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http://purl.uniprot.org/citations/37986103http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/37986103http://www.w3.org/2000/01/rdf-schema#comment"

Background

Liver metastasis is one of the most important reasons for high mortality of colorectal cancer (CRC). Growing evidence illustrates that lncRNAs play a critical role in CRC liver metastasis. Here we described a novel function and mechanisms of BACE1-AS promoting CRC liver metastasis.

Methods

qRT-PCR and in situ hybridization were performed to examine the BACE1-AS level in CRC. IGF2BP2 binding to m6A motifs in BACE1-AS was determined by RIP assay and S1m-tagged immunoprecipitation. Transwell assay and liver metastasis mice model experiments were performed to examine the metastasis capabilities of BACE1-AS knockout cells. Stemness-like properties was examined by tumor sphere assay and the expression of stemness biomarkers. Microarray data were acquired to analyze the signaling pathways involved in BACE1-AS promoting CRC metastasis.

Results

BACE1-AS is the most up-regulated in metastatic CRC associated with unfavorable prognosis. Sequence blast revealed two m6A motifs in BACE1-AS. IGF2BP2 binding to these two m6A motifs is required for BACE1-AS boost in metastatic CRC. m6A modified BACE1-AS drives CRC cells migration and invasion and liver metastasis both in vitro and in vivo. Moreover, BACE1-AS maintains the stemness-like properties of CRC cells. Mechanically, BACE1-AS promoted TUFT1 expression by ceRNA network through miR-214-3p. CRC patients with such ceRNA network suffer poorer prognosis than ceRNA-negative patients. Depletion of TUFT1 mimics BACE1-AS loss. BACE1-AS activated Wnt signaling pathway in a TUFT1 dependent manner. BACE1-AS/miR-214-3p/TUFT1/Wnt signaling regulatory axis is essential for CRC liver metastasis. Pharmacologic inhibition of Wnt signaling pathway repressed liver metastasis and stemness-like features in BACE1-AS over-expressed CRC cells.

Conclusion

Our study demonstrated BACE1-AS as a novel target of IGF2BP2 through m6A modification. m6A modified BACE1-AS promotes CRC liver metastasis through TUFT1 dependent activation of Wnt signaling pathway. Thus, targeting BACE1-AS and its downstream Wnt signaling pathways may provide a new opportunity for metastatic CRC intervention and treatment."xsd:string
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http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/author"Liu Y."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/author"Wang X."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/author"Yu L."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/author"Zhou M."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/author"Si Z."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/date"2023"xsd:gYear
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/name"J Exp Clin Cancer Res"xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/pages"306"xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/title"m6A modified BACE1-AS contributes to liver metastasis and stemness-like properties in colorectal cancer through TUFT1 dependent activation of Wnt signaling."xsd:string
http://purl.uniprot.org/citations/37986103http://purl.uniprot.org/core/volume"42"xsd:string
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