Abstract
The Fra-1 transcription factor is frequently upregulated in multiple types of tumors. Here we found that Fra-1 promotes miR-134 expression. miR-134 activates JNK and ERK by targeting SDS22, which in turn induces Fra-1 expression and leads to miR-134 upregulation. In addition, miR-134 augmented H2AX S139 phosphorylation by activating JNK and promoted non-homologous end joining (NHEJ)-mediated DNA repair. Therefore, ectopic miR-134 expression reduced chemosensitivity in ovarian cancer cells. Furthermore, miR-134 promotes cell proliferation, migration and invasion of ovarian cancer cells, and enhances tumor growth in vivo. Of particular significance, both Fra-1 and miR-134 are upregulated in ovarian cancer tissues, and Fra-1 and miR-134 expression is positively correlated. High levels of miR-134 expression were associated with a reduced median survival of ovarian cancer patients. Our study revealed that a Fra-1-miR-134 axis drives a positive feedback loop that amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells.
Highlights
Ras activation leads to the membrane recruitment and activation of RAF proteins, which subsequently leads to the activation of mitogen-activated protein kinase kinase (MEK)
We found that the levels of phosphorylated extracellular signalregulated kinase (p-ERK) and phosphorylated c-Jun NH2 kinase (p-JNK) were increased in T29H cells compared with T29 cells (Figure 1c)
Chromatin immunoprecipitation (ChIP) experiments revealed that Fra-1 binding was enriched in a region ~ 3 kb upstream of miR-134, and that this enrichment was increased in T29H cells compared with T29 cells (Figures 1f and g; Supplementary Figure S2)
Summary
RNAs (mRNAs) and participate in multiple steps during cellular transformation and tumorigenesis.[1,2] miR-134 was initially characterized as a brain-specific miRNA that regulates synaptic development, synaptic plasticity and memory formation.[3,4] Silencing miR-134 in experimental models of status epilepticus suppresses prolonged seizures and exerts neuroprotective effects.[5] miR-134 regulates the proliferation and differentiation of embryonic stem cells and cancer stem cells. miR-134 enhances the differentiation of mouse embryonic stem cells by inhibiting Nanog and LRH1 expression[6] and suppresses proliferation and migration in cancer stem cells.[7,8] Recent evidence has revealed that miR-134 has pivotal roles in tumor transformation and progression. MiR-134 enhances the differentiation of mouse embryonic stem cells by inhibiting Nanog and LRH1 expression[6] and suppresses proliferation and migration in cancer stem cells.[7,8] Recent evidence has revealed that miR-134 has pivotal roles in tumor transformation and progression. It exhibits oncogenic activity in head and neck carcinoma and lung adenocarcinoma[9,10,11] as well as tumor suppressive activity in breast cancer, glioma, hepatocellular carcinoma, osteosarcoma and renal cell carcinoma.[8,12,13,14,15].
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