Circ-FOXM1 contributes to cell proliferation, invasion, and glycolysis and represses apoptosis in melanoma by regulating miR-143-3p/FLOT2 axis

Abstract

Background: Numerous literatures have demonstrated that circular RNAs (circRNAs) are involved in multiple types of tumors. However, the effects of circRNAs in melanoma are not very clear. In this study, we aimed to investigate the roles and mechanisms of circ-FOXM1 in melanoma. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circ-FOXM1, microRNA-143-3p (miR-143-3p), and Flotillin 2 (FLOT2) mRNA. 3-(4,5-Dimethyl-2-thiazolyl)-2,5diphenyl-2-H-tetrazolium bromide (MTT) assay, flow cytometry analysis, and transwell assay were employed to test cell proliferation, apoptosis, and invasion, respectively. The glucose consumption and lactate production were examined by specific kits. Western blot assay was utilized for the detection of hexokinase2 (HK2), pyruvate kinase isozyme type M2 (PKM2), and FLOT2. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the targeting association between miR-143-3p and circ-FOXM1 or FLOT2. A murine xenograft model was established to explore the effect of circ-FOXM1 in vivo. Results: Circ-FOXM1 was elevated and miR-143-3p was reduced in melanoma tissues and cells. Circ-FOXM1 deficiency impeded cell proliferation, invasion, and glycolysis and facilitated cell apoptosis in melanoma in vitro and tumorigenesis in vivo. Circ-FOXM1 acted as a sponge of miR-143-3p and the impacts of circ-FOXM1 silencing on cell proliferation, apoptosis, invasion, and glycolysis were overturned by miR-143-3p deletion. Moreover, FLOT2 was a target gene of miR-143-3p and FLOT2 overexpression rescued the inhibitory effect of miR-143-3p on melanoma progression. Conclusion: Circ-FOXM1 facilitated the development of melanoma by upregulating FLOT2 through miR-143-3p.

Circular RNA as a Potential Biomarker for Melanoma: A Systematic Review

“…Tian et al ( 2020 ) found that circ-FOXM1 promoted cancer progression in melanoma cells, which is consistent with findings in non-small-cell lung cancer (Liu G. et al, 2019 ). circ-FOXM1 manifests a sponging effect for miR-143-3p, a regulatory element of Flotillin 2 (FLOT2).…”

“…Red and blue color indicated the oncogenic and suppressive functions of circRNAs in different biological processes involved in melanoma progression, respectively. Up and down arrows indicated the activation and inhibition of physiological processes in melanoma pathogenesis, respectively (Bian et al, 2018 ; Ju et al, 2018 ; Luan et al, 2018 ; Wang Q. et al, 2018 ; Lin et al, 2019 ; Shang et al, 2019 ; Zou et al, 2019 ; Chen J. et al, 2020 ; Chen Z. et al, 2020 ; Hanniford et al, 2020 ; Jin et al, 2020 ; Lu and Li, 2020 ; Lu et al, 2020 ; Qian et al, 2020 ; Tian et al, 2020 ; Wei et al, 2020 ; Liu et al, 2021 ; Yin et al, 2021 ).…”

“…FLOT2 is a cell progression and motility factor associated with lymph node metastasis and Breslow depth in melanoma. FLOT2 elevation abrogates the effects of miR-143-3p on proliferation, apoptosis, invasion, and glycolysis in melanoma cells (Tian et al, 2020 ).…”

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

“…Furthermore, it has been well defined that through their capability to simultaneously bind numerous miRNAs, circRNAs can act to sponge and inhibit the activity of various miRNAs [ 366 , 367 , 368 , 369 , 370 , 371 ], and similar to what is observed with many lncRNAs, this can result in profound alterations to the biological and metabolic processes important to tumorigenesis [ 368 ]. Studies have revealed that various circRNAs may act as oncogenic promoters in breast cancer [ 372 ], NSCLC [ 373 ], melanoma [ 374 ], gastric cancer [ 375 ], gallbladder cancer [ 376 ], and CRC [ 377 ] models. Furthermore, some of these studies have revealed that circRNAs may enhance carcinogenesis through impacting glycolysis and PKM2 expression levels ( Table 5 ).…”

“…These effects were mediated through the regulation of miR-143-3p. Although the link between miR-143-3p and PKM2 is yet to be determined, the overexpression of miR-143-3p abolished lactate production and glycolysis in A2058 and A375 melanoma cells [ 374 ]. Likewise, the expression level of circ-NRIP1 in gastric cancer tissue and cells was shown to be upregulated.…”