Abstract
Circular RNAs (circRNAs) are emerging regulators in the development of human cancers. However, the role of circRNAs in melanoma is poorly understood. Microarray analysis and qRT-PCR was applied to screen out circRNAs that were differentially expressed in melanoma cells compared to normal cells. Currently, we first proved that inhibition of CYR61, an angiogenesis factor with controversial functions in melanoma, restrained cell migration, invasion and angiogenesis in melanoma. Thereafter, a novel circRNA hsa_circ_0027247 derived from GLI1 (circ-GLI1) was identified to positively modulate CYR61 expression in melanoma cell lines. Besides, silencing circ-GLI1 hindered melanoma cell metastasis as well. Interestingly, we unveiled that circ-GLI1 enhanced CYR61 transcription by an indirect manner. Meanwhile, circ-GLI1 activated Hedgehog/GLI1 and Wnt/β-catenin pathways by affecting the degradation of GLI1 and β-catenin. Moreover, we found that circ-GLI1 interacted with p70S6K2 to induce GSK3β phosphorylation at Ser9, and therefore blocked the binding of GSK3β with GLI1 and β-catenin so as to elevate their protein expression. Of note, CYR61 was transcriptionally activated by MYC, a well-recognized downstream target of both GLI1 and β-catenin. In conclusion, circ-GLI1 exacerbates the metastasis and angiogenesis of melanoma by upregulating Cyr61 via p70S6K2-dependent activation of Hedgehog/GLI1 and Wnt/β-catenin pathways.
Highlights
Melanoma is the most malignant tumor that occurs in skin[1] and has an increasing incidence in recent years[2]
This study focused on the role of circ-GLI1 in melanoma metastasis and its correlation with Cyr[61]
We silenced Cyr[61] expression in A375 and B16 cells which expressed the highest level of Cyr[61]
Summary
Melanoma is the most malignant tumor that occurs in skin[1] and has an increasing incidence in recent years[2]. Discovering novel molecules and developing new effective therapeutic targets are of great significance to improve the prognosis in melanoma patients. Cyr[61] has been considered as an angiogenic factor which functions in different biological behaviors. Cyr[61] has been validated to exert facilitating role in tumorigenesis of many cancer types, such as colorectal cancer[10] and ovarian cancer[11]. Several reports revealed that Cyr[61] can act as a tumor suppressor in lung cancer[12] and hepatocellular carcinoma[13]. The role of Cyr[61] in melanoma is still unclear.
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