miR-103/107 prolong Wnt/β-catenin signaling and colorectal cancer stemness by targeting Axin2

• Published in: Scientific reports 2019-07, Vol.9 (1), p.9687-13, Article 9687
• Main Authors: Chen, Hsin-Yi, Lang, Yaw-Dong, Lin, Han-Nan, Liu, Yun-Ru, Liao, Chun-Chieh, Nana, André Wendindondé, Yen, Yun, Chen, Ruey-Hwa
• Format: Article
• Language: English
• Subjects: 13/109; 13/31; 13/51; 59; 631/67/1504/1885/1393; 631/67/322; 64/60; Animals; Apoptosis; Axin Protein - genetics; Axin Protein - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Cell Proliferation; Cell self-renewal; Chemoresistance; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Female; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; multidisciplinary; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Science; Science (multidisciplinary); Tumor Cells, Cultured; Wnt protein; Wnt Signaling Pathway; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; Xenograft Model Antitumor Assays; β-Catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41053-z

Cancer stemness drives tumor initiation, progression, metastasis, recurrence, and therapy resistance. However, mechanisms that potentiate the acquisition and maintenance of stemness fate of cancer cells remain incompletely understood. Here, we show that miR-103/107 stimulate multiple stem-like features in colorectal cancer, including expression of stem-like markers, appearance of side-population cells, and capabilities in self-renewal, tumor initiation, recurrence, and chemoresistance. Mechanistically, these stemness-promoting functions are mediated by miR-103/107-dependent repression of Axin2, a negative feedback regulator of Wnt/β-catenin signaling. Through inhibiting Axin2, miR-103/107 trigger a prolonged duration of Wnt/β-catenin signaling and a sustained induction of Wnt responsive genes. In colorectal cancer patients, miR-103/107 expression correlates inversely with Axin2 expression and a signature of miR-103/107 high and Axin2 low expression profile correlates with poor prognosis. Together, our study identifies a novel function of miR-103/107 in promoting colorectal cancer stemness by targeting Axin2 and elucidates the clinical relevance and prognostic value of this axis in colorectal cancer.