CircRNA amyloid precursor protein by competitive adsorption of microRNA-6838-5p mediates CDV3 expression to enhance malignant behavior and Warburg effect in Gastrointestinal Stromal Tumor

TL;DR

This study shows that a circular RNA called circAPP promotes cancer growth and metabolism in gastrointestinal stromal tumors by interacting with a microRNA and a protein called CDV3.

Contribution

The novel finding is that circAPP mediates the miR-6838-5p/CDV3 axis to enhance GIST proliferation and the Warburg effect.

Findings

CircAPP knockdown inhibits GIST cell proliferation and the Warburg effect.

CircAPP promotes CDV3 expression by competitively adsorbing miR-6838-5p.

CircAPP knockdown reduces tumor growth and liver metastasis in animal models.

Abstract

•Knockdown of circAPP inhibits GIST proliferation and the Warburg effect.•miR-6838-5p induces GIST proliferation and the Warburg effect.•CircAPP activates GIST proliferation and the Warburg effect by regulating the miR-6838-5p/CDV3 axis.

Knockdown of circAPP inhibits GIST proliferation and the Warburg effect.

miR-6838-5p induces GIST proliferation and the Warburg effect.

CircAPP activates GIST proliferation and the Warburg effect by regulating the miR-6838-5p/CDV3 axis.

Dysregulated circular RNA (circRNA) expression profiles and their carcinogenic contributions have been noted in nearly all human cancers. This study aimed to unearth the role of circRNA Amyloid Precursor Protein (circAPP), an abnormally highly expressed circRNA in Gastrointestinal Stromal Tumors (GIST). As the results found, circAPP was upregulated in GIST tissues and cells. FISH experiment, dual-luciferase reporter experiment, and RIP experiment confirmed that circAPP promoted CDV3 expression by absorption of miR-6838-5p in GIST. Cell experiments confirmed that silencing circAPP inhibited GIST cell proliferation, migration, invasion, glucose consumption, lactate production, ATP level, expression of HK2 and PKM2, decreased ATP/ADP, and increased NAD+/NADH, but promoted apoptosis, whereas overexpression of circAPP did the exact opposite. Furthermore, miR-6838-5p depletion and CDV3 overexpression abolished the influences of downregulating circAPP and overexpressing circAPP on GIST cells, respectively. Animal experiments displayed that circAPP knockdown inhibited GIST tumor growth and liver metastasis. All in all, circAPP promotes GIST cell proliferation and the Warburg effect by miR-6838-5p/CDV3 axis and circAPP may be a potential future therapeutic target for GIST.

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