The lncRNA-GAS5/miR-221-3p/DKK2 Axis Modulates ABCB1-Mediated Adriamycin Resistance of Breast Cancer via the Wnt/β-Catenin Signaling Pathway

Abstract

Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially expressed lncRNAs, mRNAs, and mi-croRNAs (miRNAs) in MCF-7 and MCF-7/ADR cell lines through RNA sequencing (RNA-seq) technologies. GAS5 level was downregulated whereas ABCB1 level was upregulated in the resistant breast cancer tissues and cells. Overexpression of GAS5 significantly enhanced the ADR sensitivity and apoptosis, and it inhibited the efflux function and expression of ABCB1 in vitro, while knockdown of GAS5 had the opposite effects. Further mechanism-related investigations indicated that GAS5 acted as an endogenous "sponge" by competing for miR-221-3p binding to regulate its target dickkopf 2 (DKK2), and then it inhibited the activation of the Wnt/b-catenin pathway. Functionally, GAS5 enhanced the anti-tumor effect of ADR in vivo. Collectively, our findings reveal that GAS5 exerted regulatory function in ADR resistance possibly through the miR-221-3p/DKK2 axis, providing a novel approach to develop promising therapeutic strategy for overcoming chemoresistance in breast cancer patients.

WITHDRAWN: PADI4 regulates osteosarcoma proliferation primarily via Wnt/β-catenin and MEK/ERK signaling pathway

“…Wnt signaling pathway is an evolutionarily conserved signaling pathway that regulates cell growth, differentiation, apoptosis, and self-renewal. In the occurrence and development of many types of human cancers, Wnt signaling pathway is often abnormally activated and can cooperate with or antagonize other signaling pathways to regulate tumor proliferation [16]. The mark of Wnt signaling is accumulation of active β-catenin, which transfers in nucleus and acts as transcription factor to induce transcription of target genes involved in cell division [17].…”

LncRNA BANCR Attenuates the Killing Capacity of Cisplatin on Gastric Cancer Cell through the ERK1/2 Pathway

“…LncRNAs have been reported to play essential roles in drug resistance in multiple cancers, such as breast cancer (16), gastric cancer (17), and lung cancer (18). For example, lnc-ATB/miR-200c promoted resistance to trastuzumab and then induced an invasion-metastasis cascade in breast cancer via upregulating ZEB1 and ZNF-217 (19).…”

Low expression of lncRNA CTB-104H12.5 induces resistance to adriamycin in HER2 negative breast cancer by downregulating GAS7C

“…Among these ncRNAs, lncRNAs, as the promising molecular markers for forecasting drug resistance of breast cancer, are becoming new targets for treating breast cancer in the future. For example, LOC645166, lncRNA GAS5, and lncRNA H19 regulate adriamycin resistance in breast cancer cells [4,19,20], and lncRNA UCA1 and lncRNA NONHSAT141924 modulates paclitaxel resistance [21,22], while lncRNA HOTAIRM1 and BLACAT1 can induce tamoxifen resistance in ER + breast cancer cells [23,24]. However, all these lncRNAs were identi ed from breast cancer tissue or cell lines, which limits their utilities in the clinic as a dynamic monitoring biomarker.…”

“…As one type of ncRNA transcripts, long non-coding RNAs (lncRNA) have been reported to function in a wide variety of cellular processes including drug resistance [4]. For example, NONHSAT101069, which serve as a ceRNA (competing endogenous RNA), promotes the epirubicin resistance of breast cancer cells by sponging miR-129-5p [5].…”