Linc-ROR facilitates progression and angiogenesis of hepatocellular carcinoma by modulating DEPDC1 expression.
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ABSTRACT:
SUBMITTER: Tian C
PROVIDER: S-EPMC8571363 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long non‑coding RNAs are associated with cancer progression. Long intergenic non‑protein coding RNA (linc)‑regulator of reprogramming (ROR) enhances tumor development in hepatocellular carcinoma (HCC). However, the effect of chemoresistance and its underlying mechanisms in HCC are not completely understood. The present study aimed to identify the effect of ROR on sensitivity to doxorubicin (DOX) in HCC cells. In the present study, Cell Counting Kit‑8 and EdU assays were performed to assess cell viability and proliferation, respectively. In addition, E‑cadherin and vimentin protein expression levels were assessed via western blotting and immunofluorescence.The results of the present study demonstrated that HCC cells with high linc‑ROR expression levels were more resistant to DOX, and linc‑ROR knockdown increased HCC cell DOX sensitivity compared with the control group. The results indicated that compared with the NC siRNA group, linc‑ROR knockdown notably suppressed epithelial‑mesenchymal transition by downregulating twist family bHLH transcription factor 1 (TWIST1) expression. TWIST1 knockdown displayed a similar effect on HCC cell DOX sensitivity to linc‑ROR knockdown. Moreover, linc‑ROR knockdown‑induced HCC cell DOX sensitivity was inhibited by TWIST1 overexpression. The present study provided evidence that linc‑ROR promoted HCC resistance to DOX by inducing EMT via interacting with TWIST1. Therefore, linc‑ROR might serve as a therapeutic target for reducing DOX resistance in HCC.
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Project description:BACKGROUND:Novel therapies tailored to the molecular composition of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. We investigated the regulatory network of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) and sex-determining region Y-box 9 (SOX9), and their therapeutic relevance in ESCC. METHODS:Linc-ROR and SOX9 expression were examined in ESCC specimens, cell lines, and cultured tumorspheres. We investigated the effects of linc-ROR on SOX9 expression and malignant phenotypes by CCK8, colony formation, Transwell, and sphere-forming assay. The linc-ROR/SOX9 interaction mediated by multiple microRNAs (miRNAs) was confirmed by bioinformatic analysis, luciferase assay, and RNA-binding protein immunoprecipitation, transient overexpression or antagonizing endogenous candidate miRNAs. The effect of linc-ROR depletion on tumor growth was assessed by xenograft assay. RESULTS:A positive correlation between linc-ROR and SOX9 expression was found in clinical ESCC specimens (r = 0.562, P = 0.036), cell lines, and tumorspheres. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity. Mechanistically, linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR-15b, miR-33a, miR-129, miR-145, and miR-206. Antagonizing these miRNAs counteracted with linc-ROR silencing, whereas the repression of SOX9 abrogated malignant phenotypes induced by the cocktail of miRNA inhibitors. Moreover, linc-ROR disruption was sufficient to attenuate tumor growth and cancer stem cell marker expression in vivo. CONCLUSIONS:Our results demonstrate that the linc-ROR-miRNA-SOX9 regulatory network may represent a novel therapeutic target for ESCC.
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Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated death worldwide. Indeed, despite the benefit of sorafenib in the treatment of some patients with HCC, the majority of these patients have a poor response to or intolerance of sorafenib, resulting in further tumor progression. Exploring the mechanisms underlying sorafenib resistance is essential to the treatment of HCC. Long noncoding RNAs (lncRNAs) are known as participants in tumorigenesis. In this study, we identified that long intergenic non-protein coding RNA, regulator of reprogramming (LINC-ROR), was upregulated in HCC cell lines, which was transcriptionally activated by FOXM1. Furthermore, the sponging of miR-876-5p by LINC-ROR released FOXM1, thereby forming a positive-feedback loop. Additionally, we demonstrated that upregulation of both FOXM1 and LINC-ROR impaired the sensitivity to sorafenib in HCC cells. The role of this feedback loop was demonstrated by rescue assays. These results revealed a novel molecular feedback loop between LINC-ROR and FOXM1 and elucidated their functions in sorafenib sensitivity of HCC cell lines.
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Project description:Functional polymorphisms in Linc-ROR may change its ability of regulation by regulating Linc-ROR expression. However, these functional polymorphisms in Linc-ROR and their associations with breast cancer (BC) susceptibility were scarcely reported. In this molecular epidemiological study, four SNPs (rs6420545, rs4801078, rs1942348 and rs9636089) were selected in Linc-ROR by bioinformatics method. Unconditional logistic regression model was performed to analyze the associations between four SNPs and BC susceptibility adjusted for reproductive factors. Quantitative real-time (qRT) PCR was used to evaluate relative expression of Linc-ROR in plasma. The interactions of gene reproductive factors were assessed by Multifactor Dimensionality Reduction (MDR) method. A novel finding showed TT (OR: 1.79; 95%CI: 1.20-2.68) genotype of rs4801078 in Linc-ROR had a significant association with the higher risk of BC and the expression of Linc-ROR mRNA was closely related with the alleles of rs4801078. In addition, we found the interaction of rs4801078, number of pregnancy and menopausal status might increase BC risk (OR: 2.78; 95%CI: 2.74-3.61). Our results suggest that interactions of SNPs in Linc-ROR and reproductive factors might contribute to BC risk, and alleles of rs4801078 might affect Linc-ROR expression level.
| S-EPMC5856846 | biostudies-literature
Project description:DEP domain containing 1 (DEPDC1) functions as an oncogene in hepatocellular carcinoma (HCC). However, the underlying mechanism of DEPDC1 remains largely unknown. The present study revealed that DEPDC1 knockdown inhibited HCC cell proliferation, colony formation and invasion in vitro and suppressed the growth of HCC xenografts in vivo. Furthermore, DEPDC1 overexpression promoted HCC cell proliferation, colony formation and invasion. DNA microarray, reverse transcription‑quantitative‑PCR and western blotting results demonstrated that DEPDC1 knockdown in Huh‑7 significantly inhibited the expression of chemokine (C‑C motif) ligand 20 (CCL20) and chemokine (C‑C motif) receptor 6 (CCR6). In addition, the expression of CCL20 and CCR6 were upregulated in HCC tissues and cell lines, and were positively correlated with DEPDC1 expression. CCL20 or CCR6 knockdown via small interfering RNA reversed the effects of DEPDC1 overexpression in HCC cells. Furthermore, it was revealed that conditioned medium from DEPDC1 upregulated Li‑7 and Hep3B cells led to angiogenesis in vitro, whereas CCL20 knockdown in Li‑7 and Hep3B cells or CCR6 knockdown in human umbilical vein endothelial cells reversed the angiogenic effect of DEPDC1 overexpression. In conclusion, DEPDC1 facilitated cell proliferation, invasion and angiogenesis via the CCL20/CCR6 pathway in HCC.
| S-EPMC6667871 | biostudies-literature
Project description:Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis.
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Project description:Exosomes are small vesicles with a diameter of 30-150 nm secreted by cells, which can be used as signal carriers to transfer nucleic acids, proteins, lipids and other functional substances to the recipient cells and play a role in cell communication. Hepatocellular carcinoma is the fourth most common cause of cancer-related death worldwide. Studies have shown that long non-coding RNAs (lncRNAs) are involved in the development and progression of many types of tumors. Our present study found that linc-FAM138B was reduced in HCC tissues and cell lines, low expression of linc-FAM138B indicated a poor prognosis in HCC patients. Interestingly, linc-FAM138B could be packaged into cancer cells. And exo-FAM138B inhibited the proliferation, migration and invasion of HCC cells. Furthermore, linc-FAM138B sponged miR-765 levels. And exo-si-FAM138B promoted HCC progression, while deletion of miR-765 reversed the role of exo-si-FAM138B. In vivo tumorigenesis experiments showed that exo-FAM138B suppressed HCC growth via modulating miR-765. In conclusion, exo-linc-FAM138B secreted by cancer cells inhibited HCC development via targeting miR-765, which provided a new idea and perspective for in-depth understanding of the complex signal regulation in HCC process.
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Project description:Ezrin, one of the ezrin-radixin-moesin (ERM) proteins, is involved in the formation of cell membrane processes and has been implicated in the promotion of cancer proliferation and metastasis. However, the possible role of ezrin in hepatocellular carcinoma (HCC) metastasis and glycolysis reprogramming has remained unclear. In this study, we found that ezrin was upregulated in HCC tissues, and its overexpression was linked with HCC patients' aggressive tumor characteristics and poor prognosis. Functional experiments further revealed that ezrin overexpression promoted HCC cell proliferation, epithelial-to-mesenchymal transition (EMT) progression and angiogenesis. In addition, by measuring glucose consumption, lactate production, ATP levels and the expression of glucose metabolism-related markers in HCC cells, we investigated whether ezrin regulated glucose metabolism. Moreover, 2-deoxy-D-glucose (2-DG) affected ezrin-mediated proliferation, migration and EMT of HCC cells, which suggested that ezrin may, at least in part, promote HCC progression by regulating glycolysis reprogramming. Based on our results, we proposed that ezrin was involved in HCC progression and may be a valid prognostic marker.
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Project description:BACKGROUND:Circular RNA (circRNA) is emerging as an important player in human diseases, especially cancer. In our previous study, we identified a series of deregulated circRNAs in hepatocellular carcinoma (HCC) by performing circRNA microarray expression profile. Here, we aimed to explore the role of circ-LRIG3 (hsa_circ_0027345) in HCC. METHODS:qRT-PCR and western blot were used to asses gene and protein expression, respectively. CCK-8, EdU and Transwell assays were used to detect cell proliferation, migration and invasion. GSEA software was applied to analyze the pathway related to circ-LRIG3. Co-IP, RIP and ChIP assays were used to identify the positive feedback axis of circ-LRIG3/EZH2/STAT3. Animal study was carried to test the role of circ-LRIG3 in vivo. RESULTS:Circ-LRIG3 was notably upregulated in HCC and promoted HCC cell proliferation, migration, invasion and reduced apoptosis. Circ-LRIG3 formed a ternary complex with EZH2 and STAT3, facilitating EZH2-induced STAT3 methylation and subsequent phosphorylation, resulting in the activation of STAT3 signaling. In turn, activated STAT3 could directly bind to circ-LRIG3 promoter to increase circ-LRIG3 transcription activity, thus forming a positive feedback loop. The animal models showed that exogenous expression of circ-LRIG3 enhanced tumorigenicity and metastasis in vivo, whereas these effects were blocked after treatment with C188-9, a specific STAT3 small-molecule inhibitor. Clinically, high circ-LRIG3 was closely linked with aggressive clinicopathological features and was identified as an independent risk prognostic factor of overall survival. Importantly, plasma circ-LRIG3 was found to be a highly sensitive and specific non-invasive diagnostic indicator for HCC. CONCLUSIONS:Our study reveals the carcinogenic role of circ-LRIG3 in HCC, which may provide a new therapeutic target for HCC patients.
| S-EPMC7682056 | biostudies-literature