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

Abstract

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.

Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin

“…Colorectal cancer is one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancements in cancer therapeutics ( 1 ). Over 50% of human CRCs are reported to have defective p53 expression ensued by a mutated TP53 gene and this defect often contributes to drug resistance, challenging the clinicians in devising chemotherapeutic strategies for management of cancer patients with this mutation ( 15 , 37 ). In normal cells, p53 expression is induced in response to stressful conditions and the p53 activation indeed induce cell death via processes such as cell cycle arrest, DNA repair, senescence or apoptosis ( 38 – 40 ).…”

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

“…As a negative feedback regulator of Wnt/β-catenin signaling, Axin2 could control Wnt-induced transcriptional responses. Suppression of Axin2 by miR-103/107 was demonstrated to enhance CRC chemoresistance by promoting cell stemness via Wnt/β-catenin signaling [49]. Moreover, accumulation of nuclear β-catenin enhances both the chemoresistance and radioresistance of locally advanced rectal cancer through regulating EMT/CSC properties, and nuclear β-catenin in pretreatment-biopsied samples is promising in predicting the efficacy of chemoradiotherapy in rectal cancer patients [50].…”

“…As a critical feature in the tumor microenvironment, hypoxia self-perpetuates mainly through the regulation of the vasculature. Under hypoxia, the expression levels of miR-103 and miR-107 are elevated, and miR-103/107-Axin2 axis contributes to chemoresistance to oxaliplatin and cisplatin through prolonging Wnt/β-catenin signaling duration in HCT116 cells [49]. Hypoxia has also been shown to activate GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer.…”

BRD4 promotes glioma cell stemness via enhancing miR‐142‐5p‐mediated activation of Wnt/β‐catenin signaling

“…Although the promoting effects of Wnt/β‐catenin signaling have been firmly confirmed in various CSC progression, its inhibitors are not in clinical trials, this might be due to the unidentified upstream regulators of this signaling. Many studies have shown that miRNAs or other ncRNAs are the important regulators of Wnt/β‐catenin signaling, for example, miR‐103/107 enhances colorectal cancer stemness by targeting Axin2 and prolonging Wnt/β‐catenin signaling; LncRNA LUCAT1 facilitates stem cell‐like properties of breast cancer cells by competitively binding miR‐5582‐3p with TCF7L2 and enhancing the Wnt/β‐catenin signaling . MiR‐612 reduces the stemness of liver cancer via targeting Wnt/β‐catenin signaling …”