QKI, a miR‐200 target gene, suppresses epithelial‐to‐mesenchymal transition and tumor growth

• Published in: International journal of cancer Vol. 145; no. 6; pp. 1585 - 1595
• Main Authors: Kim, Eun Ju, Kim, Jeong Seon, Lee, Sieun, Lee, Heejin, Yoon, Jung‐Sook, Hong, Ji Hyung, Chun, Sang Hoon, Sun, Der Sheng, Won, Hye Sung, Hong, Soon Auck, Kang, Keunsoo, Jo, Jeong Yeon, Choi, Minyoung, Shin, Dong Hoon, Ahn, Young‐Ho, Ko, Yoon Ho
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15-09-2019; Wiley Subscription Services, Inc
• Subjects: 3' Untranslated Regions; Adenocarcinoma; Animals; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell adhesion & migration; Cell Line, Tumor; Cell lines; Cell migration; Cell Proliferation - genetics; Epithelial-Mesenchymal Transition - genetics; epithelial‐to‐mesenchymal transition; Feedback loops; Female; Gene Expression; Gene Knockdown Techniques; Genomes; Head & neck cancer; Heterografts; Humans; Inflammation Mediators - metabolism; Lung cancer; Lungs; Medical research; Mesenchyme; Mice; Mice, Inbred BALB C; MicroRNAs - genetics; miRNA; miRNA‐200; Mouth Neoplasms - genetics; Mouth Neoplasms - pathology; Negative feedback; Oral cancer; Oral squamous cell carcinoma; Phenotypes; Prognosis; QKI; Regulators; Repressors; RNA-binding protein; RNA-Binding Proteins - genetics; Squamous cell carcinoma; Transcription factors; Tumor suppressor genes; Tumorigenesis; Tumors; lung cancer; QKI; miRNA-200; oral cancer; epithelial-to-mesenchymal transition
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32372

The microRNA‐200 (miR‐200) family plays a major role in specifying epithelial phenotype by preventing expression of the transcription repressors ZEB1 and ZEB2, which are well‐known regulators of the epithelial‐to‐mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether miR‐200 family members control RNA‐binding protein quaking (QKI), a newly identified tumor suppressor that is regulated during EMT. We predicted that miR‐200a and miR‐200b could recognize QKI 3′‐UTR by analyzing TargetScan and The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) dataset. Forced expression of miR‐200b/a/429 inhibited expression of ZEB1/2 and decreased cell migration in OSCC cell lines CAL27 and HSC3. QKI expression was also suppressed by miR‐200 overexpression, and the 3′‐UTR of QKI mRNA was directly targeted by miR‐200 in luciferase reporter assays. Interestingly, shRNA‐mediated knockdown of QKI led to pronounced EMT and protumor effects in both in vitro and in vivo studies of OSCC. Furthermore, high expression of QKI protein is associated with favorable prognosis in surgically resected HNSCC and lung adenocarcinoma. In conclusion, QKI increases during EMT and is targeted by miR‐200; while, it suppresses EMT and tumorigenesis. We suggest that QKI and miR‐200 form a negative feedback loop to maintain homeostatic responses to EMT‐inducing signals.
What's new?
The epithelial‐mesenchymal transition is controlled by various transcription factors and non‐coding RNAs. The miR‐200 family of microRNAs inhibit the EMT by targeting certain transcription factors. In this study, the authors identified the gene QKI as a novel target of miR‐200 in oral and lung cancer cells. These microRNAs suppressed QKI expression, and QKI knockdown reduced miR‐200 expression, suggesting the two interact in a negative feedback loop. QKI knockdown also promoted cell growth, EMT, and invasion. On the other hand, microarray data from surgical samples showed that high QKI expression correlated with good outcomes for patients with HSNCC and lung cancer.