Circ_ZNF124 promotes non-small cell lung cancer progression by abolishing miR-337-3p mediated downregulation of JAK2/STAT3 signaling pathway

Abstract

Background: Previous genome-wide transcriptome profiling found circ_ZNF124 was highly expressed in lung adenocarcinoma, however, the role of circ_ZNF124 in non-small cell lung cancer (NSCLC) is still unknown. The purpose of this study was to investigate the role and molecular mechanism of circ_ZNF124 in NSCLC development. Methods: The expression of circ_ZNF124, miR-337-3p and JAK2 (Janus Kinase 2) in lung cancer cell lines and normal epithelial cells were detected by qRT-PCR (quantitative real-time PCR). siRNA was used to knockdown circ_ZNF124 expression in cells. The effects of circ_ZNF124 in NSCLC cells were determined by cell growth, cell migration, cell cycle analysis and colony formation. Bioinformatics analysis, RNA immunoprecipitation, luciferase assay and western blots were used to study the molecular mechanism of circ_ZNF124 in NSCLC. Results: The results showed that circ_ZNF124 expression was highly upregulated in NSCLC cells than in normal epithelial cells. Knockdown of circ_ZNF124 by using siRNA significantly decreased cell growth, promoted cell cycle arrested in sub-G1 phase, impaired cell migration and colony formation. Bioinformatic analysis discovered that miR-337-3p was a direct target of circ_ZNF124. In contrast to circ_ZNF124, miR-337-3p expression was significantly downregulated in NSCLC cells. Biotin labeled circ_ZNF124 immunoprecipitation and luciferase assay showed that miR-337-3p could directly bind to and affect circ_ZNF124 activity. The regulation of circ_ZNF124 on miR-337-3p was also investigated. Further analysis showed that despite STAT3 (signal transducer and activator of transcription 3), JAK2 was also a target of miR-337-3p, overexpression of miR-337-3p greatly downregulated JAK2, STAT3 and JAK2/STAT3 downstream regulated oncogenes HIF1a (Hypoxia-inducible factor 1-alpha), BCL2 (B cell lymphoma 2) and c-FOS expression, however, the roles of miR-337-3p in JAK2/STAT3 signaling pathway were greatly inhibited in the presence of circ_ZNF124. Conclusion: In NSCLC, highly expressed circ_ZNF124 promoted the activation of JAK2/STAT3 signaling pathway by acting as a sponge of miR-337-3p, thus promoting the occurrence and development of NSCLC. Circ_ZNF124 could be a potential biomarker or target for the treatment of NSCLC patients in the future.

<p>Circ_SATB2 Attenuates the Anti-Tumor Role of Celastrol in Non-Small-Cell Lung Carcinoma Through Targeting miR-33a-5p/E2F7 Axis</p>

“…24 Circ_ZNF124 contributed to NSCLC progression by targeting miR-337-3p/JAK2/ STAT3 signaling. 25 Zhang et al found that circ_SATB2 accelerated NSCLC progression through acting as miR-326 sponge to up-regulate FSCN1 expression. 15 Here, we found that circ_SATB2 was highly expressed in NSCLC tissues and cell lines.…”

Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer

“…Moreover, correlation heat map indicated that the nine genes were highly relevant to miR-337-3p ( Fig. 4c) and STAT3 was selected for further study as previous evidence proved that it was targeted by miR-337-3p 29,30 , and played a crucial role in EMT 31 .…”

Value of circular RNA 0007385 in disease monitoring and prognosis estimation in non–small‐cell lung cancer patients

“…Another study reports that circ‐FGFR1 overexpression enhances migration, invasion, proliferation and immune evasion in vitro as well as promotes resistance to anti‐PD‐1 treatment in vivo in NSCLC 21 . In addition, circ‐ZNF124 provokes growth, the arrest in sub‐G1 phase of cell cycle, migration, and colony formation of NSCLC cells through abrogating the decrease of Janus tyrosine kinase‐2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway regulated by miR‐337‐3p 22 . And circ‐PIP5K1A enhances proliferation and metastasis in mice model of NSCLC by mediating miR‐600/HIF‐1α signaling 13 .…”