Extracellular disposal of tumor-suppressor miRs-145 and -34a via microvesicles and 5-FU resistance of human colon cancer cells.
Extracellular disposal of tumor-suppressor miRs-145 and -34a via microvesicles and 5-FU resistance of human colon cancer cells.
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DOI：
10.3390/ijms15011392
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发表时间：
2014-01-20
影响因子：
5.6
通讯作者：
Yamada N
中科院分区：
文献类型：
--
作者：
Akao Y;Khoo F;Kumazaki M;Shinohara H;Miki K;Yamada N
microRNA （miRNA）表达的失调引起各种疾病。特别是，在人类肿瘤细胞中经常观察到miRNA表达水平的改变，并与癌症的发病机制有关。早期，我们从亲代5-FU敏感的DLD-1细胞中建立了氟尿嘧啶（5-FU）耐药的人结肠癌DLD-1细胞（DLD-1/ 5fu）。在本研究中，我们检测了5-FU治疗前后各细胞系及其细胞外微泡（MVs）中miRNA的表达。在两种细胞中标记有EU的抗肿瘤miR-34a和-145新生rna被证明可以转移到两种细胞系的mv中。在两种细胞系中，细胞及其mv中的miR-34a和-145水平没有太大差异，即使在稳态条件下，两种细胞系也会分泌大量的这两种mirna。两种细胞系暴露于5-FU后，在5-FU敏感的DLD-1细胞中，miR-145和miR-34a的细胞内水平均显著升高，而在DLD-1/ 5fu细胞中，miR水平均未升高。有趣的是，在5-FU处理后，在脱落到亲代细胞培养基中的小mv中检测到的miR-145的量减少了。另一方面，即使在稳态条件下，与亲代DLD-1细胞相比，DLD-1/ 5fu细胞内miR-34a的表达也有所下调。miR-34a分泌到mv中，经5-FU处理后，DLD-1/ 5fu细胞中miR-34a水平的升高大于亲本DLD-1细胞。因此，细胞内和细胞外的miR-145和-34a与5-FU耐药密切相关，耐药的部分原因是miR-145和-34a通过mv分泌增强，导致细胞内这两种mirna水平较低。
The dysregulation of microRNA (miRNA) expression causes various kinds of diseases. Especially, alterations in miRNA expression levels are frequently observed in human tumor cells and are associated with cancer pathogenesis. Earlier we established Fluorouracil (5-FU)-resistant human colon cancer DLD-1 cells (DLD-1/5FU) from parental 5-FU- sensitive DLD-1 cells. In the present study, we examined the expression of miRNA in each cell line and in its extracellular microvesicles (MVs) before and after treatment with 5-FU. The nascent RNAs of anti-oncogenic miR-34a and -145 labeled with EU in both cells were proved to be transferred into MVs in both cell lines. The levels of miR-34a and -145 in the cells and in their MVs were not largely different in the two cell lines, and a substantial amount of both miRNAs was secreted by both cell lines even in the steady-state condition. The exposure of both cell lines to 5-FU significantly increased the intracellular levels of miR-145 and miR-34a in the 5-FU-sensitive DLD-1 cells, whereas the level of neither miR was elevated in the DLD-1/5FU cells. Interestingly, the amount of miR-145 detected in the small MVs shed into the medium of the parental cells was reduced after the treatment with 5-FU. On the other hand, the intracellular expression of miR-34a in the DLD-1/5FU cells was down-regulated compared with that in the parental DLD-1 cells even in the steady-state condition. As to the miR-34a secreted into MVs, the increase in the level in DLD-1/5FU cells was greater than that in the parental DLD-1 cells after the treatment with 5-FU. Thus, the intra- and extracellular miR-145 and -34a were closely associated with 5-FU resistance, and the resistance was in part due to the enhanced secretion of miR-145 and -34a via MVs, resulting in low intracellular levels of both miRNAs.
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影响因子：
4.6
作者：
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