Abstract
In this study, we identified a novel circRNA, circ_0002483, and further investigated its functions in the progression and Taxol resistance of NSCLC. We found that circ_0002483 was expressed at low levels in NSCLC tissues and cell lines. Functional assays indicated that circ_0002483 overexpression significantly inhibited NSCLC cell proliferation and invasion in vitro and in vivo and enhanced the sensitivity of NSCLC cells to Taxol. Mechanistically, circ_0002483 was identified to sponge multiple miRNAs including miR-182-5p (also named miR-182), miR-520q-3p, miR-582-3p, miR-587, and miR-655. In addition, circ_0002483 was also demonstrated to regulate the expression of GRB2, FOXO1, and FOXO3, three target genes of miR-182-5p, by sponging miR-182-5p. Circ_0002483 was demonstrated to inhibit NSCLC progression in vitro and in vivo and enhanced the sensitivity of NSCLC cells to Taxol by sponging miR-182-5p to release the inhibition on GRB2, FOXO1, and FOXO3 mRNAs.
Highlights
According to the annual estimate by the AmericanCancer Society for 2019, there will be ~1,762,450 new cancer cases and 606,880 cancer deaths projected to occur in the United States, among which lung cancer remains one of the most common cancers both in terms of incidence and mortality[1]
Due to the lack of effective diagnostic measures and biomarkers, most Non-small cell lung cancer (NSCLC) patients are diagnosed at the advanced stage IIIB or IV, which is characterized by distant metastasis and poor prognosis[4,5]
To further evaluate the biological functions of specific circRNAs in NSCLC, we knocked down the expression of the top 20 downregulated circRNAs individually, followed by treatment with Taxol and RT-qPCR analysis of the transfection effects or a Cell Counting Kit-8 (CCK-8) analysis of cell viability (Fig. 1a, b upper panel)
Summary
According to the annual estimate by the AmericanCancer Society for 2019, there will be ~1,762,450 new cancer cases and 606,880 cancer deaths projected to occur in the United States, among which lung cancer remains one of the most common cancers both in terms of incidence and mortality[1]. Due to the lack of effective diagnostic measures and biomarkers, most NSCLC patients are diagnosed at the advanced stage IIIB or IV, which is characterized by distant metastasis and poor prognosis[4,5]. Tumor cell metastasis is considered to be the leading cause of NSCLC-associated deaths in clinical therapy, and so far, there have been no effective measures to suppress NSCLC cell metastasis[8,9]. Taxol (generic name paclitaxel), belonging to a group of diterpenoid alkaloids with anti-tumor capacity, is an antimicrotubule agent that targets taxane binding sites and subsequently blocks depolymerization, inhibiting cell proliferation[10]. Taxol is widely used as a first-line chemotherapy agent in the treatment of multiple types of tumors, including NSCLC10,11. Taxol-based combination therapy with cisplatin or carboplatin is a preferred choice for advanced NSCLC patients with metastatic activity[12].
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