A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/β-Catenin Signaling Promotes Metastasis of Colon Cancer

Abstract

We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic β-catenin impeded casein kinase 1 (CK1)-induced β-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, β-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear β-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with β-catenin, and the positive feed-forward circuit of CYTOR-β-catenin might be a useful therapeutic target in antimetastatic strategy.

Improved characterization of the relationship between long intergenic non‐coding RNA Linc00152 and the occurrence and development of malignancies

“…In colorectal cancer, linc00152 promotes the proliferation, migration, and invasion in the miR‐139‐5p/NOTCH 1 axis, while also inducing the resistance of colorectal cancer cells to 5‐fluorouracil‐mediated apoptosis . Moreover, linc00152 can facilitate the epithelial‐to‐mesenchymal transition and metastasis in colon cancer by binding to cytoplasmic β‐catenin, thereby impeding casein kinase 1 (CK1)‐induced β‐catenin phosphorylation and enabling β‐catenin as well as linc00152 to be translocated into the nucleus in a positive feed‐forward circuit …”

“…50,51 Moreover, linc00152 can facilitate the epithelial-to-mesenchymal transition and metastasis in colon cancer by binding to cytoplasmic β-catenin, thereby impeding casein kinase 1 (CK1)-induced β-catenin phosphorylation and enabling β-catenin as well as linc00152 to be translocated into the nucleus in a positive feed-forward circuit. 52 The progression of renal cell carcinoma is correlated with the elevated level of linc00152, which contributes to lymph node metastases, advances in TNM stage, and shorter overall survival. Additionally, downregulated linc00152 expression decreases cell proliferation and shortens the S phase, possibly because of the epigenetic suppression of P16 and inhibition of miR-205.…”

lncRNA-CYTOR Works as an Oncogene Through the CYTOR/miR-3679-5p/MACC1 Axis in Colorectal Cancer

“…As far as we know, this study was the first assessment of clinical value of CYTOR expression in CRC patients based on the large sample investigation and data analysis. The poor prognosis may be due to the high-CYTOR expression that promoted proliferation and metastasis in CRC cells as previously reported (Yue et al, 2018). Meanwhile, resistance to antitumor drugs may be another reason for poor…”

Identification of a prognostic long non-coding RNA signature in breast cancer

“…CYTOR is also called LINC00152, previous studies showed that the expression of lncRNA CYTOR was up-regulated in multiple malignant diseases, such as gastrointestinal cancer, liver cancer, lung adenocarcinoma and esophageal squamous cell carcinoma [25][26][27][28]. Yue et al [29] showed that CYTOR promoted metastasis of colon cancer through Wnt/β-catenin signal pathway. Reon et al [30] reported that CYTOR promoted invasion via a 3'-hairpin structure, and as a effective biomarker for predicting survival of glioblastoma.…”