BackgroundWith more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC.MethodsWe examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells.ResultsIn this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a-5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that β-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/β-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/β-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p.ConclusionsOur study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/β-catenin signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0583-1) contains supplementary material, which is available to authorized users.
Sorafenib displays a limited efficacy for advanced hepatocellular carcinoma (HCC). Some patients with HCC initially respond to sorafenib, but eventually succumb to the disease, indicating that the acquired resistance to sorafenib reduces its beneficial effects. No alternative drugs are available after the failure of sorafenib therapy. Therefore, investigation of the mechanisms underlying the acquired resistance and development of second‐line treatments for sorafenib‐resistant HCC are urgently required. In this study, sorafenib‐resistant HCC cells generated from sorafenib‐sensitive human HCC cells were shown to overproduce hepatocyte growth factor (HGF) and overexpress c‐Met kinase and its phosphorylated form, leading to the activation of Akt and ERK (extracellular signaling‐regulated kinase) pathways. Use of specific c‐Met inhibitors enhanced the effects of sorafenib by inhibiting the growth of sorafenib‐resistant HCC cells. Akt inhibitors, a class of second‐line therapeutic drugs under investigation for treating HCC in clinical trials, enhanced the effects of sorafenib, but also activated the c‐Met pathway in sorafenib‐resistant cells. Dual inhibition of Akt and c‐Met by their respective inhibitors, MK2206 and capmatinib, additively or synergistically suppressed sorafenib‐resistant HCC cells in vitro and sorafenib‐resistant HCC xenografts in mice. The anticancer activities of MK2206 mainly rely on its ability to induce cell apoptosis and autophagic death, while capmatinib treatment leads to cell cycle arrest at phase G1. These results provide strong evidence for further investigation on the clinical utility of dual inhibition of Akt and c‐Met, particularly MK2206 and capmatinib, as a second‐line therapy for advanced HCC that has acquired resistance to sorafenib.
Sorafenib resistance remains a major obstacle for the effective treatment of hepatocellular carcinoma (HCC), and a number of miRNAs contribute to this resistance. However, the regulatory networks of miRNAs are very complex, thus inhibiting a single miRNA may sequentially activate other compensatory pathways. In the present study, we generated an artificial long non-coding RNA (AlncRNA), which simultaneously targets multiple miRNAs including miR-21, miR-153, miR-216a, miR-217, miR-494 and miR-10a-5p. These miRNAs have been shown to be upregulated in sorafenib-resistant cells and participate in the mechanisms underlying sorafenib resistance. The AlncRNA contains tandem sequences of 6 copies of the complementary binding sequences to the target miRNAs and is expressed by an adenoviral vector (Ad5-AlncRNA). Infection of Ad5-AlncRNA into sorafenib-resistant HCC cells blocked the function of miRNAs, and sequentially inhibited the downregulation of PTEN and activation of AKT. Ad5-AlncRNA significantly inhibited proliferation and induced apoptosis of sorafenib-resistant cells and enhanced the effects of sorafenib in vitro and in animal models. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to Ad5-AlncRNA, while its induction had the opposite effect. These results indicate that targeting multiple miRNAs by the artificial lncRNA could be a potential promising strategy for overcoming sorafenib resistance in the treatment of HCC.
Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.