Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

• Published in: Oncogene Vol. 35; no. 24; pp. 3151 - 3162
• Main Authors: Zhang, Q, Wei, T, Shim, K, Wright, K, Xu, K, Palka-Hamblin, H L, Jurkevich, A, Khare, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.06.2016; Nature Publishing Group
• Subjects: 631/67; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Biomarkers; Cadherins - biosynthesis; Cadherins - metabolism; Cell Biology; Cellular biology; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Epithelial-Mesenchymal Transition; Female; Genetic aspects; Genetic regulation; Health aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mice; Oncology; Original; original-article; Phosphoproteins - genetics; Phosphoproteins - metabolism; Plasma; Proto-Oncogene Proteins c-akt - blood; Proto-Oncogene Proteins c-akt - metabolism; Transfection; Tumor suppressor genes; Up-Regulation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.365

Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241–5253). We investigated the mechanisms by which SPRY regulates epithelial–mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3′ untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1 −/− and Spry2 −/− double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.