Aurora-A inhibitor synergistically enhances the inhibitory effect of anlotinib on hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a global prevalence. In addition to the existing clinical guidelines, the effectiveness of anlotinib and Aurora-A inhibitors in treating HCC has also been demonstrated. However, Anlotinib, as an anti-angiogenesis therapy, has shown significant benefits in clinical trials but is limited by its single-agent treatment and the development of drug resistance. Aurora-A inhibitors are currently being tested in clinical trials but have limited efficacy. Combination therapy may offer clear advantages over monotherapy in this context. METHODS: In this study, we used HCC cell lines to investigate whether the combination of the two drugs could enhance their individual strengths and mitigate their weaknesses, thereby providing greater clinical benefits both in vitro and in vivo. RESULTS: Our findings confirmed that the Aurora-A inhibitor alisertib and anlotinib exhibited a time-dose-dependent inhibitory effect on HCC cells. In vitro cytological experiments demonstrated that the combination of the two drugs synergistically inhibited cell proliferation, invasion, and metastasis, while promoting cell apoptosis. Furthermore, we identified the underlying molecular mechanism by which the combination of the Aurora-A inhibitor alisertib and anlotinib inhibited HCC through the inhibition of the NF-ĸB signaling pathway. CONCLUSIONS: In summary, we have demonstrated the effectiveness of combining anlotinib with an Aurora-A inhibitor, which expands the potential applications of anlotinib in the clinical treatment of HCC in the future.

Linc-ROR facilitates progression and angiogenesis of hepatocellular carcinoma by modulating DEPDC1 expression.

Linc-ROR have been well-demonstrated to play important roles in cancer progression and angiogenesis. However, the underlying oncogenic mechanism of Linc-ROR in hepatocellular carcinoma is poorly understood. In this study, we demonstrate that Linc-ROR plays an oncogenic role in part through its positive regulation of DEPDC1 expression. Mechanistically, Linc-ROR acts as competing endogenous RNA to stabilize DEPDC1 mRNA and regulates DEPDC1 mRNA stability by binding HNRNPK. Thus, these findings suggest that function of Linc-ROR-mediated DEPDC1 could predispose hepatocellular carcinoma patients to progression and angiogenesis, and may serve as a potential target for anticancer therapies.

The role of Aurora-A in human cancers and future therapeutics.

Aurora-A is a mitotic serine/threonine-protein kinase and an oncogene. In normal cells, Aurora-A appears from G2 phase and localizes at the centrosome, where it participates in centrosome replication, isolation and maturation. Aurora-A also maintains Golgi apparatus structure and spindle assembly. Aurora-A undergoes ubiquitination-mediated degradation after the cell division phase. Aurora-A is abnormally expressed in tumor cells and promotes cell proliferation by regulating mitotic substrates, such as PP1, PLK1, TPX2, and LAST2, and affects other molecules through a non-mitotic pathway to promote cell invasion and metastasis. Some molecules in tumor cells also indirectly act on Aurora-A to regulate tumor cells. Aurora-A also mediates resistance to chemotherapy and radiotherapy and is involved in tumor immunotherapy. Clinical trials of Aurora-A molecular inhibitors are currently underway, and clinical transformation is just around the corner.

The functional role of long non-coding RNAs and their underlying mechanisms in drug resistance of non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid cancer and the main origin of cancer-related deaths worldwide. Current strategies to treat advanced NSCLC are based on a combined approach of targeted therapy and chemotherapy. But most patients will eventually get resistance to either chemotherapy or targeted therapy, leading to the poor prognosis. The mechanism of NSCLC drug resistance is inconclusive and is affected by multiple factors. Long non-coding RNAs (LncRNAs) are non-coding RNAs (ncRNAs) longer than 200 nucleotides. Recent studies show that lncRNAs are involved in many cellular physiological activities, including drug resistance of NSCLC. It is of great clinical significance to understand the specific mechanisms and the role of lncRNAs in it. CONCLUSIONS: Herein, we focus on the functional roles and the underlying mechanisms of lncRNAs in acquired drug resistance of NSCLC. LncRNAs have potential values as novel prognostic biomarkers and even therapeutic targets in the clinical management of NSCLC.

Corrigendum: Oncolytic Adenovirus-A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC.

[This corrects the article DOI: 10.3389/fonc.2019.01182.].

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

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

Non-coding RNAs: emerging regulators of glucose metabolism in hepatocellular carcinoma.

Reprogramming of metabolism is one of the hallmarks of cancer, among which glucose metabolism dysfunction is the most prominent feature. The glucose metabolism of tumor cells is significantly different from that of normal cells. Glucose metabolism reprogramming of hepatocellular carcinoma (HCC) has become an important research hotspot in the field of HCC, a variety of tumor metabolic interventions have been applied clinically. Moreover, various Non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding (lncRNAs) as well as circular RNAs (circRNAs), have recently been proved to play potential roles in glucose metabolism. This review summarizes the effects of ncRNAs on HCC that participate in glucose metabolism and discuss the related mechanisms to find potential and effective targeted treatments for HCC.

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.

Oncolytic Adenovirus-A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, particularly in China. Despite the development of HCC treatment strategies, the survival rate remains unpleasant. Gene-targeted oncolytic viral therapy (GTOVT) is an emerging treatment modality-a kind of cancer-targeted therapy-which creates viral vectors armed with anti-cancer genes. The adenovirus is a promising agent for GAOVT due to its many advantages. In spite of the oncolytic adenovirus itself, the host immune response is the determining factor for the anti-cancer efficacy. In this review, we have summarized recent developments in oncolytic adenovirus engineering and the development of novel therapeutic genes utilized in HCC treatment. Furthermore, the diversified roles the immune response plays in oncolytic adenovirus therapy and recent attempts to modulate immune responses to enhance the anti-cancer efficacy of oncolytic adenovirus have been discussed.

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.