circ_PPAPDC1A is Associated with Brain Metastasis of Non-Small-Cell Lung Cancer via the miR-30a-3p/SPOCK1 Pathway.

[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.