| Expression pattern: |
DN |
| Associated gene: |
BiP / GRP78 |
| Associated microRNA: |
- |
| Biological function: |
circATF6 synergizes with EGFR-TKIs/osimertinib, selectively promotes apoptosis in DTP cells, suppresses DTP tumor regeneration and tumor growth, disrupts proteostasis and ER homeostasis, and triggers cytoplasmic calcium overload. |
| Molecular mechanism: |
circATF6 binds the ATPase domain of BiP/GRP78, stabilizes BiP association with UPR sensors, prevents UPR activation, causes misfolded protein accumulation and proteostasis disruption, induces ER fragmentation and calcium release into the cytoplasm, leading to calcium overload-mediated apoptosis; ADAR1 suppresses circATF6 biogenesis in DTP cells. |
| Biological pathway or process: |
apoptosis (promotes); proliferation (inhibits); drug resistance (inhibits); chemoresistance (inhibits); other pathway/process (inhibits); mitochondrial function (other); cell cycle (inhibits) |
| Detected method: |
Q
S
|
| Validation methods: |
Back-Splice Junction PCR / divergent primers PCR; RNase R Treatment; Sanger Sequencing; Actinomycin D / DRB Stability Assay; RT-qPCR; RNA-seq; FISH / smFISH; Nuclear-Cytoplasmic Fractionation; Clinical Sample Validation; RIP (RNA Immunoprecipitation); CLIP; RNA Pull-Down; Co-IP; Luciferase Reporter Assay; Transfection; CCK8; EdU Staining; Colony Formation Assay; Annexin V/PI Flow Cytometry; Cell Cycle Assay; Flow Cytometry（Non-apoptosis/cycle）; TUNEL; In Vivo Animal Model; H&E Staining; IHC (Immunohistochemistry); IF (Immunofluorescence); Western Blot; Bioinformatics Analysis |
| Clinical significance: |
circATF6-LNP combined with EGFR-TKIs is proposed as a promising RNA-based therapeutic strategy for eradicating DTP cells and overcoming EGFR-TKI resistance in NSCLC. |
| Description: |
circATF6 is a human ATF6-derived circRNA that is selectively downregulated in EGFR-TKI-induced NSCLC DTP cells through ADAR1-mediated splicing regulation. Restoring or delivering circATF6 sensitizes DTP cells and tumors to osimertinib by binding BiP/GRP78, blocking adaptive UPR signaling, disrupting proteostasis and ER calcium homeostasis, and inducing calcium overload-mediated apoptosis. |
| Confidence score: |
0.8878 |