Circular RNA circDNM3OS Functions as a miR-145-5p Sponge to Accelerate Cholangiocarcinoma Growth and Glutamine Metabolism by Upregulating MORC2

Abstract

Background Cholangiocarcinoma (CCA) is the second most common liver malignant tumor. CircRNA hsa_circ_0005230 (circDNM3OS) has been reported to exert an oncogenic role in CCA. However, the mechanisms related to circDNM3OS in CAA progression have not been fully elucidated. Methods The expression of circDNM3OS, microRNA (miR)-145-5p, and MORC2 (MORC Family CW-Type Zinc Finger 2) mRNA were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, colony formation, migration, invasion, and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8), colony formation, transwell, wound-healing, and flow cytometry assays. The levels of glutamine, α-KG (α-ketoglutarate), and ATP (adenosine triphosphate) were detected using commercial kits. The relationship between circDNM3OS or MORC2 and miR-145-5p was verified by dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Protein level of MORC2 was measured by Western blotting. The role of circDNM3OS in CCA growth was verified by xenograft experiment. Results CircDNM3OS and MORC2 were upregulated while miR-145-5p was downregulated in CCA tissues and cells. Inhibition of circDNM3OS reduced xenograft tumor growth in vivo and constrained proliferation, colony formation, migration, invasion, induced apoptosis, and reduced glutamine metabolism of CCA cells in vitro. CircDNM3OS sponged miR-145-5p to elevate MORC2 expression. MiR-145-5p silencing overturned circDNM3OS knockdown-mediated influence on malignancy and glutamine metabolism of CCA cells. Also, MORC2 overexpression reversed the repressive impact of miR-145-5p mimic on malignancy and glutamine metabolism of CCA cells. Conclusion CircDNM3OS facilitates CCA growth and glutamine metabolism by regulating the miR-145-5p/MORC2 pathway, offering a novel mechanism to understand the progression of CCA.

Microrchidia CW-Type Zinc Finger 2, a Chromatin Modifier in a Spectrum of Peripheral Neuropathies

“…For example, a perturbation of MORC2 localization disrupts adipocyte homeostasis in mice (Hallenborg et al, 2021), leading to an increase in adipose tissue mass, glucose intolerance and hepatic steatosis in young mice. On the other hand, an increase in MORC2 expression promotes the growth of cholangiocarcinoma associated with increased glutamine metabolism (Su et al, 2021).…”

Precision Oncology Targets in Biliary Tract Cancer

“… Prevalence of genomic aberrations by anatomic classification in cholangiocarcinoma [ 91 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. …”

Current Advances in Basic and Translational Research of Cholangiocarcinoma

“…circ-CCAC1 sponges miR-514a, which regulates YY1 expression, and high levels of circ-CCAC1 in circulating EVs promoted CCA growth and metastases in xenograft mouse models [99]. A study using 35 paired CCA tissues and adjacent normal tissues identified elevated expression of circ-DNM3OS associated with TNM stage and lymph node invasion in CCA patients [100]. circ-DNM3OS induces MORC family CW-type zinc finger 2 (MORC2) expression via sponging miR-145, and inhibition of circ-DNM3OS decreased tumor growth by upregulation of miR-145 and downregulation of MORC2 in xenograft mice [100].…”