Gastroenterology 2011 Dec;141 (6): 2076-2087.e6. [IF:12.032]
HER2 Interacts With CD44 to Up-regulate CXCR4 via Epigenetic Silencing of microRNA-139 in Gastric Cancer Cells.
Bao W , Fu HJ , Xie QS , Wang L , Zhang R , Guo ZY , Zhao J , Meng YL , Ren XL , Wang T , Li Q , Jin BQ , Yao LB , Wang RA , Fan DM , Chen SY , Jia LT , Yang AG .
State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China; Nanjing Bayi Hospital, Nanjing, China.
西安第四军医大学肿瘤生物学国家重点实验室，南京八一医院
Abstract
Human epidermal growth factor receptor 2 (HER2) (neu/ERBB2) is overexpressed on many types of cancer cells, including gastric cancer cells; HER2 overexpression has been associated with metastasis and poor prognosis. We investigated the mechanisms by which HER2 regulates cell migration and invasion. HER2 expression or activity was reduced in gastric cancer cell lines using small interfering RNAs or the monoclonal antibody, trastuzumab. We identified proteins that interact with HER2 or microRNAs (miRNAs) involved in HER2 signaling. We used various software programs to identify miRNAs that regulate factors in the HER2 signaling pathway. We analyzed expression patterns of these miRNAs in gastric cancer cell lines and tumor samples from patients. We found that CD44 binds directly to HER2, which up-regulates the expression of metastasis-associated protein-1, induces deacetylation of histone H3 lysine 9, and suppresses transcription of microRNA139 (miR-139) to inhibit expression of its target gene, C-X-C chemokine receptor type 4 (CXCR4). Knockdown of HER2 and CD44 reduced invasive activity of cultured gastric cancer cells and suppressed tumor growth in nude mice. Lymph node metastasis was associated with high levels of HER2, CD44, and CXCR4, and reduced levels of miR-139 in human metastatic gastric tumors. Cultures of different types of metastatic cancer cells with histone deacetylase inhibitors and/or DNA methyltransferase resulted in up-regulation of miR-139. HER2 interaction with CD44 up-regulates CXCR4 by inhibiting expression of miR-139, at the epigenetic level, in gastric cancer cells. These findings indicate how HER2 signaling might promote gastric tumor progression and metastasis.
摘要:
人表皮生长因子受体2在许多种癌细胞中过表达； HER2的过表达与癌的转移和预后差相关。我们研究了HER2调节细胞迁移和侵袭的机制。使用小干扰RNA或曲妥珠单抗的单克隆抗体后HER2的表达及其活性降低了。我们鉴定了与HER2相互作用的蛋白，并用小RNA干扰HER2的信号。我们使用各种软件程序来鉴定调节HER2信号通路成员的小RNA。我们分析了胃癌细胞系和胃癌病人的肿瘤标本中的这些小RNA的表达情况。我们发现CD44可与HER2直接结合，如此，可上调转移相关蛋白1，并引起组胺H3的9号位赖氨酸的脱乙酰基作用，并抑制小RNA139的转录从而抑制其靶基因C-X-C家族趋化因子受体4(CXCR4)的表达。敲掉HER2和CD44可减少培养的胃癌细胞的侵袭力并可抑制裸鼠中肿瘤的生长。淋巴结转移与人转移性胃肿瘤中HER2、CD44和 CXCR4的高表达水平和miR-139的表达水平减少有关。在各种转移癌细胞培养中加入组蛋白脱乙酰基酶抑制物和/或DNA甲基转移酶将会导致miR-139表达上调。在表观遗传学水平，胃癌细胞中HER2与CD44相互作用可抑制miR-139的表达从而上调CXCR4。这些发现提示了HER2信号可能促进胃肿瘤的进展和转移。
