Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1network in triple-negative breast cancer
Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1network in triple-negative breast cancer
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DOI：
10.3892/ijo.2016.3319
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发表时间：
2016-03-01
影响因子：
5.2
通讯作者：
Lv, Shijun
中科院分区：
文献类型：
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作者：
Li, Wentong;Liu, Chuanliang;Lv, Shijun
整合素是参与双向信号转导的黏附受体，在正常动态平衡和病理条件下，如肿瘤进展和转移，对各种细胞反应至关重要。在本研究中，我们证明了阻断β3整合素介导的细胞-细胞外基质相互作用抑制了三阴性乳腺癌(TNBC)的生长，并且上调的β3整合素可以触发ERK/ETS-1信号通路的重新连接，从而促进细胞的生长和侵袭。MiRNA的异位表达参与了整合素表达和活性的调节，阻断肿瘤的发展和进展，以及转移表型的获得。MIR-30a-5p的表达与乳腺癌的进展有关。MiR-30a-5p过表达抑制了乳腺癌细胞的增殖、迁移和侵袭。相反，抑制miR-30a-5p通过抑制ERK/Ets-1信号的表达而促进TNBC细胞的增殖、迁移和侵袭。在TNBC组织中miR-30a-5p和β3整合素的mRNA表达呈负相关。此外，生物信息学分析表明，在β3整合素的3‘-非编码区存在miR-30结合位点。荧光素酶活性检测结果显示，miR-30a-5p和野生型3‘-UTR型β3整合素对荧光素酶活性有较强的抑制作用。在TNBC细胞中，miR-30a-5p通过特异性靶向β3整合素亚基从而阻断β3整合素/Erk/ETS-1网络，促进上皮表型，抑制侵袭。
Integrins are adhesion receptors involved in bidirectional signaling and are crucial for various cellular responses during normal homeostasis and pathological conditions, such as cancer progression and metastasis. In the present study, we demonstrated that blockage of beta 3 integrin-mediated cell-extracellular matrix interactions restrained triple-negative breast cancer (TNBC) growth, and elevated beta 3 integrin can trigger the rewiring of Erk/Ets-1 signaling pathways, thereby enhancing cell growth and invasion. Ectopic expression of miRNA has been implicated in the deregulation of integrin expression and activity, blocking of cancer tumor development and progression, and acquisition of metastatic phenotype. miR-30a-5p expression has been implicated in the progression of breast cancer. Overexpression of miR-30a-5p suppressed the proliferation, migration and invasion of breast cancer cells. On the contrary, inhibition of miR-30a-5p promoted the proliferation, migration, and invasion of TNBC cells by suppressing the expression of ERK/Ets-1 signal. An inverse correlation was found between the mRNA expressions of miR-30a-5p and beta 3 integrin in TNBC samples. Furthermore, bioinformatics analysis revealed the putative miR-30 binding sites in the 3'-UTR of beta 3 integrin. Results of luciferase assay revealed a strong repression of luciferase activity after transfection with miR-30a-5p and wild-type 3'-UTR of beta 3 integrin. In TNBC cells, miR-30a-5p promoted an epithelial phenotype and suppressed invasion by specifically targeting beta 3 integrin subunit to subsequently interdict the beta 3 integrin/Erk/Ets-1 network.