蛋白跨膜4β基因编码的LAPTM4B-35在超过80%的HCC中过表达，是HCC转移、复发和术后生存的新型独立预后因素。在本研究中，我们利用 L02 细胞（一种源自人类正常肝细胞的细胞系）研究了 LAPTM4B-35 在恶性转化和肿瘤发生中的作用。我们的数据表明，复制缺陷型腺病毒载体介导的 LAPTM4B-35 上调可促进贴壁依赖性增殖和对阿霉素诱导的细胞凋亡的抵抗。对潜在机制的研究表明，这些过程中涉及的分子事件发生了变化，包括磷酸肌醇 3 激酶 (PI3K)/丝氨酸/苏氨酸蛋白激酶 B (PKB/AKT)/bcl-xL/bcl-2 相关死亡启动子同源物 (Bad) 信号通路的激活、caspase-3 激活的抑制、Bcl-2 的上调和 Bax 的下调。此外，L02细胞中LAPTM4B-35的上调导致接种的裸鼠100%（6/6）发生肿瘤，并加速体内异种移植小鼠的死亡。总之，LAPTM4B-35通过促进增殖失调和抑制细胞凋亡来促进人肝L02细胞系的恶性转化和肿瘤发生。这些发现表明，LAPTM4B-35 的过度表达可能在肝癌发生中发挥关键作用，因此可能是 HCC 的治疗靶点。 Anat Rec，294:1135-1142，2011。(C)2011Wiley-Liss, Inc.
Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycin-induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and down-regulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC. Anat Rec, 294:1135-1142, 2011. (C) 2011Wiley-Liss, Inc.