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circ_PPAPDC1A is Associated with Brain Metastasis of Non-Small-Cell Lung Cancer via the miR-30a-3p/SPOCK1 Pathway
Fang-Wen Zou1, Sheng-Hao Shi1, Chenhao Wu2
1Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
Background:
Brain metastasis (BM) is a leading cause of mortality in non-small-cell lung cancer (NSCLC). The abnormal expression and regulation of circular RNA (circRNA) is involved in the pathogenesis of various tumors. However, the involvement of circRNAs in BM of NSCLC remains to be elucidated.
Methods:
In this study, we established an in vitro blood-brain barrier (BBB) model using BM NSCLC cell lines H2030-BrM3 and PC9-BrM3. We investigated the impact of circ_phosphatidic acid phosphatase type 2 domain containing 1A (PPAPDC1A) on BM of NSCLC in vitro. The interaction between circ_PPAPDC1A and sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) axes was validated through RNA pull-down and dual-luciferase reporter assays.
Results:
Our findings revealed that circ_PPAPDC1A was significantly upregulated in NSCLC with BM (P=0.018). Moreover, exosomes of circ_PPAPDC1A exhibited high diagnostic accuracy for BM, with an area under the curve of 0.83 (P = 0.003), and were closely associated with shorter progression-free survival (6.15 vs. 9.25 months; P = 0.019) and BM-free survival (5.41 vs. 7.75 months; P = 0.18). Functionally, circ_PPAPDC1A overexpression was associated with enhanced in vitro features related to BM, whereas silencing circ_PPAPDC1A showed opposite trends (P < 0.05). Mechanistically, circ_PPAPDC1A functions as efficient microRNA (miR-30a-3p) sponges, thereby activating its downstream functional target, SPOCK1 (P < 0.05).
Conclusions:
For the first time, we identified that circ_PPAPDC1A is significantly upregulated and associated with oncogenic effects in NSCLC with BM, potentially via sponging the miR-30a-3p-SPOCK1 pathway. circ_PPAPDC1A shows potential as a diagnostic biomarker and therapeutic target candidate for patients with NSCLC with BM, pending further validation.
Insights
Circular RNA PPAPDC1A (circ_PPAPDC1A) is upregulated in non-small-cell lung cancer with brain metastasis (NSCLC with BM). Circ_PPAPDC1A may serve as a diagnostic biomarker and therapeutic target for NSCLC with BM.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Brain metastasis (BM) is a primary cause of death in non-small-cell lung cancer (NSCLC).
- Circular RNAs (circRNAs) are implicated in tumor pathogenesis, but their role in NSCLC BM is unclear.
Purpose of the Study:
- To investigate the role of circ_phosphatidic acid phosphatase type 2 domain containing 1A (circ_PPAPDC1A) in non-small-cell lung cancer brain metastasis (NSCLC BM).
- To explore the diagnostic and prognostic potential of circ_PPAPDC1A in NSCLC BM.
Main Methods:
- Established an in vitro blood-brain barrier (BBB) model using NSCLC BM cell lines.
- Assessed the impact of circ_PPAPDC1A on NSCLC BM features in vitro.
- Validated the interaction between circ_PPAPDC1A, miR-30a-3p, and SPOCK1 using RNA pull-down and dual-luciferase reporter assays.
Main Results:
- Circ_PPAPDC1A was significantly upregulated in NSCLC with BM.
- Exosomes containing circ_PPAPDC1A showed high diagnostic accuracy (AUC=0.83) for BM and correlated with shorter survival.
- Overexpression of circ_PPAPDC1A enhanced BM-related features in vitro, while silencing had opposite effects.
- Circ_PPAPDC1A acts as a miR-30a-3p sponge, activating its target SPOCK1.
Conclusions:
- Circ_PPAPDC1A is upregulated in NSCLC with BM and promotes oncogenic effects via the miR-30a-3p-SPOCK1 pathway.
- Circ_PPAPDC1A is a potential diagnostic biomarker and therapeutic target for NSCLC BM.
