Abstract
Wnt/β-catenin signaling is essential for proliferation and maintenance of cancer stem cell-like traits of various cancer cells. In non-small-cell lung carcinoma (NSCLC), the mechanisms underlying the hyperactivation of Wnt signaling remain unclear, as mutations in APC and β-catenin genes are rare in NSCLC. RIF1 has been shown upregulated in breast and cervical cancer, this study intends to find out the potential effects of the expression and biological functions of RIF1 in NSCLC. Here we revealed that RIF1 was highly expressed in NCSLC at both mRNA and protein levels. RIF1 expression was significantly associated with clinical stage (P < 0.05) and prognosis (P < 0.001) of NSCLC patients. RIF1 knockdown inhibited NSCLC cell growth in vitro and in vivo, whereas overexpression of RIF1 in NSCLC cell lines promoted cell growth, cell cycle progression and cancer stem cell (CSC)-like properties via promoting PP1–AXIN interaction and thereby activating Wnt/β-catenin signaling. Inhibition of PP1 in RIF1-overexpressed cells counteracted the effects of RIF1 on cell growth and CSC-like phenotype, as well as the Wnt/β-catenin signaling. RIF1 expression was positively correlated with β-catenin at the protein level in 32 NSCLC tissues. RIF1 expression closely related to MYC (r = 0.28, P < 0.001) and CCND1 (r = 0.14, P < 0.01) expression at the mRNA level in cohorts of The Cancer Genome Atlas (TCGA). These results indicated that RIF1 had an oncogenic role as a novel positive regulator of Wnt/β-catenin signaling by directing PP1 to dephosphorylate AXIN; this novel mechanism may present a new therapeutic target for NSCLC.
Highlights
Despite advances in diagnosis and therapeutic technologies, lung cancer remains the leading cause of cancer mortality among males and females throughout the world[1]
These results suggested that the expression level of RIF1 was upregulated in lung cancer tissues and aberrant activation of RIF1 was associated with mortality of lung cancer patients
RIF1 has recently been demonstrated to contribute to the regulation of stem cell pluripotency, DNA replication regulation and DNA repair pathway, but little is known about the role of RIF1 in cancer progression
Summary
Despite advances in diagnosis and therapeutic technologies, lung cancer remains the leading cause of cancer mortality among males and females throughout the world[1]. Non-small-cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases[2]. Because of the fact that most patients are often diagnosed at advanced or metastatic stage, NSCLC is difficult to cure[3]. Cancer stem cells (CSCs), including the lung. In NSCLC, the aberrant activated Wnt/β-catenin signaling has been illuminated to be essential for cancer progression and the maintenance of CSCs, leading to poor prognosis of patients[6,7,8,9]. Underlying mechanism is described as follows: when Wnt signaling is activated, cytosolic β-catenin accumulates and subsequently translocates into the cell nucleus.
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