Tumor recurrence and metastases are the major obstacles to improving the prognosis of patients with hepatocellular carcinoma (HCC). To identify novel risk factors associated with HCC recurrence and metastases, we have established a panel of recurrence-associated microRNAs (miRNAs) by comparing miRNA expression in recurrent and nonrecurrent human HCC tissue samples using microarrays (recurrence is defined as recurrent disease occurring within a 2-year time point of the original treatment). Among the panel, expression of the miR-216a/217 cluster was consistently and significantly upregulated in HCC tissue samples and cell lines associated with early tumor recurrence, poor disease-free survival, and an epithelial-mesenchymal transition (EMT) phenotype. Stable overexpression of miR-216a/217-induced EMT increased the stem-like cell population, migration, and metastatic ability of epithelial HCC cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were subsequently identified as two functional targets of miR-216a/217, and both PTEN and SMAD7 were down-regulated in HCC. Ectopic expression of PTEN or SMAD7 partially rescued miR-216a/217-mediated EMT, cell migration, and stem-like properties of HCC cells. Previously, SMAD7 was shown to be a transforming growth factor beta (TGF-b) type 1 receptor antagonist. Here, we further demonstrated that overexpression of miR216a/217 acted as a positive feedback regulator for the TGF-b pathway and the canonical pathway involved in the activation of phosphoinositide 3-kinase/protein kinase K (PI3K/Akt) signaling in HCC cells. Additionally, activation of the TGF-b-and PI3K/ Akt-signaling pathways in HCC cells resulted in an acquired resistance to sorafenib, whereas blocking activation of the TGF-b pathway overcame miR-216a/217-induced sorafenib resistance and prevented tumor metastases in HCC. Conclusion: Overexpression of miR-216a/217 activates the PI3K/Akt and TGF-b pathways by targeting PTEN and SMAD7, contributing to hepatocarcinogenesis and tumor recurrence in HCC. (HE-PATOLOGY 2013;58:629-641) H epatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third-leading cause of deaths from cancer worldwide. Recurrent disease is one of the most serious challenges for managing patients with HCC. 1Although hepatic resection is a well-accepted therapy for early-stage HCC, many patients develop tumor recurrence and this converts the situation to a dismal prognosis.2 Coupled with the inherent high resistance of HCC to chemotherapeutic drugs, recurrent disease forms the main cause of death in long-term evaluations. The identification of predictive molecular factors
ObjectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence.DesignPRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1.ResultsPRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling.ConclusionsWe identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence.
The down-regulation of miR-214 has previously been observed in human hepatocellular carcinoma (HCC). Here, we demonstrated the down-regulation of miR-214 is associated with cell invasion, stem-like traits and early recurrence of HCC. Firstly, we validated the suppression of miR-214 in human HCC by real-time quantitative RT-PCR (qRT-PCR) in 20 paired tumor and non-tumor liver tissues of HCC patients and 10 histologically normal liver tissues from colorectal cancer patients with liver metastases. Further qRT-PCR analysis of 50 HCC tissues from an independent cohort of HCC patients of whom 29 with early recurrent disease (<2 years) and 21 with late recurrent disease demonstrated that the suppression of miR-214 was significantly more suppressed in samples from HCC patients with early recurrent disease compared those from patients with no recurrence. Re-expression of miR-214 significantly suppressed the growth of HCC cells in vitro and reduced their tumorigenicity in vivo. The enhancer of zeste homologue 2 (EZH2) and β-catenin (CTNNB1) was identified as two potential direct downstream targets of miR-214 through bioinformatics analysis and experimentally validated the miRNA-target interactions with a dual-firefly luciferase reporter assay. In corroborate with this, both EZH2 and CTNNB1 are found to be significantly overexpressed in human HCC biopsies. Since EZH2 can regulate CTNNB1, CTNNB1 can also be an indirect target of miR-214 through EZH2. Silencing EZH2 or CTNNB1 expression suppressed the growth and invasion of HCC cells and induced E-cadherin (CDH1), known to inhibit cell invasion and metastasis. Furthermore, the silencing of miR-214 or overexpression of EZH2 increased EpCAM+ stem-like cells through the activation of CTNNB1. Interestingly, the up-regulation of EZH2, CTNNB1 and the down-regulation of CDH1 in HCC patients correlated with early recurrent disease and can be an independent predictor of poor survival. Therefore, miR-214 can directly or indirectly target CTNNB1 to modulate the β-catenin signaling pathway in HCC.
Brain metastasis often has a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Therefore, it is urgent to identify factors associated with lung cancer brain metastasis. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) also known as noncoding nuclear-enriched abundant transcript 2 is a long noncoding RNA, which is highly conserved amongst mammals. It has been shown to be increased in a variety of tumors including NSCLC and regulate the expression of metastasis-associated genes. However, the role of MALAT1 in lung cancer brain metastasis has not been investigated. In this study, we examined the level of MALAT1 in 78 cases of NSCLC samples with 19 brain metastasis and 59 non-brain metastasis by qRT-PCR. We observed that the level of MALAT1 was significantly higher in brain metastasis than that of non brain metastasis samples (P < 0.001). The level of MALAT1 was associated with patients' survival. To investigate the role of MALAT1 in brain metastasis, we established a highly invasive and metastatic cell subline using the brain metastasis lung cancer cell H1915. We found that MALAT1 is increased in highly invasive subline of brain metastasis lung cancer cells. Further functional studies indicate that silencing MALAT1 inhibits highly invasive subline of brain metastasis lung cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, increased level of long noncoding RNA MALAT1 promotes lung cancer brain metastasis by inducing EMT, which may be a promising prognosis factor and therapeutic target to treat lung cancer brain metastasis in future.
Background: miR-124 is a brain-enriched microRNA that has been shown to be down-regulated in glioma. Results: miR-124 inhibits glioma cell invasion and tumorigenicity and reduces neurosphere formation, CD133ϩ cell subpopu-
Response rates to conventional chemotherapeutics remain unsatisfactory for hepatocellular carcinoma (HCC) due to the high rates of chemoresistance and recurrence. Tumor-initiating cancer stem-like cells (CSLCs) are refractory to chemotherapy, and their enrichment leads to subsequent development of chemoresistance and recurrence. To overcome the chemoresistance and stemness in HCC, we synthesized a Pt nanocluster assembly (Pt-NA) composed of assembled Pt nanoclusters incorporating a pH-sensitive polymer and HCC-targeting peptide. Pt-NA is latent in peripheral blood, readily targets disseminated HCC CSLCs, and disassembles into small Pt nanoclusters in acidic subcellular compartments, eventually inducing damage to DNA. Furthermore, treatment with Pt-NA downregulates a multitude of genes that are vital for the proliferation of HCC. Importantly, CD24+ side population (SP) CSLCs that are resistant to cisplatin are sensitive to Pt-NA, demonstrating the immense potential of Pt-NA for treating chemoresistant HCC.
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