Journal
CELL DEATH & DISEASE
Volume 12, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-020-03346-4
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Funding
- Medical Science & Technology Support Project of Henan Province, Provincial & Ministerial Joint Projects [201601024]
- Science & Technology Support Project of Henan Province [132102310187, 122102310137, 172102310517]
- 23456 Talent Support Project of Henan people's hospital
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The study showed that LINC00665 plays a crucial role in gemcitabine resistance of CCA cells by regulating BCL9L expression, leading to modulation of EMT, stemness, and Wnt/β-Catenin activation.
Gemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients. Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells. The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers. In addition, Wnt/beta-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/beta-Catenin activation. B-cell CLL/lymphoma 9-like (BCL9L), the nucleus transcriptional regulators of Wnt/beta-Catenin signaling, plays a key role in the nucleus translocation of beta-Catenin and promotes beta-Catenin-dependent transcription. In our study, we found that LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p. Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/beta-Catenin activation in resistant CCA cells. In conclusion, our results disclosed the important role of LINC00665 in gemcitabine resistance of CCA cells, and provided a new biomarker or therapeutic target for CCA treament.
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