RUNDC3A-AS1 is an adverse prognostic factor for triple-negative breast cancer which mediates the Warburg effect and Adriamycin resistance by targeting miR-224-3p/COL5A2.

Breast cancer has become the most common malignant tumor among women worldwide, among which triple-negative breast cancer (TNBC) is a subtype with the worst prognosis. Although the function of long non-coding RNA (lncRNA) RUNDC3A-AS1 in other cancers has been revealed, it has not been reported in TNBC. To explore the functional mechanism of RUNDC3A-AS1 in TNBC by regulating miR-224-3p/COL5A2, the predictive value of RUNDC3A-AS1 for disease prognosis was evaluated by using its serum level in TNBC patients. miR-224-3p/COL5A2, as a potential downstream of RUNDC3A-AS1, was predicted by the lncRNASNP-human and miRDB databases. Their binding relationships were verified through RNA pull-down experiment. The function of this signaling axis in aerobic glycolysis of TNBC cells was evaluated by detecting glucose uptake, ATP production, and extracellular acidification rate (ECAR). The Adriamycin (ADR)-resistant TNBC cell lines were introduced to explore the function of RUNDC3A-AS1/miR-224-3p/COL5A2 axis in chemotherapy resistance. TNBC patients with high RUNDC3A-AS1 expression showed lower survival rates and shorter overall survival time. RUNDC3A-AS1 competed with COL5A2 mRNA in binding to miR-224-3p, and it increased COL5A2 expression by negatively regulating miR-224-3p. The overexpression of RUNDC3A-AS1 promoted aerobic glycolysis in TNBC cells, which was reversed by the miR-224-3p agonist. Meanwhile, COL5A2 overexpression reversed the inhibitory function of miR-224-3p agonist on aerobic glycolysis. Silencing RUNDC3A-AS1/COL5A2 or upregulating miR-224-3p reduced lactic acid production in ADR-resistant cells and increased their sensitivity to ADR. In conclusion, as a sponge of miR-224-3p, RUNDC3A-AS1 mediated the Warburg effect and chemotherapy resistance in TNBC by up-regulating COL5A2.