scholarly journals MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhe-bin Dong ◽  
Heng-miao Wu ◽  
Yi-cheng He ◽  
Zhong-ting Huang ◽  
Yi-hui Weng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Early Recurrence ◽  
Advanced Hepatocellular Carcinoma ◽  
Curative Surgery ◽  
Multikinase Inhibitor ◽  
Key Factor ◽  
Nuclear Location ◽  
Induced Apoptosis

AbstractAs a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

scholarly journals Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chao Liang ◽  
Zhebin Dong ◽  
Xianlei Cai ◽  
Jie Shen ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Term Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Clinical Prognosis ◽  
Nuclear Location ◽  
Long Term Therapy ◽  
Hcc Cells

AbstractSorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

scholarly journals Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

2021 ◽  
Vol 27 ◽  
Author(s):  
Xili Jiang ◽  
Wei Zhang ◽  
Lifeng Li ◽  
Shucai Xie
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Pearson Correlation ◽  
Acquired Resistance ◽  
Rank Aggregation ◽  
Health Concern ◽  
Hub Genes ◽  
Multikinase Inhibitor

Hepatocellular carcinoma (HCC), a high mortality malignancy, has become a worldwide public health concern. Acquired resistance to the multikinase inhibitor sorafenib challenges its clinical efficacy and the survival benefits it provides to patients with advanced HCC. This study aimed to identify critical genes and pathways associated with sorafenib resistance in HCC using integrated bioinformatics analysis. Differentially expressed genes (DEGs) were identified using four HCC gene expression profiles (including 34 sorafenib-resistant and 29 sorafenib-sensitive samples) based on the robust rank aggregation method and R software. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING), and small molecules reversing sorafenib resistance were searched for using the connectivity map (CMAP) database. Pearson correlation and survival analyses of hub genes were performed using cBioPortal and Gene Expression Profiling and Interactive Analysis (GEPIA). Finally, the expression levels of hub genes in sorafenib-resistant HCC cells were verified using quantitative polymerase chain reaction (q-PCR). A total of 165 integrated DEGs (66 upregulated and 99 downregulated in sorafenib resistant samples compared sorafenib sensitive ones) primarily enriched in negative regulation of endopeptidase activity, extracellular exosome, and protease binding were identified. Some pathways were commonly shared between the integrated DEGs. Seven promising therapeutic agents and 13 hub genes were identified. These findings provide a strategy and theoretical basis for overcoming sorafenib resistance in HCC patients.

scholarly journals Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

2017 ◽  
Vol 44 (2) ◽  
pp. 716-727 ◽  
Author(s):  
Ting Sun ◽  
Hongchun Liu ◽  
Liang Ming
Keyword(s):  
Hepatocellular Carcinoma ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Multiple Roles ◽  
Multikinase Inhibitor ◽  
Advanced Hcc ◽  
Cellular Autophagy ◽  
Advanced Stages ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.

scholarly journals Treatment with a new benzimidazole derivative bearing a pyrrolidine side chain overcomes sorafenib resistance in hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fat-Moon Suk ◽  
Chao-Lien Liu ◽  
Ming-Hua Hsu ◽  
Yu-Ting Chuang ◽  
Jack P. Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Benzimidazole Derivative ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Side Chain ◽  
Mesenchymal Transition ◽  
New Compounds ◽  
Line Drug

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Currently, sorafenib is the standard first-line drug for patients with advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity of tumour cells to the drug, leading to acquired resistance. Therefore, developing new compounds to treat sorafenib resistance is urgently needed. Although benzimidazole and its derivatives have been reported to exert antimicrobial and antitumour effects, the anti-drug resistance potential of these molecules is still unknown. In this study, we established sorafenib-resistant (SR) cell lines and an acquired sorafenib resistance xenograft model. We showed that treatment with a benzimidazole derivative bearing a pyrrolidine side chain (compound 9a) inhibited the proliferation of SR cells by blocking the phosphorylation of AKT, p70S6 and the downstream molecule RPS6. In addition, caspase 3/PARP-dependent apoptotic signals were induced in 9a-treated cells. Regarding epithelial-mesenchymal transition (EMT) activities, 9a treatment significantly suppressed the migration of SR cells. In particular, the levels of EMT-related transcription factors (snail, slug and twist) and mesenchymal markers (vimentin and N-cadherin) were downregulated. In the acquired sorafenib resistance xenograft model, compound 9a administration decreased the growth of tumours with acquired sorafenib resistance and the expression of the HCC markers α-fetoprotein, glypican 3 and survivin. In conclusion, treatment with this compound may be a novel therapeutic strategy for patients with sorafenib resistance.

scholarly journals Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

2018 ◽  
Vol 19 (10) ◽  
pp. 3127 ◽  
Author(s):  
Young-Seon Kim ◽  
Yoon-Mi Lee ◽  
Taek-In Oh ◽  
Dong Shin ◽  
Geon-Hee Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cholesterol Metabolism ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Akt Signaling ◽  
Chinese Herbs ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Anti Cancer ◽  
Sensitizing Effect

Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC.

scholarly journals miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Yue Zhou ◽  
Enjiang Chen ◽  
Yuexiao Tang ◽  
Jiayan Mao ◽  
Jian Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Term Therapy ◽  
Autophagic Flux ◽  
Doxorubicin Resistance ◽  
Novel Mirna ◽  
Mouse Xenograft Model ◽  
Hcc Cells

Abstract Doxorubicin is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. Autophagy, a conserved catabolic process for cellular self-protection and adaptation to the changing environment, is regarded as a potential clinical target to overcome doxorubicin resistance. In this study, the potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human HCC cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. We found that the well-defined miR-223 is expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibits the doxorubicin-induced autophagy that contributes to chemoresistance. Blockade of autophagic flux by chloroquine resulted in the failure of miR-223 inhibitor to suppress doxorubicin sensitivity of HCC cells. We further identified FOXO3a as a direct downstream target of miR-223 and primary mediator of the regulatory effect of miR-223 on doxorubicin-induced autophagy and chemoresistance in HCC cells. Finally, we confirmed the enhancement of doxorubicin sensitivity by agomiR-223 in xenograft models of HCC. These findings establish a novel miRNA-based approach for autophagy interference to reverse doxorubicin resistance in future chemotherapy regimens against human HCC.

scholarly journals Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling

Liver Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Robin K. Kelley ◽  
Nancy M. Joseph ◽  
Halla S. Nimeiri ◽  
Jimmy Hwang ◽  
Laura M. Kulik ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Advanced Hepatocellular Carcinoma ◽  
Next Generation ◽  
Serious Adverse Events ◽  
Multikinase Inhibitor

<b><i>Background:</i></b> The mammalian target of rapamycin (<i>mTOR</i>) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of <i>mTOR</i> pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. <b><i>Methods:</i></b> We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d<i>.</i> The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. <b><i>Results:</i></b> Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor <i>mTOR</i> pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. <b><i>Conclusions:</i></b> The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of <i>mTOR</i> pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

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