ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a
ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a
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DOI：
10.1038/s41419-019-1921-6
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发表时间：
2019-09-12
影响因子：
9
通讯作者：
Kadakia, Madhavi P.
中科院分区：
文献类型：
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作者：
Aljagthmi, Amjad A.;Hill, Natasha T.;Kadakia, Madhavi P.
Delta Np 63 α是转录因子p53家族的成员，在许多癌症中过表达，并在增殖、分化、迁移和侵袭中起作用。Delta Np 63 alpha已被证明可以调节参与发育和癌症的几种microRNA。我们鉴定了miRNA miR-320 a作为Delta Np 63 α的正调控靶点。先前的研究表明，miR-320 a在结直肠癌中下调，并靶向小的GTdR Rac 1，导致非经典WNT信号传导和EMT减少，从而抑制肿瘤转移和侵袭。我们发现miR-320 a是Delta Np 63 alpha的直接靶点。HaCaT和A431细胞中Delta Np 63 α的敲低下调miR-320 a水平，并导致PKC相应升高。转录物和蛋白质水平。在没有Delta Np 63 α的情况下，Rac 1在Ser 71的磷酸化增加，而Delta Np 63 α的过表达逆转了Rac 1的S71磷酸化。此外，增加PKC。通过过表达miR-320 a模拟物或Rac 1沉默，在敲低Delta Np 63 α后观察到的水平、Rac 1磷酸化和细胞侵袭被逆转。最后，沉默PKC。或用PKC抑制剂Go 6976处理逆转了在沉默Δ Np 63 α后观察到的Rac 1磷酸化和细胞侵袭的增加。综上所述，我们的数据表明Delta Np 63 α正调控miR-320 a，从而抑制PKC。表达、Rac 1磷酸化和癌症侵袭。
Delta Np63 alpha, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration, and invasion. Delta Np63 alpha has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of Delta Np63 alpha. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonical WNT signaling and EMT, thereby inhibiting tumor metastasis and invasion. We showed that miR-320a is a direct target of Delta Np63 alpha. Knockdown of Delta Np63 alpha in HaCaT and A431 cells downregulates miR-320a levels and leads to a corresponding elevation in PKC. transcript and protein levels. Rac1 phosphorylation at Ser71 was increased in the absence of Delta Np63 alpha, whereas overexpression of Delta Np63 alpha reversed S71 phosphorylation of Rac1. Moreover, increased PKC. levels, Rac1 phosphorylation and cell invasion observed upon knockdown of Delta Np63 alpha was reversed by either overexpressing miR-320a mimic or Rac1 silencing. Finally, silencing PKC. or treatment with the PKC inhibitor Go6976 reversed increased Rac1 phosphorylation and cell invasion observed upon silencing Delta Np63 alpha. Taken together, our data suggest that Delta Np63 alpha positively regulates miR-320a, thereby inhibiting PKC. expression, Rac1 phosphorylation, and cancer invasion.