MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail.
MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail.
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MicroRNA-22通过直接靶向MMP14和Snail抑制胃癌肿瘤生长和转移
DOI：
10.1038/cddis.2015.297
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发表时间：
2015-11-26
影响因子：
9
通讯作者：
Zou QM
中科院分区：
文献类型：
--
作者：
Zuo QF;Cao LY;Yu T;Gong L;Wang LN;Zhao YL;Xiao B;Zou QM
微小RNA（miRNAs）的失调在人类胃癌（GC）中是常见的，但参与这种疾病的特定miRNAs的作用仍然难以捉摸。MiR-22先前被报道在多种癌症中充当肿瘤抑制因子或致癌基因。然而，它们在胃癌中的准确表达、功能和机制在很大程度上还不清楚。在此，我们发现，与配对的相邻正常组织相比，临床GC组织中miR-22的表达显著降低，并且与患者中更具侵袭性的GC表型显著相关，并且miR-22低表达与总体生存率差相关。miR-22的导入显著抑制了胃癌细胞的生长、迁移和侵袭，而抑制miR-22则促进了胃癌细胞的增殖、迁移和侵袭。我们进一步证明了miR-22通过靶向细胞外基质（ECM）重塑成员基质金属蛋白酶14（MMP 14）和上皮-间质转化（EMT）诱导剂Snail在GC中发挥肿瘤抑制剂的作用。此外，异位表达MMP 14或Snail可恢复miR-22对胃癌细胞迁移和侵袭的抑制作用，胃癌中miR-22的表达与MMP 14或Snail mRNA水平呈负相关。最后，miR-22的过表达在体内抑制肿瘤生长、腹膜播散和肺转移。综上所述，我们确定miR-22是GC中有效的肿瘤抑制因子。miR-22的下调通过上调MMP 14和Snail的表达促进胃癌的侵袭和转移，进而诱导ECM重塑和EMT。这些发现提供了更好的了解GC的发展和进展，并可能是一个重要的意义，为未来的治疗GC。
MicroRNAs (miRNAs) deregulation is frequent in human gastric cancers (GCs), but the role of specific miRNAs involved in this disease remains elusive. MiR-22 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here, we found that the expression of miR-22 was significantly reduced in clinical GC tissues compared with paired adjacent normal tissues, and was significantly correlated with a more aggressive phenotype of GC in patients, and miR-22 low expression correlated with poor overall survival. The introduction of miR-22 markedly suppressed GC cell growth, migration and invasion, and inhibition of miR-22 promoted GC cell proliferation, migration and invasion in vitro. We further demonstrated that miR-22 acted as tumor suppressors through targeting extracellular matrix (ECM) remodeling member matrix metalloproteinase 14 (MMP14) and epithelial-to-mesenchymal transition (EMT) inducer Snail in GC. Moreover, ectopic expression of MMP14 or Snail restored inhibitory effects of miR-22 on cell migration and invasion in GC cells, and a negative relationship between the miR-22 expression and MMP14 or Snail mRNA levels was observed in GC. Finally, overexpression of miR-22 suppressed tumor growth, peritoneal dissemination and pulmonary metastasis in vivo. Taken together, we identified that miR-22 is a potent tumor suppressor in GC. MiR-22 downregulation promotes GC invasion and metastasis by upregulating MMP14 and Snail, and then inducing ECM remodeling and EMT. These findings provide a better understanding of the development and progression of GC and may be an important implication for future therapy of the GC.