DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma

Qingqing Wu, Xiaoyang Luo, Mikkel G. Terp, Qingrun Li, Yuan Li, Lei Shen, Ying Chen, Kirstine Jacobsen, Trever G. Bivona, Haiquan Chen, Rong Zeng*, Henrik J. Ditzel

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Abstrakt

Background: Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. Methods: We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC. Results: We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B. Conclusion: We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.

OriginalsprogEngelsk
Artikelnummer108
TidsskriftMolecular Cancer
Vol/bind20
Antal sider17
ISSN1476-4598
DOI
StatusUdgivet - 26. aug. 2021

Bibliografisk note

Funding Information:
R. Zeng was supported by grants from the National Key Research and Development Program of China (2017YFA0505500), the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDA12010000). H.J. Ditzel was supported by the Danish Cancer Society and Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital.

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