Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of Bim
Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to anoikis through inhibition of Bim
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DOI：
10.1074/jbc.m508421200
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发表时间：
2006-04-07
影响因子：
4.8
通讯作者：
Hait, WN
中科院分区：
文献类型：
--
作者：
Yang, JM;O'Neill, P;Hait, WN
细胞外基质金属蛋白酶诱导剂（EMMPRIN或CD147）是免疫球蛋白家族的一员，是一种富集于肿瘤细胞表面的糖蛋白，其过表达可促进恶性细胞的侵袭、转移、生长和存活，并对某些化疗药物产生耐药性。然而，EMMPRIN作用的分子机制尚不完全清楚。在这项研究中，我们试图确定EMMPRIN是否通过抑制anoikis（一种由细胞-细胞或细胞-基质锚定的丢失或改变引起的细胞凋亡形式）来促进乳腺癌的恶性表型，并探索相关的信号通路。我们发现，在没有附着的情况下，表达高水平EMMPRIN的人乳腺癌细胞形成的聚集体更紧凑，表面积更大，纤维连接蛋白基质组装更少，具有更高的活力，并且对疾病有抵抗力。通过RNA干扰（小干扰RNA或短发夹RNA）敲低EMMPRIN的表达会使癌细胞对anoikis敏感，正如caspase-3的激活所证明的那样，增加了DNA片段，降低了细胞活力。此外，我们观察到表达EMMPRIN的细胞中Bim（一种促进凋亡的BH3-only蛋白）的积累减少，而沉默EMMPRIN表达可提高Bim蛋白水平并增强细胞对anoikis的敏感性。用MEK抑制剂（U0126）或蛋白酶体抑制剂（环氧霉素）处理细胞也会上调Bim的积累，并使细胞对anoikis更敏感。这些结果表明，EMMPRIN的表达可以保护癌细胞免受疾病的侵袭，这种作用至少部分是由MAP激酶依赖性的Bim减少介导的。由于anoikis缺乏是上皮癌细胞肿瘤转化和侵袭性生长的关键特征，我们对EMMPRIN在anoikis耐药中的作用及其机制的研究强调了EMMPRIN表达作为预后标志物和癌症治疗新靶点的潜力。
Overexpression of extracellular matrix metalloproteinase inducer ( EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference ( small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor ( epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.