Circ_PIP5K1A regulates cisplatin resistance and malignant progression in non-small cell lung cancer cells and xenograft murine model via depending on miR-493-5p/ROCK1 axis.

Chemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) function as important regulators in chemoresistance. This study aimed to explore the regulation of circRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A) in DDP resistance. The expression analysis of circ_PIP5K1A, micoRNA-493-5p (miR-493-5p) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) was conducted through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell sensitivity was determined using 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell proliferation and cell viability were evaluated by colony formation assay and MTT assay, respectively. Cell cycle and apoptosis detection was performed via flow cytometry. Cell motility was examined by transwell migration or invasion assay. Dual-luciferase reporter assay was applied to confirm the target binding. ROCK1 protein level was assayed via Western blot. In vivo assay was carried out using xenograft model in mice. Circ_PIP5K1A level was abnormally increased in DDP-resistant NSCLC tissues and cells. Silencing circ_PIP5K1A reduced DDP resistance, proliferation, cell cycle progression and cell motility in DDP-resistant NSCLC cells. Circ_PIP5K1A directly interacted with miR-493-5p in NSCLC cells. The function of circ_PIP5K1A was dependent on the negative regulation of miR-493-5p. MiR-493-5p directly targeted ROCK1 and circ_PIP5K1A regulated the ROCK1 level via acting as a sponge of miR-493-5p. Overexpression of miR-493-5p inhibited chemoresistance and cancer progression by downregulating ROCK1 expression in DDP-resistant NSCLC cells. Circ_PIP5K1A regulated DDP sensitivity in vivo via the miR-493-5p/ROCK1 axis. These findings suggested that circ_PIP5K1A upregulated the ROCK1 expression to promote DDP resistance and cancer progression in NSCLC by sponging miR-493-5p.

Feng N ，Guo Z ，Wu X ，Tian Y ，Li Y ，Geng Y ，Yu Y ... -  《RESPIRATORY RESEARCH》

Exosomal circ_PIP5K1A regulates the progression of non-small cell lung cancer and cisplatin sensitivity by miR-101/ABCC1 axis.

Shao N ，Song L ，Sun X 《-》

Hsa_circ_0017639 regulates cisplatin resistance and tumor growth via acting as a miR-1296-5p molecular sponge and modulating sine oculis homeobox 1 expression in non-small cell lung cancer.

Chang F ，Li J ，Sun Q ，Wei S ，Song Y ... -  《-》

Circular RNA circ-RNF121 contributes to cisplatin (DDP) resistance of non-small-cell lung cancer cells by regulating the miR-646/SOX4 axis.

Chemo-resistance is considered a major obstacle in the clinical treatment of non-small-cell lung cancer (NSCLC). Circular RNA (circRNA) circ-RNF121 (hsa_circ_0023404) has been identified to be related to the cisplatin (DDP) resistance. However, the role and mechanism of circ-RNF121 in the DDP resistance in NSCLC are still unknown. Real-time quantitative PCR (RT-qPCR) was applied to detect the levels of circ-RNF121, microRNA-646 (miR-646) and SRY-related HMG box transcription factor 4 (SOX4). Cell viability, proliferation, apoptosis, migration, invasion and cell cycle progression were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, wound-healing, transwell and flow cytometry assays, severally. The binding relationship between miR-646 and circ-RNF121 or SOX4 was predicted by the circular RNA interactome or Target Scan Human7.2 and then verified by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. SOX4 protein level was measured by western blot assay. The biological role of circ-RNF121 on NSCLC tumor growth and drug resistance was examined by the xenograft tumor model in vivo. Circ-RNF121 and SOX4 were increased, and miR-646 was declined in DDP-resistant NSCLC tissues and cells. Furthermore, the circ-RNF121 deficiency could enhance DDP sensitivity by inhibiting cell proliferation, migration, invasion, cell cycle progression and promoting apoptosis in DDP-resistant NSCLC cells in vitro. Mechanically, circ-RNF121 served as a sponge of miR-646 to increase SOX4 expression. Circ-RNF121 knockdown improved the drug sensitivity of NSCLC in vivo. Circ-RNF121 silencing could reduce the DDP resistance of NSCLC cells by regulating SOX4 expression via miR-646. These findings hinted at a promising therapeutic target for NSCLC treatment.

Liu Y ，Zhai R ，Hu S ，Liu J ... -  《-》

circ_0007385 served as competing endogenous RNA for miR-519d-3p to suppress malignant behaviors and cisplatin resistance of non-small cell lung cancer cells.

Circular RNAs (circRNAs) have been closely implicated in competing endogenous RNA (ceRNA) network among human cancers including non-small cell lung cancer (NSCLC). However, the role of most circRNAs in NSCLC remains to be determined. Here, we aimed to investigate the role of hsa_circ_0007385 (circ_0007385) in NSCLC cells. Expression of hsa_circ_0007385 (circ_0007385), miRNA (miR)-519d-5p and high-mobility group box 1 (HMGB1) was measured by real-time quantitative PCR and western blotting. Functional experiments were evaluated by cell counting kit (CCK)-8, flow cytometry, fluorescein active caspase-3 staining kit, transwell assays, western blotting, and xenograft experiment. The relationship among circ_0007385,miR-519d-5p and HMGB1 was testified by dual-luciferase reporter assay. Kaplan-Meiersurvival curve identified overall survival in NSCLC patients. circ_0007385 expression was higher in NSCLC tissues and cell lines, and was associated with poor overall survival. Silencing circ_0007385 could suppress cell proliferation, migration and invasion in A549 and H1975 cells, as well as cisplatin (DDP) resistance. Moreover, circ_0007385 silence retarded tumor growth of A549 cells in vivo. Molecularly, there was a direct interaction between miR-519d-3p and either circ_0007385 or HMGB1; expression of miR-519d-3p was downregulated in NSCLC tumors in a circ_0007385-correlated manner, and circ_0007385 could indirectly regulate HMGB1 via miR-519d-3p. Functionally, both inhibiting miR-519d-3p and restoring HMGB1 could overturn the suppressive effect of circ_0007385 knockdown on cell proliferation, migration, invasion, and DDP resistance. Collectively, circ_0007385 deletion could function anti-tumor role in NSCLC by suppressing malignant behaviors and DDP resistance in vitro and in vivo via circ_0007385/miR-519d-3p/HMGB1 axis. These outcomes might enhance our understanding of the molecular mechanisms underlying the malignant progression of NSCLC. SIGNIFICANT FINDINGS OF THE STUDY: circ_0007385 was upregulated in NSCLC tissues and cells, and was associated with poor overall survival. Silenced circ_0007385 suppressed NSCLC cell proliferation, migration, invasion, and DDP resistance in vitro, and tumor growth in vivo. circ_0007385 was upregulated in NSCLC tissues and cells, and was associated with poor overall survival. miR-519d-3p could directly interact with circ_0007385 and HMGB1 in NSCLC cells. A promising circ_0007385/miR-519d-3p/HMGB1 regulatory pathway was determined in NSCLC cells.

Ye Y ，Zhao L ，Li Q ，Xi C ，Li Y ，Li Z ... -  《-》