1
|
Zhang F, Lo EKK, Chen C, Lee JCY, Felicianna, Ismaiah MJ, Leung HKM, Tsang DHL, El-Nezami H. Probiotics Mixture, Prohep: a Potential Adjuvant for Low-Dose Sorafenib in Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma Suppression Through Modulating Gut Microbiota. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10593-4. [PMID: 40405038 DOI: 10.1007/s12602-025-10593-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2025] [Indexed: 05/24/2025]
Abstract
Targeting gut microbiota is an innovative approach to mitigate the development of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC). This study aims to investigate the effects of Prohep, a probiotic mixture, both as a prophylactic measure and as an adjuvant therapy for low-dose sorafenib. A MASLD-HCC mice model was established by diethylnitrosamine (DEN) injection with feeding of a high-fat high-cholesterol (HFHC) diet. Gut microbiome profiles were later identified through shotgun sequencing. Our findings demonstrated that Prohep supplementation effectively suppressed MASLD-HCC development in mice. This protective effect was attributed to the modulation of gut microbiota and the increased production of short-chain fatty acids (SCFAs), propionate, and valerate. Prohep also activated AMPK, which decreased lipogenesis, reduced lipid uptake, and enhanced antioxidant enzyme expressions. Additionally, the cancer proliferation pathway PI3K/mTOR was inhibited in response to Prohep treatment. As an adjuvant therapy, Prohep improved the efficacy of low-dose sorafenib, as indicated by reduced tumor counts, alleviated inflammation, and increased hepatic superoxide dismutase (SOD) expression. The combination led to enhanced butyrate production, contributing to the overall therapeutic effects, thanks to the gut microbiota modulatory effects of Prohep. These results underscore Prohep's anti-tumorigenic properties and its potential to enhance the therapeutic outcomes of low-dose sorafenib in MASLD-HCC treatment. The study highlights the importance of gut microbiota modulation for developing effective neoadjuvant therapies and long-term management strategies for MASLD-HCC.
Collapse
Affiliation(s)
- Fangfei Zhang
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Jetty Chung-Yung Lee
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Marsena Jasiel Ismaiah
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Hoi Kit Matthew Leung
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Dorothy Hin Lam Tsang
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China.
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, 70211, Finland.
| |
Collapse
|
2
|
Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
Collapse
Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| |
Collapse
|
3
|
Xiong K, Huang K, Liu Y, Pang H, Chen P, Zheng Y, Li T, Li Z, Zhang M, Zheng D, Huang X, Cao M, Li Q, Liang J, Fan H, Li D, Sun J, Wen Z, Jiang Y. Efficacy and safety of TACE combined with TKIs and PD-1 inhibitors in HCC patients with prior TIPS. Front Oncol 2025; 15:1570029. [PMID: 40342829 PMCID: PMC12058502 DOI: 10.3389/fonc.2025.1570029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Purpose To compare the efficacy and safety of TACE combined with TKIs and PD-1 inhibitors between HCC patients with and without prior TIPS. Methods This retrospective propensity score matching (PSM) study included advanced HCC patients treated with prior TIPS followed by TKIs, PD-1 inhibitors, and TACE between January 2021 and January 2023. Patients were matched with a control group of HCC patients who had not undergone TIPS (non-TIPS). Outcome measures included objective response rate (ORR) using modified RECIST (mRECIST v1.1), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety assessed by CTCAE v5.0. Results A total of 172 patients were included before PSM. After PSM, 42 patients with prior TIPS were matched with 71 non-TIPS patients. ORR was 31.0% in the TIPS group and 57.7% in the non-TIPS group (p = 0.007), Both PFS and OS were longer in the non-TIPS group, with a median PFS of 7.9 months for TIPS patients versus 12.3 months for non-TIPS patients (hazard ratio [HR] = 2.253, p < 0.001), and a median OS of 13.5 months versus 21.1 months, respectively (HR = 2.282, p = 0.002). Treatment-related adverse events showed no significant differences between the two groups. Conclusion TACE combined with TKIs and PD-1 inhibitors showed lower efficacy in HCC patients with prior TIPS, but it remains a viable option, providing a favorable safety profile and effective disease control.
Collapse
Affiliation(s)
- Kai Xiong
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Kuiyuan Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Yulong Liu
- Department of Vascular Intervention, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Huajin Pang
- Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yalu Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Tengzheng Li
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Zhangyun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Moran Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Dandan Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaohong Huang
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Mingrong Cao
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Qiang Li
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Junjie Liang
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Huizhen Fan
- Department of Gastroenterology, The People′s Hospital of Yichun City, Yichun, Jiangxi, China
| | - Deju Li
- Department of Vascular Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Jian Sun
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Zhili Wen
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Yuchuan Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| |
Collapse
|
4
|
Liu X, Pan B, Ding J, Zhai X, Hong J, Zheng J. Identifying potential signatures of immune cells in hepatocellular carcinoma using integrative bioinformatics approaches and machine-learning strategies. Immunol Res 2025; 73:46. [PMID: 39904830 DOI: 10.1007/s12026-024-09585-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 12/24/2024] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor regulated by the immune system. Immunotherapy using checkpoint inhibitors has shown encouraging outcomes in a subset of HCC patients. The main challenges in checkpoint immunotherapy for HCC are to expand treatment options and to broaden the beneficiary population. Therefore, the search for potential signatures of immune cells is meaningful in the development of immunotherapy for HCC. The HCC related datasets were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Differential expression analysis and functional analysis were performed first. Then support vector machine-recursive feature elimination (SVM-RFE), random forests (RF), least absolute shrinkage and selection operation (LASSO), and weighed gene co-expression network analysis (WGCNA) were employed to screen for critical genes, and receiver operating characteristic (ROC) analysis was performed to compare diagnostic performance. Subsequently, single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between signatures and immune cells. Finally, we validated the expression of these biomarkers in human HCC samples. 531 overlapping differentially expressed genes (DEGs) were identified. Furthermore, enrichment analysis revealed pathways associated with immune activation processes, immune cell involvement and inflammatory signaling. After using multiple machine-learning strategies, extracellular matrix protein 1 (ECM1), leukemia inhibitory factor receptor (LIFR), sushi repeat containing protein X-linked (SRPX), and thromboxane A2 receptor (TBXA2R) were identified as critical signatures, and exhibited high expression in tumor-adjacent normal tissues. According to the ssGSEA results, ECM1, LIFR, SRPX and TBXA2R were all significantly associated with diverse immune cells, such as monocytes and neutrophils. Moreover, immunostaining of human HCC samples showed that these critical signatures all colocalized with CD14-positive monocytes. Our findings report the potential signatures of immune cells in HCC and confirm that they localize in monocytes of tumor-adjacent normal tissues. ECM1, LIFR, SRPX and TBXA2R could become new potential targets for predictive diagnosis, early intervention and immunotherapy of HCC in the future.
Collapse
Affiliation(s)
- Xingchen Liu
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Bo Pan
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China
| | - Jie Ding
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Xiaofeng Zhai
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Jing Hong
- Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
- Department of Integrative Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Jianming Zheng
- Department of Pathology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| |
Collapse
|
5
|
Jiang Y, Chen J, Xu L, Lv L, Gan X. Development of a Novel four-gene Model for Monitoring the Progression from Metabolic Dysfunction-associated Steatotic Liver Disease to Hepatocellular Carcinoma in Males. J Cancer 2025; 16:917-931. [PMID: 39781352 PMCID: PMC11705051 DOI: 10.7150/jca.100724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/14/2024] [Indexed: 01/12/2025] Open
Abstract
The pathogenesis of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC) is complex and exhibits sex-specific differences. Effective methods for monitoring MASLD progression to HCC are lacking. Transcriptomic data from liver tissue samples sourced from multiple public databases were integrated. Utilizing both differential expression analysis and robust rank aggregation analysis, differentially expressed genes (DEGs) in patients with MASLD-HCC were identified. Based on these DEGs, diagnostic prediction models for MASLD (DP.MASLD) and HCC (DP.HCC) were constructed using elastic net analysis for various comparisons, including steatosis versus normal, steatohepatitis versus steatosis, and cancer versus non-cancer. Weighted gene correlation network analysis and gene set enrichment analysis were conducted to unveil the underlying pathogenesis of MASLD-HCC in males. Five overlapping DEGs with diagnostic significance in the progression from MASLD to HCC were identified, namely, AKR1B10, CYR61, FABP4, GNMT, and THBS1. DP.HCC demonstrated excellent predictive accuracy, with an area under the curve of 0.910 in the training group and 0.981 in the validation group. Similarly, DP.MASLD showed robust predictive accuracy. The pathogenesis of MASLD-HCC in males primarily involves extracellular matrix-receptor interaction, DNA replication, cell cycle, and T-cell receptor signaling. Overall, our study provides a quantitative assessment tool for the early detection and monitoring of MASLD-HCC, highlighting the male-specific molecular characteristics involved in its progression.
Collapse
Affiliation(s)
- Yuchuan Jiang
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China
| | - Jiejian Chen
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Lin Xu
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Lin Lv
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
| | - Xiaoning Gan
- Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China
- Department, University, City, Postcode, Country Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| |
Collapse
|
6
|
Xiao Y, Tao P, Zhang K, Chen L, Lv J, Chen Z, He L, Jia H, Sun J, Cao M, Hong J, Qu C. Myofibroblast-derived extracellular vesicles facilitate cancer stemness of hepatocellular carcinoma via transferring ITGA5 to tumor cells. Mol Cancer 2024; 23:262. [PMID: 39574133 PMCID: PMC11580229 DOI: 10.1186/s12943-024-02170-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 11/05/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Myofibroblasts constitute a significant component of the tumor microenvironment (TME) and play a pivotal role in the progression of hepatocellular carcinoma (HCC). Integrin α5 (ITGA5) is a crucial regulator in myofibroblasts of malignant tumors. Therefore, the potential of ITGA5 as a novel target for the therapeutic strategy of HCC should be investigated. METHODS Digital scanning and analysis of the HCC tissue microarray were performed to locate the distribution of ITGA5 and conduct the prognosis analysis. CRISPR Cas9-mediated ITGA5 knockout was performed to establish the ITGA5-KO myofibroblast cell line. Extracellular vesicles (EVs) derived from LX2 were extracted for the treatment of HCC cells. Subsequently, the sphere-forming ability and the stemness markers expression of the treated HCC cells were examined. An orthotopic HCC mouse model with fibrotic injury was constructed to test the outcomes of ITGA5-targeting therapy and its efficacy in the programmed death-ligand 1 (PD-L1) treatment. Co-immunoprecipitation/mass spectrometry and transcriptome data were integrated to delve into the mechanism. RESULTS The tissue microarray results revealed that ITGA5 was highly enriched in the stromal myofibroblasts of HCC tissues and contributed to enhanced tumor progression and poor prognosis. Notably, ITGA5 transmission via extracellular vesicles (EVs) from myofibroblasts to HCC cells induced the acquisition of cancer stem cell-like properties. Mechanistically, ITGA5 directly bind to YES1, facilitating the activation of YES1 and its downstream pathways, thereby enhancing the stemness of HCC cells. Furthermore, the blockade of ITGA5 impeded tumor progression driven by ITGA5+ myofibroblasts and enhanced the efficacy of treatment with PD-L1 in a mouse model of HCC. CONCLUSIONS Our findings elucidated a novel mechanism by which the EV-mediated transfer of ITGA5 from myofibroblasts to tumor cells augmented HCC stemness. ITGA5-targeting therapy helped prevent the progression of HCC and improved the efficacy of PD-L1 treatment.
Collapse
Affiliation(s)
- Yang Xiao
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China
- Endoscopy Department, Sichuan Cancer Center, Sichuan Cancer Hospital and Institute, Affiliate Cancer Hospital of University of Electronic Science and Technology of China (UESTC), Chengdu, 610000, China
| | - Ping Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Keke Zhang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China
| | - Liuyan Chen
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China
| | - Jinyu Lv
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China
| | - Zhiwei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Lu He
- Department of Radiotherapy, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510000, China
| | - Hongling Jia
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510000, China
| | - Jian Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Mingrong Cao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China
| | - Jian Hong
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, China.
| | - Chen Qu
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510000, China.
| |
Collapse
|
7
|
Zhang QY, Ding W, Mo JS, Ou-Yang SM, Lin ZY, Peng KR, Liu GP, Lu JJ, Yue PB, Lei JP, Wang YD, Zhang XL. Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma. Acta Pharmacol Sin 2024; 45:1701-1714. [PMID: 38609562 PMCID: PMC11272795 DOI: 10.1038/s41401-024-01261-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 03/03/2024] [Indexed: 04/14/2024]
Abstract
Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.
Collapse
Affiliation(s)
- Qi-Yi Zhang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Wen Ding
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jian-Shan Mo
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Shu-Min Ou-Yang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Zi-You Lin
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ke-Ren Peng
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Guo-Pin Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Pei-Bin Yue
- Department of Medicine, Division of Hematology-Oncology, and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Jin-Ping Lei
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yan-Dong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
| | - Xiao-Lei Zhang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
| |
Collapse
|
8
|
Lu Y, Cen Y, He X, Mo X, Luo F, Zhong Y. Magnetic resonance imaging-based rim enhancement could effectually predict poor prognosis in hepatocellular carcinoma: a meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:505-512. [PMID: 38555599 PMCID: PMC10965130 DOI: 10.1097/meg.0000000000002727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/06/2023] [Indexed: 04/02/2024]
Abstract
Recent studies have initially shown that MRI-based rim enhancement associates with poor prognosis in hepatocellular carcinoma (HCC) patients, but their sample sizes are small, leading to a necessary of comprehensive analyses to make a relatively solid statement. Thus, this meta-analysis aimed to summarize the correlation between MRI-based rim enhancement and prognosis in HCC patients. Until March 2023, a literature search was conducted on Web of Science, PubMed, EMBASE, Cochrane, CNKI, Wangfang, and CQVIP databases in order to identify studies that report the correlation between MRI-based rim enhancement and the prognosis of HCC patients. MRI-based rim enhancement and prognostic data were extracted and analyzed. In our study, eight studies containing 1816 HCC patients were analyzed. Generally, the presence of MRI-based rim enhancement was related to shortened disease-free survival (DFS) [hazard ratio (HR): 2.77, 95% confidence interval (CI): 2.11-3.62, P < 0.001], and worse overall survival (OS) (HR: 5.43, 95% CI: 2.14-13.79, P < 0.001). While no other prognostic data could be retrieved. Funnel plots, Begg's test, and Egger's test all indicated that no publication bias existed; and the risk score by Newcastle-Ottawa Scale criteria ranged from 7-9 points, suggesting a generally low risk of bias. Meanwhile, the sensitivity analysis showed that the significant findings did not change by omitting each study. Then, subgroup analyses revealed that no matter stratified by tumor size, treatment option, or sample size, rim enhancement was linked with unsatisfied DFS (all P < 0.05). Conclusively, MRI-based rim enhancement could effectually estimate poor survival in HCC patients, indicating its good prognostic value.
Collapse
Affiliation(s)
- Yumin Lu
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Yongyi Cen
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Xin He
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaping Mo
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Fang Luo
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Yubao Zhong
- Department of Radiology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| |
Collapse
|
9
|
Chen J, Sun S, Li H, Cai X, Wan C. IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis. Front Immunol 2024; 15:1373321. [PMID: 38596684 PMCID: PMC11003268 DOI: 10.3389/fimmu.2024.1373321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/12/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. Methods The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Results Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Conclusions Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.
Collapse
Affiliation(s)
- Junzhang Chen
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiran Sun
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Li
- Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiong Cai
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chidan Wan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
10
|
Li J, Zhang L, Ge T, Liu J, Wang C, Yu Q. Understanding Sorafenib-Induced Cardiovascular Toxicity: Mechanisms and Treatment Implications. Drug Des Devel Ther 2024; 18:829-843. [PMID: 38524877 PMCID: PMC10959117 DOI: 10.2147/dddt.s443107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 03/09/2024] [Indexed: 03/26/2024] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have been recognized as crucial agents for treating various tumors, and one of their key targets is the intracellular site of the vascular endothelial growth factor receptor (VEGFR). While TKIs have demonstrated their effectiveness in solid tumor patients and increased life expectancy, they can also lead to adverse cardiovascular effects including hypertension, thromboembolism, cardiac ischemia, and left ventricular dysfunction. Among the TKIs, sorafenib was the first approved agent and it exerts anti-tumor effects on hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) by inhibiting angiogenesis and tumor cell proliferation through targeting VEGFR and RAF. Unfortunately, the adverse cardiovascular effects caused by sorafenib not only affect solid tumor patients but also limit its application in curing other diseases. This review explores the mechanisms underlying sorafenib-induced cardiovascular adverse effects, including endothelial dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated autophagy, and ferroptosis. It also discusses potential treatment strategies, such as antioxidants and renin-angiotensin system inhibitors, and highlights the association between sorafenib-induced hypertension and treatment efficacy in cancer patients. Furthermore, emerging research suggests a link between sorafenib-induced glycolysis, drug resistance, and cardiovascular toxicity, necessitating further investigation. Overall, understanding these mechanisms is crucial for optimizing sorafenib therapy and minimizing cardiovascular risks in cancer patients.
Collapse
Affiliation(s)
- Jue Li
- Engineering Research Center of Brain Health Industry of Chinese Medicine, Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Pharmacology of Chinese medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China
| | - Lusha Zhang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases and Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, 710021, People’s Republic of China
| | - Teng Ge
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases and Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, 710021, People’s Republic of China
| | - Jiping Liu
- Engineering Research Center of Brain Health Industry of Chinese Medicine, Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Pharmacology of Chinese medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China
| | - Chuan Wang
- Engineering Research Center of Brain Health Industry of Chinese Medicine, Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Pharmacology of Chinese medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China
| | - Qi Yu
- Engineering Research Center of Brain Health Industry of Chinese Medicine, Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine, Pharmacology of Chinese medicine, Shaanxi University of Chinese Medicine, Xianyang, 712046, People’s Republic of China
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases and Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, 710021, People’s Republic of China
| |
Collapse
|
11
|
Morkunas E, Vaitkeviciute E, Varkalaite G, Pilvinis V, Skieceviciene J, Kupcinskas J. Diagnostic and Prognostic Value of IL-10, FABP2 and LPS Levels in HCC Patients. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2191. [PMID: 38138294 PMCID: PMC10744942 DOI: 10.3390/medicina59122191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023]
Abstract
Hepatocellular carcinoma (HCC) still lacks valuable diagnostic and prognostic tools. This study aimed to investigate the potential diagnostic and prognostic value of baseline interleukin (IL)-10, fatty acid-binding protein 2 (FABP2) and lipopolysaccharide (LPS) levels in patients with HCC. Serum levels of IL-10, FABP2 and LPS in 47 newly diagnosed HCC patients and 50 healthy individuals were estimated and compared. The best cut-off points for baseline IL-10, FABP2 and LPS levels predicting overall survival (OS) were evaluated. Both levels of FABP2 and IL-10 were significantly higher in HCC patients vs. control group (median 2095 vs. 1772 pg/mL, p = 0.026; 9.94 vs. 4.89 pg/mL, p < 0.001) and may serve as potential biomarkers in complex HCC diagnostic tools. The cut-off value of 2479 pg/mL for FABP2 was determined to have the highest sensitivity (66.7%) and specificity (55.6%) to distinguish patients with a median OS longer than 17 months. However, the median OS of patients with high and low levels of FABP2 were not significantly different (p = 0.896). The prognostic value of LPS as well as FABP2 and IL-10 for HCC patients appears to be limited.
Collapse
Affiliation(s)
- Egidijus Morkunas
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
| | - Evelina Vaitkeviciute
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (E.V.)
| | - Greta Varkalaite
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (E.V.)
| | - Vidas Pilvinis
- Department of Anesthesiology, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (E.V.)
| | - Juozas Kupcinskas
- Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (E.V.)
| |
Collapse
|
12
|
Jain S, Rana M. From the discovery of helminths to the discovery of their carcinogenic potential. Parasitol Res 2023; 123:47. [PMID: 38095695 DOI: 10.1007/s00436-023-08022-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023]
Abstract
Cancer involves a major aberration in the normal behaviour of cells, making them divide continuously, which interferes with the normal physiology of the body. The link between helminths and their cancer-inducing potential has been proposed in the last century. The exact pathway is still not clear but chronic inflammation in response to the deposited eggs, immune response against soluble egg antigens, and co-infection with a third party (a bacteria, a virus, or infection leading to a change in microbiome) seems to be the reasons for cancer induction. This review looks into the historical outlook on helminths along with their epidemiology, morphology, and life cycle. It then focuses on providing correlations between helminth infection and molecular mechanism of carcinogenesis by elaborating upon epidemiological, clinical, and surgical studies. While the cancer-inducing potential has been convincingly established only for a few helminths and studies point out towards possible cancer-inducing ability of the rest of the helminths elucidated in this work, however, more insights into the immunobiology of helminths as well as infected patients are required to conclusively comment upon this ability of the latter.
Collapse
Affiliation(s)
- Sidhant Jain
- Institute for Globally Distributed Open Research and Education (IGDORE), Rewari, Haryana, India.
| | - Meenakshi Rana
- Dyal Singh College, University of Delhi, Lodhi Road, Pragati Vihaar, New Delhi, India
| |
Collapse
|
13
|
Sun SQ, Du FX, Zhang LH, Hao-Shi, Gu FY, Deng YL, Ji YZ. Prevention of STAT3-related pathway in SK-N-SH cells by natural product astaxanthin. BMC Complement Med Ther 2023; 23:430. [PMID: 38031104 PMCID: PMC10685499 DOI: 10.1186/s12906-023-04267-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 11/20/2023] [Indexed: 12/01/2023] Open
Abstract
PURPOSE Neuroblastoma (NB) is the most common solid malignancy in children. Despite current intensive treatment, the long-term event-free survival rate is less than 50% in these patients. Thus, patients with NB urgently need more valid treatment strategies. Previous research has shown that STAT3 may be an effective target in high-risk NB patients. However, there are no effective inhibitors in clinical evaluation with low toxicity and few side effects. Astaxanthin is a safe and natural anticancer product. In this study, we investigated whether astaxanthin could exert antitumor effects in the SK-N-SH neuroblastoma cancer cell line. METHOD MTT and colony formation assays were used to determine the effect of astaxanthin on the proliferation and colony formation of SK-N-SH cells. Flow cytometry assays were used to detect the apoptosis of SK-N-SH cells. The migration and invasion ability of SK-N-SH cells were detected by migration and invasion assays. Western blot and RT-PCR were used to detect the protein and mRNA levels. Animal experiments were carried out and cell apoptosis in tissues were assessed using a TUNEL assay. RESULT We confirmed that astaxanthin repressed proliferation, clone formation ability, migration and invasion and induced apoptosis in SK-N-SH cells through the STAT3 pathway. Furthermore, the highest inhibitory effect was observed when astaxanthin was combined with si-STAT3. The reason for this may be that the combination of astaxanthin and si-STAT3 can lower STAT3 expression further than astaxanthin or si-STAT3 alone. CONCLUSION Astaxanthin can exert anti-tumor effect on SK-N-SH cells. The inhibitory effect was the higher when astaxanthin was combined with si-STAT3.
Collapse
Affiliation(s)
- Shao-Qian Sun
- School of Medical Technology, Beijing Institute of Technology, No. 5 Zhongguancun South Street, Haidian District, Beijing, 100081, China
| | - Feng-Xiang Du
- Biochemical Engineering College, Beijng Union University, Beijing, 100023, China
| | - Li-Hua Zhang
- Biochemical Engineering College, Beijng Union University, Beijing, 100023, China
| | - Hao-Shi
- Biochemical Engineering College, Beijng Union University, Beijing, 100023, China
| | - Fu-Ying Gu
- Biochemical Engineering College, Beijng Union University, Beijing, 100023, China
| | - Yu-Lin Deng
- School of Medical Technology, Beijing Institute of Technology, No. 5 Zhongguancun South Street, Haidian District, Beijing, 100081, China.
| | - Yi-Zhi Ji
- Biochemical Engineering College, Beijng Union University, Beijing, 100023, China.
| |
Collapse
|
14
|
Zhang Y, Jin F, Wu Y, Wang B, Xie J, Li Y, Pan Y, Liu Z, Shen W. Prognostic impact of gamma-glutamyl transpeptidase to platelets ratio on hepatocellular carcinoma patients who have undergone surgery: a meta-analysis and systematic review. Eur J Gastroenterol Hepatol 2023; 35:803-811. [PMID: 37395231 DOI: 10.1097/meg.0000000000002572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Gamma-glutamyl transpeptidase to platelet ratio (GPR) is an inflammatory index and has been used as a prognostic index for a variety of tumors. However, the association between GPR and hepatocellular carcinoma (HCC) still remained controversial. Therefore, we performed a meta-analysis to determine the prognostic impact of GPR on HCC patients. PubMed, Embase, Cochrane Library, Web of Science, the Chinese National Knowledge Infrastructure, Wanfang Database, Chinese VIP Database, the US Clinical Trials Registry, and the Chinese Clinical Trials Registry were searched from inception to December 2022. A hazard ratio (HR) with a 95% confidence interval (CI) was used to evaluate the association between preoperative GPR and the prognosis of HCC patients. Ten cohort studies including 4706 HCC patients were identified. This meta-analysis showed that higher GPRs were closely related to worse overall survival (HR: 1.79; 95% CI: 1.35-2.39; P < 0.001; I2 = 82.7%), recurrence-free survival (HR: 1.30; 95% CI: 1.16-1.46; P < 0.001; I2 = 0%), and disease-free survival (HR: 1.84; 95% CI: 1.58-2.15; P < 0.001; I2 = 25.4%) in patients with HCC. This meta-analysis suggests that preoperative GPR appears to be significantly associated with the prognosis of HCC patients who have undergone surgery and may be an effective prognostic marker. Trial registration: PROSPERO: CRD42021296219.
Collapse
Affiliation(s)
- Yang Zhang
- Department of Internal Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine
| | - Fangfang Jin
- Department of Internal Medicine, Heilongjiang University of Chinese Medicine
| | - Yuan Wu
- Department of Internal Medicine, Heilongjiang University of Chinese Medicine
| | - Bingyu Wang
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine
| | - Jingri Xie
- Department of Internal Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine
| | - Yu Li
- Department of Oncology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin
| | - Yujia Pan
- Cixi People's Hospital Medical and Health Group, Ningbo
| | - Zhaolan Liu
- Evidence Based Medicine Center, Beijing University of Chinese Medicine, Beijing
| | - Wenjuan Shen
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
15
|
Engel BJ, Paolillo V, Uddin MN, Gonzales KA, McGinnis KM, Sutton MN, Patnana M, Grindel BJ, Gores GJ, Piwnica-Worms D, Beretta L, Pisaneschi F, Gammon ST, Millward SW. Gender Differences in a Mouse Model of Hepatocellular Carcinoma Revealed Using Multi-Modal Imaging. Cancers (Basel) 2023; 15:3787. [PMID: 37568603 PMCID: PMC10417617 DOI: 10.3390/cancers15153787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
The worldwide incidence of hepatocellular carcinoma (HCC) continues to rise, in part due to poor diet, limited exercise, and alcohol abuse. Numerous studies have suggested that the loss or mutation of PTEN plays a critical role in HCC tumorigenesis through the activation of the PI3K/Akt signaling axis. The homozygous knockout of PTEN in the livers of mice results in the accumulation of fat (steatosis), inflammation, fibrosis, and eventually progression to HCC. This phenotype bears a striking similarity to non-alcoholic steatohepatitis (NASH) which is thought to occupy an intermediate stage between non-alcoholic fatty liver disease (NAFLD), fibrosis, and HCC. The molecular and physiological phenotypes that manifest during the transition to HCC suggest that molecular imaging could provide a non-invasive screening platform to identify the hallmarks of HCC initiation prior to the presentation of clinical disease. We have carried out longitudinal imaging studies on the liver-specific PTEN knockout mouse model using CT, MRI, and multi-tracer PET to interrogate liver size, steatosis, inflammation, and apoptosis. In male PTEN knockout mice, significant steatosis was observed as early as 3 months using both magnetic resonance spectroscopy (MRS) and computed tomography (CT). Enhanced uptake of the apoptosis tracer 18F-TBD was also observed in the livers of male PTEN homozygous knockout mice between 3 and 4 months of age relative to heterozygous knockout controls. Liver uptake of the inflammation tracer [18F]4FN remained relatively low and constant over 7 months in male PTEN homozygous knockout mice, suggesting the suppression of high-energy ROS/RNS with PTEN deletion relative to heterozygous males where the [18F]4FN liver uptake was elevated at early and late time points. All male PTEN homozygous mice developed HCC lesions by month 10. In contrast to the male cohort, only 20% (2 out of 10) of female PTEN homozygous knockout mice developed HCC lesions by month 10. Steatosis was significantly less pronounced in the female PTEN homozygous knockout mice relative to males and could not accurately predict the eventual occurrence of HCC. As with the males, the [18F]4FN uptake in female PTEN homozygous knockout mice was low and constant throughout the time course. The liver uptake of 18F-TBD at 3 and 4.5 months was higher in the two female PTEN knockout mice that would eventually develop HCC and was the most predictive imaging biomarker for HCC in the female cohort. These studies demonstrate the diagnostic and prognostic role of multi-modal imaging in HCC mouse models and provide compelling evidence that disease progression in the PTEN knockout model is highly dependent on gender.
Collapse
Affiliation(s)
- Brian J. Engel
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vincenzo Paolillo
- Cyclotron Radiochemistry Facility, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Md. Nasir Uddin
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kristyn A. Gonzales
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kathryn M. McGinnis
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Margie N. Sutton
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Madhavi Patnana
- Department of Abdominal Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Brian J. Grindel
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | | | - David Piwnica-Worms
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Federica Pisaneschi
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM) at the University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Seth T. Gammon
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Steven W. Millward
- Department of Cancer Systems Imaging, UT MD Anderson Cancer Center, Houston, TX 77030, USA
| |
Collapse
|
16
|
Hashemi M, Sabouni E, Rahmanian P, Entezari M, Mojtabavi M, Raei B, Zandieh MA, Behroozaghdam M, Mirzaei S, Hushmandi K, Nabavi N, Salimimoghadam S, Ren J, Rashidi M, Raesi R, Taheriazam A, Alexiou A, Papadakis M, Tan SC. Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance. Cell Mol Biol Lett 2023; 28:33. [PMID: 37085753 PMCID: PMC10122325 DOI: 10.1186/s11658-023-00438-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/15/2023] [Indexed: 04/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial-mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Eisa Sabouni
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Behnaz Raei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Arad Zandieh
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mitra Behroozaghdam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| |
Collapse
|
17
|
Lai HC, Lin HJ, Jeng LB, Huang ST. Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:19-35. [PMID: 36684056 PMCID: PMC9850766 DOI: 10.4251/wjgo.v15.i1.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 12/07/2022] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths in the world. HCC has a reported recurrence rate of 70%-80% after 5 years of follow-up. Controlling tumor recurrence is the most critical factor associated with HCC mortality. Conventional salvage therapies for recurrent HCC include re-hepatectomy or liver transplantation, transcatheter arterial chemoembolization, Y-90, target therapy, and immunotherapy; however, these conventional treatment modalities have yet to achieve consistently favorable outcomes. Meanwhile, previous studies have demonstrated that conventional therapies in combination with traditional Chinese medicine (TCM), acupuncture, moxibustion or dietary supplements could notably benefit patients with HCC recurrence by strengthening and augmenting the overall management strategy. However, systemic reviews related to the interactions between complementary therapies and conventional therapy in recurrent HCC are limited. In this review, we discuss the molecular mechanisms underlying the functions of complementary therapies for recurrent HCC, which include augmenting the local control to improve the congestion status of primary tumors and reducing multicentric tumor occurrence via inducing autophagy, apoptosis or cell cycle arrest. TCM and its derivatives may play important roles in helping to control HCC recurrence by inhibiting epithelial-mesenchymal transition, migration, invasion, and metastasis, inhibiting cancer stem cells, and ameliorating drug resistance.
Collapse
Affiliation(s)
- Hsiang-Chun Lai
- Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40447, Taiwan
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan
| | - Hung-Jen Lin
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 40447, Taiwan
| | - Sheng-Teng Huang
- Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40447, Taiwan
- Cancer Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
- An-Nan Hospital, China Medical University, Tainan 709204, Taiwan
| |
Collapse
|
18
|
Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
Collapse
Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
| |
Collapse
|
19
|
Tian X, Yan T, Liu F, Liu Q, Zhao J, Xiong H, Jiang S. Link of sorafenib resistance with the tumor microenvironment in hepatocellular carcinoma: Mechanistic insights. Front Pharmacol 2022; 13:991052. [PMID: 36071839 PMCID: PMC9441942 DOI: 10.3389/fphar.2022.991052] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 07/25/2022] [Indexed: 11/26/2022] Open
Abstract
Sorafenib, a multi-kinase inhibitor with antiangiogenic, antiproliferative, and proapoptotic properties, is the first-line treatment for patients with late-stage hepatocellular carcinoma (HCC). However, the therapeutic effect remains limited due to sorafenib resistance. Only about 30% of HCC patients respond well to the treatment, and the resistance almost inevitably happens within 6 months. Thus, it is critical to elucidate the underlying mechanisms and identify effective approaches to improve the therapeutic outcome. According to recent studies, tumor microenvironment (TME) and immune escape play critical roles in tumor occurrence, metastasis and anti-cancer drug resistance. The relevant mechanisms were focusing on hypoxia, tumor-associated immune-suppressive cells, and immunosuppressive molecules. In this review, we focus on sorafenib resistance and its relationship with liver cancer immune microenvironment, highlighting the importance of breaking sorafenib resistance in HCC.
Collapse
Affiliation(s)
- Xinchen Tian
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tinghao Yan
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fen Liu
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Qingbin Liu
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Jing Zhao
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining, China
- *Correspondence: Huabao Xiong, ; Shulong Jiang,
| | - Shulong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Huabao Xiong, ; Shulong Jiang,
| |
Collapse
|
20
|
Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, Sabet S, Khoshbakht MA, Hashemi M, Hushmandi K, Sethi G, Zarrabi A, Kumar AP, Tan SC, Papadakis M, Alexiou A, Islam MA, Mostafavi E, Ashrafizadeh M. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol 2022; 15:83. [PMID: 35765040 PMCID: PMC9238168 DOI: 10.1186/s13045-022-01305-4] [Citation(s) in RCA: 317] [Impact Index Per Article: 105.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/13/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment.
Collapse
Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohamad Javad Naghdi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sina Sabet
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Amin Khoshbakht
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey.
| |
Collapse
|
21
|
Marin JJG, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Sanchez-Martin A, Fabris L, Briz O. Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems. Semin Liver Dis 2022; 42:87-103. [PMID: 34544160 DOI: 10.1055/s-0041-1735631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.
Collapse
Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Department of Internal Medicine, Yale Liver Center (YLC), School of Medicine, Yale University New Haven, Connecticut
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| |
Collapse
|
22
|
Dai Z, Wang X, Peng R, Zhang B, Han Q, Lin J, Wang J, Lin J, Jiang M, Liu H, Lee TH, Lu KP, Zheng M. Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma. Cancer Lett 2022; 524:161-171. [PMID: 34687791 DOI: 10.1016/j.canlet.2021.10.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/24/2021] [Accepted: 10/17/2021] [Indexed: 12/24/2022]
Abstract
Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed. Interleukin-6 receptor alpha (IL-6Rα) is the receptor of IL-6, a multi-functional cytokine, which plays key roles in liver-regeneration, inflammation and development of hepatocellular carcinoma (HCC). Here we show the expression of IL-6Rα was induced in response to sorafenib. Depletion of IL-6Rα abolished IL-6 induced STAT3 phosphorylation at 705th tyrosine and tumor growth of HCC cells under sorafenib treatment. Mechanistically, activating transcription factor 3 (ATF3) was induced in response to sorafenib and subsequently bound to the promoter of IL-6Rα, leading to its transcriptional activation. Depletion of ATF3 or its upstream transcription factor, ATF4, attenuated IL-6Rα induction and IL-6 mediated sorafenib resistance. The ATF4-ATF3-IL-6Rα cascade is also activated by regorafenib. Furthermore, blockade of IL-6Rα with the FDA approved IL-6Rα antibody drug, Sarilumab, drastically attenuated both sorafenib and regorafenib resistance in patient-derived xenograft (PDX) tumors, where human IL-6 could be detected by a novel in situ hybridization technique, named RNAscope. Together, our data reveal that ATF3-mediated IL-6Rα up-regulation promotes both sorafenib and regorafenib resistance in HCC, and targeting IL-6Rα represents a novel therapeutic strategy to enhance sorafenib/regorafenib efficacy for advanced HCC treatment.
Collapse
Affiliation(s)
- Zichan Dai
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Xiaohan Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Rangxin Peng
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Binghui Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Qi Han
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Jie Lin
- Shengli Clinical Medical College, Fujian Medical University & Department of Pathology, Fujian Provincial Hospital, Fujian, PR China
| | - Jichuang Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Junjin Lin
- Public Technology Service Center, Fujian Medical University, Fujian, PR China
| | - Mingting Jiang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Hekun Liu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Kun Ping Lu
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Min Zheng
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China; Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China.
| |
Collapse
|
23
|
Zhang W, Wang Y, Dong X, Yang B, Zhou H, Chen L, Zhang Z, Zhang Q, Cao G, Han Z, Li H, Cui Y, Wu Q, Zhang T, Song T, Li Q. Elevated serum CA19-9 indicates severe liver inflammation and worse survival after curative resection in hepatitis B-related hepatocellular carcinoma. Biosci Trends 2021; 15:397-405. [PMID: 34880159 DOI: 10.5582/bst.2021.01517] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
We explored the prognostic value of preoperative CA19-9 in α-fetoprotein (AFP)-positive and -negative HCC with hepatitis B virus (HBV) background (HBV-HCC), and explored the underlying mechanism. Recurrence-free survival (RFS) and overall survival (OS) were assessed in HBV-HCC patients who underwent curative resection (Cohort 1). Immunohistochemical staining of CA19-9 in HCC and liver parenchyma were quantified in another cohort of 216 patients with resected HCC (Cohort 2). Immunohistochemical staining of CA19-9 and serum CA19-9 level was also compared between patients with HCC and intrahepatic cholangiocarcinoma (ICC) (Cohort 3). In Cohort 1, CA19-9 ≥ 39 U/mL was an independent risk factor for RFS (HR = 1.507, 95% CI = 1.087-2.091, p = 0.014) and OS (HR = 1.646, 95% CI = 1.146-2.366, p = 0.007). CA19-9 ≥ 39 U/mL was also associated with significantly higher incidence of macrovascular invasion (MaVI) compared with CA19-9 < 39 U/mL (23.0% vs. 7.2%, p = 0.002), and elevated aminotransferase and aspartate aminotransferase to platelet ratio index (APRI), and lower albumin. Immunohistochemical staining of CA19-9 revealed that CA19-9 expression was found exclusively in the background liver but not in HCC tumor cells. In contrast, tumor tissue was the main source of CA19-9 in ICC patients. CA19-9 ≥ 39 U/mL was associated with worse OS and RFS in both AFP-positive and negative HCC patients. CA19-9 indicated more severe inflammation and cirrhosis in the liver of HCC patients.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yingying Wang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiang Dong
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Department of Department of General Surgery, Hebei Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou City, Hebei Province, China
| | - Bo Yang
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Hongyuan Zhou
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Lu Chen
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zewu Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qin Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Guangtai Cao
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhiqiang Han
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Huikai Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Wu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China
| |
Collapse
|
24
|
Ding H, Huang Y, Shi J, Wang L, Liu S, Zhao B, Liu Y, Yang J, Chen Z. Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation. Cancer Cell Int 2021; 21:655. [PMID: 34876150 PMCID: PMC8650342 DOI: 10.1186/s12935-021-02363-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 11/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND SWI/SNF, a well-known ATP-dependent chromatin-remodeling complex, plays an essential role in several biological processes. SNF5, the core subunit of the SWI/SNF remodeling complex, inactivated in 95% of malignant rhabdoid tumors (MRT), highlighting its significance in tumorigenesis. However, the role of SNF5 in bladder cancer (BC) remains unknown. In this study, we aimed to investigate the function and potential clinical applicability of SNF5 in BC. METHODS Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were used to evaluate the clinical significance of SNF5 in BC. We performed Gene Set Enrichment Analysis (GSEA) and functional assays to investigate the role of SNF5 in BC. Genomics of Drug Sensitivity in Cancer (GDSC) and drug-susceptibility tests were performed to identify the potential value of SNF5 in the treatment of BC. RESULTS Low SNF5 expression conferred a poor prognosis and was significantly associated with the N-stage in BC. ROC curves indicated that SNF5 could distinguish BC from the normal tissues. In vitro and in vivo functional assays demonstrated that attenuated SNF5 expression could promote cell proliferation and enhance migration by STAT3 activation. We imputed that low SNF5 expression could confer greater resistance against conventional first-line drugs, including cisplatin and gemcitabine in BC. GDSC and drug-resistance assays suggested that low SNF5 expression renders T24 and 5637 cells high sensitivity to EGFR inhibitor gefitinib, and combination of EZH2 inhibitor GSK126 and cisplatin. CONCLUSIONS To the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.
Collapse
Affiliation(s)
- Hua Ding
- Department of Urology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yaqin Huang
- Department of Cell Biology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Jiazhong Shi
- Department of Cell Biology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Liwei Wang
- Department of Urology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.,Unit 32357 of People's Liberation Army, Pujiang, 611630, China
| | - Sha Liu
- Department of Cell Biology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Baixiong Zhao
- Department of Urology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yuting Liu
- Department of Cell Biology, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Jin Yang
- Department of Cell Biology, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Zhiwen Chen
- Department of Urology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| |
Collapse
|
25
|
Shi Y, Liu JB, Deng J, Zou DZ, Wu JJ, Cao YH, Yin J, Ma YS, Da F, Li W. The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma. Hereditas 2021; 158:44. [PMID: 34758879 PMCID: PMC8582193 DOI: 10.1186/s41065-021-00208-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/12/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide due to its high degree of malignancy, high incidence, and low survival rate. However, the underlying mechanisms of hepatocarcinogenesis remain unclear. Long non coding RNA (lncRNA) has been shown as a novel type of RNA. lncRNA by acting as ceRNA can participate in various biological processes of HCC cells, such as tumor cell proliferation, migration, invasion, apoptosis and drug resistance by regulating downstream target gene expression and cancer-related signaling pathways. Meanwhile, lncRNA can predict the efficacy of treatment strategies for HCC and serve as a potential target for the diagnosis and treatment of HCC. Therefore, lncRNA serving as ceRNA may become a vital candidate biomarker for clinical diagnosis and treatment. In this review, the epidemiology of HCC, including morbidity, mortality, regional distribution, risk factors, and current treatment advances, was briefly discussed, and some biological functions of lncRNA in HCC were summarized with emphasis on the molecular mechanism and clinical application of lncRNA-mediated ceRNA regulatory network in HCC. This paper can contribute to the better understanding of the mechanism of the influence of lncRNA-mediated ceRNA networks (ceRNETs) on HCC and provide directions and strategies for future studies.
Collapse
Affiliation(s)
- Yi Shi
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China.,Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Ji-Bin Liu
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China
| | - Jing Deng
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China
| | - Da-Zhi Zou
- Department of Spine Surgery, Longhui County People's Hospital, Longhui, 422200, Hunan, China
| | - Jian-Jun Wu
- Nantong Haimen Yuelai Health Centre, Haimen, 226100, China
| | - Ya-Hong Cao
- Department of Respiratory, Nantong Traditional Chinese Medicine Hospital, Nantong, 226019, Jiangsu Province, China
| | - Jie Yin
- Department of General Surgery, Haian people's Hospital, Haian, 226600, Jiangsu, China
| | - Yu-Shui Ma
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China.
| | - Fu Da
- Cancer Institute, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
| | - Wen Li
- College of Life Sciences and Chemistry, Hunan University of Technology, Zhuzhou, 412007, Hunan, China. .,National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, Hunan, China.
| |
Collapse
|
26
|
Miyata T, Hayashi H, Yamashita YI, Matsumura K, Higashi T, Imai K, Nitta H, Chikamoto A, Beppu T, Baba H. The Impact of Histologic Liver Inflammation on Oncology and the Prognosis of Patients Undergoing Hepatectomy for Hepatocellular Carcinoma. Ann Surg Oncol 2021; 29:893-902. [PMID: 34595665 DOI: 10.1245/s10434-021-10706-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 07/03/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-γ-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.
Collapse
Affiliation(s)
- Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hidetoshi Nitta
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Chikamoto
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Toru Beppu
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.,Department of Surgery, Yamaga City Medical Center, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
| |
Collapse
|
27
|
Liu MM, Chen ZH, Zhao LY, Zhao JY, Rong DL, Ma XK, Ruan DY, Lin JX, Qi JJ, Hu PS, Wen JY, Chen J, Lin Q, Wu XY, Wei L, Dong M. Prognostic Value of Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Propensity Score-Matched Analysis. Oncol Res Treat 2021; 44:450-468. [PMID: 34380137 DOI: 10.1159/000517735] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 04/26/2021] [Indexed: 01/17/2023]
Abstract
INTRODUCTION The prognosis of advanced hepatocellular carcinoma (HCC) varies in patients receiving transcatheter arterial chemoembolization (TACE). In this study, we aimed to assess the prognostic value of serum apolipoprotein B (ApoB)/apolipoprotein A-I (ApoA-I) in this group of patients. METHODS The serum lipid levels of HCC patients undergoing TACE were obtained from routine preoperative blood lipid examination. A propensity score-matched (PSM) analysis was used to eliminate the imbalance of baseline characteristics of the high and low ApoB/ApoA-I groups. Then, univariate and multivariate analysis were conducted to evaluate the prognostic value of ApoB/ApoA-I. RESULTS In 455 HCC patients treated with TACE, ApoB/ApoA-I was positively correlated with AFP, T stage, distant metastasis, and TNM stage (p < 0.05). Patients with high ApoB/ApoA-I had a significantly shorter overall survival (OS) than those with low ApoB/ApoA-I (median OS, 21.7 vs. 39.6 months, p < 0.001). Multivariate analysis indicated that ApoB/ApoA-I was an independent prognostic index for OS (hazard ratio [HR] = 1.42, p = 0.008). After baseline characteristics were balanced, 288 patients were included in the PSM cohort. In this cohort, high ApoB/ApoA-I still predicted inferior OS in both univariate analysis (median OS, 27.6 vs. 39.3 months, p = 0.002) and multivariate analysis (HR = 1.58, p = 0.006). CONCLUSION Serum ApoB/ApoA-I is a useful biomarker in predicting aggressive clinicopathological characteristics and poor prognosis in HCC patients treated with TACE.
Collapse
Affiliation(s)
- Meng-Meng Liu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhan-Hong Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Department of Medical Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Li-Yun Zhao
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jing-Yuan Zhao
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dai-Lin Rong
- Department of Radiology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Kun Ma
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dan-Yun Ruan
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jin-Xiang Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jing-Jing Qi
- Department of Medical Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Pei-Shan Hu
- Department of Medical Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing-Yun Wen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jie Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qu Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiang-Yuan Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li Wei
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Min Dong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| |
Collapse
|
28
|
Jiang Y, Chen P, Hu K, Dai G, Li J, Zheng D, Yuan H, He L, Xie P, Tu M, Peng S, Qu C, Lin W, Chung RT, Hong J. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med 2021; 25:1568-1582. [PMID: 33410581 PMCID: PMC7875922 DOI: 10.1111/jcmm.16256] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 10/14/2019] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.
Collapse
Affiliation(s)
- Yuchuan Jiang
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Peng Chen
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Kaishun Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene RegulationMedical Research CenterSun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Guanqi Dai
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Jinying Li
- Department of GastroenterologyGuangzhou Overseas Chinese HospitalJinan UniversityGuangzhouChina
| | - Dandan Zheng
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Hui Yuan
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Lu He
- Department of RadiotherapyAffiliated Cancer Hospital & Institute of Guangzhou Medical UniversityGuangzhouChina
| | - Penghui Xie
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Mengxian Tu
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Shuang Peng
- Department of PathophysiologySchool of MedicineJinan UniversityGuangzhouChina
| | - Chen Qu
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| | - Wenyu Lin
- Liver Center and Gastrointestinal DivisionMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Raymond T. Chung
- Liver Center and Gastrointestinal DivisionMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Jian Hong
- Department of Abdominal SurgeryIntegrated Hospital of Traditional Chinese MedicineSouthern Medical UniversityGuangzhouChina
| |
Collapse
|