Circular RNA circSP5 promotes liver metastasis of colorectal cancer via SP5-mediated BAMBI transcription.

Liver metastasis of colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. Circular RNAs (circRNAs) have been widely reported to be implicated in cancer metastasis. This study aims to investigate the effect of circSP5 (has_circ_0057010) on liver metastasis of CRC. Quantitative real-time PCR (RT-qPCR) analysis was performed to detect gene expression. The level of proteins was measured by western blot. The migration and invasion of CRC cells were assessed by wound healing assay and transwell assay. In vivo assays were performed after the construction of the CRC xenograft model and CRC model with liver metastasis. Mechanism analyses were performed via RNA-binding protein immunoprecipitation (RIP), RNA pulldown, luciferase reporter, chromatin immunoprecipitation (ChIP), and DNA pulldown assays. We found that circSP5 is significantly overexpressed in CRC with liver metastasis and its depletion suppresses the progression of CRC with liver metastasis in vitro and in vivo. Moreover, circSP5 enhances the expression of Sp5 transcription factor (SP5) via competitively sponging microRNA (miR)-1249-3p and could regulate BMP and activin membrane-bound inhibitor (BAMBI) via transcriptional activation. CircSP5 promotes the migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells via BAMBI. In sum, circSP5 promotes liver metastasis of CRC by up-regulating SP5-mediated BAMBI transcription.

Long non-coding RNA ROR promotes radioresistance in hepatocelluar carcinoma cells by acting as a ceRNA for microRNA-145 to regulate RAD18 expression.

Radiotherapy plays a limited role in the treatment of hepatocellular carcinoma (HCC) due to the development of resistance. Therefore, further investigation of underlying mechanisms involved in HCC radioresistance is warranted. Increasing evidence shows that long non-coding RNAs (linc-RNAs) are involved in the pathology of various tumors, including HCC. Previously, we have shown that long noncoding RNA regulator of reprogramming (linc-ROR) promotes HCC metastasis via induction of epithelial-mesenchymal transition (EMT). However, the roles of linc-ROR in HCC radioresistance and its possible mechanisms are unclear. Here, we established two radioresistant HCC cell lines (HepG2-R and SMMC-7721-R) and found that linc-ROR was significantly upregulated in radioresistant HCC cells. Knockdown of linc-ROR reduces in vitro and in vivo radiosensitivity of parental HCC cells by reducing DNA repair capacity, while ectopic expression of linc-ROR enhances radiosensitivity of radioresistant HCC cells. Further mechanistic investigations revealed that lincRNA-ROR exerted its biological effects by acting as a competing endogenous RNA (ceRNA) for miR-145 to regulate RAD18 expression, thereby promoting DNA repair. Collectively, our findings demonstrate that linc-ROR promotes HCC radioresistance and targeting it will be a promising strategy for enhancing the efficacy of radiotherapies in HCC.

Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway.

Numerous reports have elucidated the important participation of exosomes in the communication between tumor cells and other cancer-related cells including tumor-associated macrophages (TAMs) in microenvironment. However, the interchange of exosomes between tumor cells and TAMs in the progression of lung adenocarcinoma (LUAD) remains largely enigmatic. Herein, we discovered that LUAD cells induced the M2 polarization of TAMs and the M2-polarized macrophages facilitated LUAD cell invasion and migration and tumor metastasis in vivo. In detail, LUAD cells secreted exosomes to transport miR-19b-3p into TAMs so that miR-19b-3p targeted PTPRD and inhibited the PTPRD-mediated dephosphorylation of STAT3 in TAMs, leading to STAT3 activation and M2 polarization. Also, the activated STAT3 transcriptionally induced LINC00273 in M2 macrophages and exosomal LINC00273 was transferred into LUAD cells. In LUAD cells, LINC00273 recruited NEDD4 to facilitate LATS2 ubiquitination and degradation, so that the Hippo pathway was inactivated and YAP induced the transcription of RBMX. RBMX bound to miR-19b-3p to facilitate the packaging of miR-19b-3p into LUAD cell-derived exosomes. Collectively, our results revealed the mechanism underlying the interactive communication between LUAD cells and TAMs through elucidating the exchange of exosomal miR-19b-3p and LINC00273 and proved the prometastatic effect of the interchange between two cells. These discoveries opened a new vision for developing LUAD treatment.

Corrigendum: Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma.

[This corrects the article DOI: 10.3389/fonc.2019.01156.].

FOXM1-Mediated LINC-ROR Regulates the Proliferation and Sensitivity to Sorafenib in Hepatocellular Carcinoma.

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.

Recent progress in the emerging role of exosome in hepatocellular carcinoma.

Exosomes are small membrane vesicles 50-150 nm in diameter released by a variety of cells, which contain miRNAs, mRNAs and proteins with the potential to regulate signalling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to participate in orchestrating cell-cell communication and microenvironment modulation. In this review, we summarize recent progress in our understanding of the role of exosomes in hepatocellular carcinoma (HCC). This review focuses on recent studies on HCC exosomes, considering biogenesis, cargo and their effects on the development and progression of HCC, including chemoresistance, epithelial-mesenchymal transition, angiogenesis, metastasis and immune response. Finally, we discuss the clinical application of exosomes as a therapeutic agent for HCC.

S1PR1 promotes proliferation and inhibits apoptosis of esophageal squamous cell carcinoma through activating STAT3 pathway.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, which lacks effective biomarkers for prognosis. Therefore, it is urgent to explore new potential molecular markers to discriminate patients with poorer survival in ESCC. METHODS: Bioinformatics analysis, qRT-PCR, and western blot were applied to investigate S1PR1 expression. CCK-8 assay, colony formation assay, flow cytometry dual staining assay, and immunofluorescence were performed to examine cell proliferation ability and apoptosis rate. Mouse xenograft model of TE-13 cells was established to confirm the roles of S1PR1 in vivo. Gene set enrichment analysis (GSEA) was used to investigate the downstream signaling pathways related to S1PR1 functions. Co-IP was performed to verify the direct binding of S1PR1 and STAT3. Western blot was applied to determine the phosphorylation level of STAT3. Immunohistochemistry was conducted to identify protein expression of S1PR1 and p- STAT3 in tumor tissues. RESULTS: In the present study, we found that S1PR1 expression was higher in ESCC patients and was a potential biomarker for poor prognosis. Silencing S1PR1 expression inhibited proliferation, and increased apoptosis of ESCC cells, while overexpression of S1PR1 had opposite effects. Mechanistically, S1PR1 played the roles of promoting proliferation and attenuating apoptosis through directly activating p-STAT3. Furthermore, in vivo experiments verified this mechanism. CONCLUSION: Our findings indicated that S1PR1 enhanced proliferation and inhibited apoptosis of ESCC cells by activating STAT3 signaling pathway. S1PR1 may serve as a prognostic biomarker for clinical applications.

Non-coding RNAs: Emerging Regulators of Sorafenib Resistance in Hepatocellular Carcinoma.

As the first oral multi-target anti-tumor drug proved for the treatment of patients with advanced liver cancer in 2007, sorafenib has changed the landscape of advanced hepatocellular carcinoma (HCC) treatment. However, drug resistance largely hinders its clinical application. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), and long non-coding (lncRNAs), have recently been demonstrated playing critical roles in a variety of cancers including HCC, while the mechanisms of ncRNAs in HCC sorafenib resistance have not been extensively characterized yet. Herein, we summarize the mechanisms of recently reported ncRNAs involved in sorafenib resistance and discuss the potential strategies for their application in the battle against HCC.

Regulation and functions of MicroRNA-149 in human cancers.

MicroRNAs are small non-coding RNAs that play critical roles in the regulatory mechanisms involving cell differentiation, proliferation, apoptosis and tumorigenesis. Recent research efforts have been conducted to apply these discoveries into clinical functions, including the early diagnosis and therapeutic outcome of patients with cancer. Previous studies have shown that microRNA-149 (miR-149) is dysregulated in various human cancers and exerts its effects on tumorigenesis and tumour progression. In this review, we summarized the potential roles of miR-149 dysregulation and its target genes during tumorigenesis and clinical treatment of human cancers.

A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma.

Currently, sorafenib-based therapy is the standard treatment for advanced hepatocellular carcinoma (HCC), and there is a strong rationale for investigating its use in combination with other agents to achieve better therapeutic effects. Aurora-A, a member of a family of mitotic serine/threonine kinases, is frequently overexpressed in human cancers and therefore represents a target for therapy. Here, we investigated a novel Aurora-A inhibitor, MLN8237, together with sorafenib in HCC cells in vitro and in vivo, and elucidated the possible molecular mechanism. Here, it was found that MLN8237 was strongly synergistic with sorafenib in inhibition of HCC progression by altering cell growth, cell-cycle regulation, apoptosis, migration, invasion, and angiogenesis. Mechanism dissection suggests that the combination of MLN8237 and sorafenib led to significant inhibition of the activation of phospho-Akt (p-Akt) and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and their downstream genes including CDK4, cyclinD1, and VEGFA. The activators of p-Akt and p-p38 MAPK signaling partially reversed the synergistic inhibitory effects of sorafenib and MLN8237 on HCC progression. Subsequent in vivo studies further confirmed the synergistic effects of sorafenib and MLN8237. Collectively, the newly developed sorafenib-MLN8237 combination may be a novel therapy to better inhibit HCC progression.

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib.

Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulating microRNA (miRNA) that plays a vital role in sorafenib resistance in HCC cells. Gain- and loss-of-function assays revealed that ectopic miR-142-3p upregulation sensitized HCC cells to sorafenib by reducing sorafenib-induced autophagy, enhancing sorafenib-induced apoptosis and inhibiting cell growth, whereas miR-142-3p inhibition exerted contrasting effects. Bioinformatics analysis and luciferase reporter and rescue assays showed that autophagy-related 5 (ATG5) and autophagy-related 16-like 1 (ATG16L1) are potential targets through which miR-142-3p regulates autophagy inhibition. Furthermore, we verified that PU.1 regulated the expression of miR-142-3p in conjunction with our cellular experiments and the related results in the literature. Our findings show that targeting the PU.1-miR-142-3p-ATG5/ATG16L1 axis may be a useful therapeutic strategy for preventing cyto-protective autophagy to overcome sorafenib resistance.