1
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Das S, Halder D, Jeyaprakash RS. Computational-guided approach for identification of PI3K alpha inhibitor in the treatment of hepatocellular carcinoma by virtual screening and water map analysis. J Biomol Struct Dyn 2025; 43:3886-3908. [PMID: 38197431 DOI: 10.1080/07391102.2023.2300131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/22/2023] [Indexed: 01/11/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most deadly disorders, with a relative survival rate of 36% in the last 5 years. After an extensive literature survey and pathophysiology analysis, PI3Kα was found to be a promising biological target as PIK3CA gene upregulation was observed in HCC, resulting in the loss of apoptosis of cells, which leads to uncontrollable growth and proliferation. Due to superior selectivity and promising therapeutic activity, the PI3K-targeted molecule library was selected, and the ligand preparation was executed. The study mainly focused on e-pharmacophore development, virtual screening and receptor-ligand docking analysis. Then, MMGBSA and ADME prediction analysis was performed with the top 10 molecules; for further analysis of ligand-receptor binding affinity at the catalytic binding site, induced fit docking was performed with the top two molecules. The analysis of quantum chemical stability descriptors, i.e., frontier molecular orbital analysis, was performed followed by molecular dynamics simulation of 100 ns to better understand the ligand-receptor binding. In this study, water map analysis played a significant role in the hit optimization and analysis of the thermodynamic properties of the receptor-ligand complex. The two hit molecules K894-1435 and K894-1045 represented superior docking scores, enhanced stability, and inhibitory action targeting Valine 851 amino acid residue at the catalytic binding site. Hence, the study has significance for the quest for selective PI3Kα inhibitors through the process of hit-to-lead optimization.
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Affiliation(s)
- Subham Das
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Debojyoti Halder
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - R S Jeyaprakash
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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2
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Wu Y, Guo F, Li J, Shi W, Song L, Liu J. Curcumin ameliorates heatstroke-induced lung injury by activating the PI3K/AKT pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4617-4632. [PMID: 39521756 DOI: 10.1007/s00210-024-03572-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
Heatstroke (HS) poses a significant threat to public health. Curcumin, a polyphenolic compound, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the potential therapeutic effects of curcumin on HS-induced lung injury and to elucidate its underlying molecular mechanisms. We utilized network pharmacology to predict the potential targets of curcumin and determine its possible protective effects against HS. Molecular docking was performed to assess the affinity of curcumin to proteins. Forty mice were used for in vivo experiments to evaluate the therapeutic effects of curcumin, divided into four groups (n = 10 per group): normal control (NC), high-temperature control (HTC), low-dose curcumin heatstroke (H100c, 100 mg/kg/day), and high-dose curcumin heatstroke (H200c, 200 mg/kg/day). Furthermore, we evaluated lung pathology, ultrastructural alterations, and protein expression levels of key molecules. Molecular docking indicated a high binding affinity between curcumin and PIK3R1, AKT, and CASP3. In vivo experiments confirm that curcumin pretreatment significantly mitigates HS-induced lung tissue pathology and ultrastructural damage, with the H200c group showing notably greater improvement. Furthermore, curcumin pretreatment markedly enhances the activation of the PI3K/AKT pathway and suppresses the expression of cleaved caspase3, particularly in the H200c group. Our study suggests curcumin may alleviate HS-induced lung injury via the PI3K/AKT pathway, but limitations exist. We did not test key protein knockdown/overexpression, and PI3K/AKT may not be the only pathway. Human and mouse pharmacokinetic differences could affect clinical translation.
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Affiliation(s)
- Yizhan Wu
- Department of Graduate School, Xinjiang Medical University, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Fei Guo
- Department of Emergency Trauma Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang Uygur Autonomous Region, China
| | - Jiajia Li
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Wenhui Shi
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Laiyang Song
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China
| | - Jiangwei Liu
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, No. 359 Youhao North Road, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China.
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3
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Ding Z, Shao G, Li M. Targeting autophagy in premature ovarian failure: Therapeutic strategies from molecular pathways to clinical applications. Life Sci 2025; 366-367:123473. [PMID: 39971127 DOI: 10.1016/j.lfs.2025.123473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/31/2025] [Accepted: 02/14/2025] [Indexed: 02/21/2025]
Abstract
Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy- a cellular process that helps maintain homeostasis by recycling damaged components-in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.
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Affiliation(s)
- Ziwen Ding
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Genbao Shao
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Mingyang Li
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
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4
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Zheng S, Xue T, Xue C, Li S, Zao X, Li X, Cao X, Du H, Qi W, Seetoh WS, Wang W, Zhang P, Ye Y. Regulatory mechanisms of signaling pathways in liver cancer treatment with traditional Chinese medicine. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119386. [PMID: 39848414 DOI: 10.1016/j.jep.2025.119386] [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: 06/14/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese Medicine (TCM), as a longstanding therapeutic approach, offers unique advantages and potential in the treatment of liver cancer. Recent studies have highlighted its role in preventing liver cancer progression by modulating key signaling pathways. TCM's multi-component, multi-target, and multi-pathway mechanisms of action have garnered significant attention in the medical community for their ability to address complex diseases like liver cancer. AIM OF THE STUDY This review examines the current status and challenges in the application of TCM to regulate specific signaling pathways, including PI3K/Akt, NF-κB, TGF-β, Wnt/β-Catenin, and Notch, in liver cancer treatment. The goal is to further elucidate the critical roles of these pathways in liver cancer progression and provide new insights into the modern scientific interpretation of TCM. MATERIALS AND METHODS Literature was retrieved from PubMed and Web of Science databases using keywords such as "traditional Chinese medicine," "Chinese medicine," and "signaling pathway." The articles reviewed span from 2004 to 2024. RESULTS TCM demonstrates significant therapeutic and preventive effects in liver cancer by modulating signaling pathways involved in tumorigenesis. These pathways influence processes such as cell growth, invasion, proliferation, and inflammatory responses, contributing to the anti-cancer effects of TCM. CONCLUSION By modulating key signaling pathways such as PI3K/Akt, NF-κB, TGF-β, Wnt/β-Catenin, and Notch, TCM plays an important role in both the treatment and prevention of liver cancer, offering a promising therapeutic approach grounded in traditional practices and modern scientific understanding.
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Affiliation(s)
- Shihao Zheng
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China.
| | - Tianyu Xue
- Hebei Provincial Hospital of Traditional Chinese Medicine, 050000, China
| | - Chengyuan Xue
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Size Li
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Xiaobin Zao
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China
| | - Xiaoke Li
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Xu Cao
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Hongbo Du
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Wenying Qi
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Wei Song Seetoh
- Beijing University of Chinese Medicine, 100102, China; School of Biological Sciences, Nanyang Technological University, 637551, China
| | - Wei Wang
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Peng Zhang
- Department of Spleen and Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, 100078, China.
| | - Yongan Ye
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China.
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5
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Abusaif MS, Ragab A, Fayed EA, Ammar YA, Gowifel AMH, Hassanin SO, Ahmed GE, Gohar NA. Exploring a novel thiazole derivatives hybrid with fluorinated-indenoquinoxaline as dual inhibitors targeting VEGFR2/AKT and apoptosis inducers against hepatocellular carcinoma with docking simulation. Bioorg Chem 2025; 154:108023. [PMID: 39644617 DOI: 10.1016/j.bioorg.2024.108023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/17/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks as the third most prevalent reason for cancer-related death on a global scale. Tyrosine kinase inhibitors (TKIs) continue to be the primary treatment option for advanced hepatocellular carcinoma. A series of fluoro-11H-indeno[1,2-b]quinoxaline derivatives as an HCC drug targeting the VEGFR2/AKT axis was designed and synthesized. The novel compounds were investigated against HepG-2 and HuH-7 liver tumor cell lines. Compound 5 was the most active derivative against HepG-2 and HuH-7 cell lines with IC50 = 0.75 ± 0.04 and 3.43 ± 0.16 μM, respectively, in contrast to Sorafenib which shows IC50 values of 5.23 ± 0.31 and 4.58 ± 0.21 μM, respectively. IC50 values on normal liver cells (THLE-2) show that all tests are more selective than Sorafenib, prompting further research. The most promising cytotoxic compound has virtually equal VEGFR2 inhibition efficacy to Sorafenib. The total VEGFR2 and p-VEGFR2 inhibitory effects were subsequently evaluated, showing 38.32 % and 77.64 % attenuation, respectively. Compound 5 also reduced total and phosphorylated AKT concentrations in HepG-2 cells by 55.29 % and 78.01 %, respectively. Furthermore, Compound 5 upregulated BAX and caspase-3 and downregulated Bcl-2 to promote apoptosis. Hybrid 5 stops HepG-2's cell cycle at the S phase 48.02 % higher than untreated. Docking experiments assessed AKT and VEGFR2 binding patterns.
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Affiliation(s)
- Moustafa S Abusaif
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt.
| | - Ahmed Ragab
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt; Chemistry Department, Faculty of Science, Galala University, Galala City, 43511, Suez, Egypt.
| | - Eman A Fayed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City 11754, Cairo, Egypt.
| | - Yousry A Ammar
- Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt
| | - Ayah M H Gowifel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt
| | - Soha Osama Hassanin
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11585, Egypt
| | - Ghada E Ahmed
- Canal Higher Institute for Engineering and Technology- Suez, Egypt
| | - Nirvana A Gohar
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
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6
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Ebaid MS, Abdelsattar Ibrahim HA, Kassem AF, Sabt A. Recent studies on protein kinase signaling inhibitors based on thiazoles: review to date. RSC Adv 2024; 14:36989-37018. [PMID: 39569127 PMCID: PMC11575478 DOI: 10.1039/d4ra05601a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 11/10/2024] [Indexed: 11/22/2024] Open
Abstract
Due to the important role of protein kinases in protein phosphorylation within vital cellular processes, their abnormal function, especially in cancer situations, has underscored their importance in therapy. Thiazole structures are versatile frameworks present in numerous bioactive compounds. Thiazole derivatives, as a highly favored structural motif, have garnered considerable interest from both industrial and medicinal researchers and have demonstrated notable success over past decades due to their diverse biological properties, including anticancer, antibacterial, antifungal, anti-HIV, antiulcer, and anti-inflammatory activities. Moreover, several thiazole-based drugs are widely recognized pharmaceuticals on the market. Due to their specific structural features, thiazole derivatives have a high potential for interacting with different protein kinases, leading researchers to investigate a variety of structural changes. This thorough review thoroughly examines the design and biological evaluations of small molecules utilizing thiazole as potential agents that target various kinases for anti-cancer applications. These compounds are categorized into two classes: inhibitors of serine/threonine and tyrosine kinases. The goal is to promote the development and progress of more effective, targeted compounds for cancer treatment by highlighting the potential of thiazole in inhibiting kinases.
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Affiliation(s)
- Manal S Ebaid
- Department of Chemistry, College of Science, Northern Border University Arar Saudi Arabia
| | | | - Asmaa F Kassem
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University Al-Kharj 11942 Saudi Arabia
| | - Ahmed Sabt
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center Dokki Cairo 12622 Egypt
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7
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Shi Q, He J, Chen G, Xu J, Zeng Z, Zhao X, Zhao B, Gao X, Ye Z, Xiao M, Li H. The chemical composition of Diwu YangGan capsule and its potential inhibitory roles on hepatocellular carcinoma by microarray-based transcriptomics. J Tradit Complement Med 2024; 14:381-390. [PMID: 39035694 PMCID: PMC11259662 DOI: 10.1016/j.jtcme.2023.12.002] [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: 07/18/2023] [Revised: 09/28/2023] [Accepted: 12/24/2023] [Indexed: 07/23/2024] Open
Abstract
The Traditional Chinese Medicine compound preparation known as Diwu Yanggan capsule (DWYG) can effectively hinder the onset and progression of hepatocellular carcinoma (HCC), which is recognized worldwide as a significant contributor to fatalities associated with cancer. Nevertheless, the precise mechanisms implicated have remained ambiguous. In present study, the model of HCC was set up by the 2-acetylaminofluorene (2-AAF)/partial hepatectomy (PH) in rats. To confirm the differentially expressed genes (DEGs) identified in the microarray analysis, real-time quantitative reverse transcription PCR (qRT-PCR) was conducted. In the meantime, the liquid chromatography-quadrupole time of flight mass spectrometry (LC-QTOF-MS/MS) was employed to characterize the component profile of DWYG. Consequently, the DWYG treatment exhibited the ability to reverse 51 variation genes induced by 2-AAF/PH. Additionally, there was an overlap of 54 variation genes between the normal and model groups. Upon conducting RT-qPCR analysis, it was observed that the expression levels of all genes were increased by 2-AAF/PH and subsequently reversed after DWYG treatment. Notably, the fold change of expression levels for all genes was below 0.5, with 3 genes falling below 0.25. Moreover, an investigation was conducted to determine the signaling pathway that was activated/inhibited in the HCC group and subsequently reversed in the DWYG group. Moreover, the component profile of DWYG encompassed a comprehensive compilation of 206 compounds that were identified or characterized. The findings of this study elucidated the potential alleviative mechanisms of DWYG in the context of HCC, thereby holding significant implications for its future clinical utilization and widespread adoption.
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Affiliation(s)
- Qingxin Shi
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Jiangcheng He
- Wuhan Integrated Traditional Chinese and Western Medicine Orthopedic Hospital, Affiliated Hospital of Wuhan Sports University, Wuhan, 430079, China
| | - Guangya Chen
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Jinlin Xu
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Zhaoxiang Zeng
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Xueyan Zhao
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Binbin Zhao
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Xiang Gao
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Zhihua Ye
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Mingzhong Xiao
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Hanmin Li
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China
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8
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Hussain MS, Moglad E, Afzal M, Gupta G, Hassan Almalki W, Kazmi I, Alzarea SI, Kukreti N, Gupta S, Kumar D, Chellappan DK, Singh SK, Dua K. Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathol Res Pract 2024; 258:155303. [PMID: 38728793 DOI: 10.1016/j.prp.2024.155303] [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: 03/04/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/12/2024]
Abstract
Hepatocellular carcinoma (HCC) is among the primary reasons for fatalities caused by cancer globally, highlighting the need for comprehensive knowledge of its molecular aetiology to develop successful treatment approaches. The PI3K/Akt system is essential in the course of HCC, rendering it an intriguing candidate for treatment. Non-coding RNAs (ncRNAs), such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are important mediators of the PI3K/Akt network in HCC. The article delves into the complex regulatory functions of ncRNAs in influencing the PI3K/Akt system in HCC. The study explores how lncRNAs, miRNAs, and circRNAs impact the expression as well as the function of the PI3K/Akt network, either supporting or preventing HCC growth. Additionally, treatment strategies focusing on ncRNAs in HCC are examined, such as antisense oligonucleotide-based methods, RNA interference, and small molecule inhibitor technologies. Emphasizing the necessity of ensuring safety and effectiveness in clinical settings, limitations, and future approaches in using ncRNAs as therapies for HCC are underlined. The present study offers useful insights into the complex regulation system of ncRNAs and the PI3K/Akt cascade in HCC, suggesting possible opportunities for developing innovative treatment approaches to address this lethal tumor.
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Affiliation(s)
- Md Sadique Hussain
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan 302017, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Gaurav Gupta
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Saurabh Gupta
- Chameli Devi Institute of Pharmacy, Department of Pharmacology, Khandwa Road, Village Umrikheda, Near Toll Booth, Indore, Madhya Pradesh 452020, India
| | - Dinesh Kumar
- School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; School of Medical and Life Sciences, Sunway University, 47500 Sunway City, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
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9
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Kamboj P, Mahore A, Husain A, Amir M. Benzothiazole-based apoptosis inducers: A comprehensive overview and future prospective. Arch Pharm (Weinheim) 2024; 357:e2300493. [PMID: 38212254 DOI: 10.1002/ardp.202300493] [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: 09/05/2023] [Revised: 11/24/2023] [Accepted: 12/06/2023] [Indexed: 01/13/2024]
Abstract
Cancer has become a major concern in healthcare globally, and over time, incidences and prevalence of cancer are increasing. To counter this, a lot of anticancer drugs are approved and are in clinical use, playing a pivotal role in its treatment. Due to drug resistance and adverse effects, a continuous demand for novel, potent, and safe candidates to treat cancer is always there. Over the last few decades, various heterocyclic ring-based derivatives have been explored and reported in the literature. In this regard, benzothiazole scaffold-based compound emerged as the versatile ring for developing novel and safe anticancer candidates. In this article, we have reported various benzothiazole heterocyclic ring-based derivatives demonstrating potent antiproliferative activity by induction of apoptosis via an intrinsic pathway in a dose-dependent manner. These compounds also displayed inhibition of different enzymes, for example, Aurora kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, phosphoinositide kinases, DNA topoisomerase, and tubulin polymerases. This study focused on a comprehensive overview of antiproliferative activity, structure-activity relationship, apoptosis induction activity, and enzyme inhibition by benzothiazole-based compounds.
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Affiliation(s)
- Payal Kamboj
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Anjali Mahore
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Asif Husain
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Mohammad Amir
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
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10
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Rayginia TP, Keerthana CK, Shifana SC, Pellissery MJ, Abhishek A, Anto RJ. Phytochemicals as Potential Lead Molecules against Hepatocellular Carcinoma. Curr Med Chem 2024; 31:5199-5221. [PMID: 38213177 DOI: 10.2174/0109298673275501231213063902] [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: 08/03/2023] [Revised: 10/31/2023] [Accepted: 11/16/2023] [Indexed: 01/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 85-90% of liver cancer cases and is a leading cause of cancer-related mortality worldwide. The major risk factors for HCC include hepatitis C and B viral infections, along with chronic liver diseases, such as cirrhosis, fibrosis, and non-alcoholic steatohepatitis associated with metabolic syndrome. Despite the advancements in modern medicine, there is a continuous rise in the annual global incidence rate of HCC, and it is estimated to reach >1 million cases by 2025. Emerging research in phytomedicine and chemotherapy has established the anti-cancer potential of phytochemicals, owing to their diverse biological activities. In this review, we report the major phytochemicals that have been explored in combating hepatocellular carcinoma and possess great potential to be used as an alternative or in conjunction with the existing HCC treatment modalities. An overview of the pre-clinical observations, mechanism of action and molecular targets of some of these phytochemicals is also incorporated.
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Affiliation(s)
- Tennyson Prakash Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | - Chenicheri Kizhakkeveettil Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | | | - Maria Joy Pellissery
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - Ajmani Abhishek
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
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Liu WF, Zhang QW, Quan B, Zhang F, Li M, Lu SX, Dong L, Yin X, Liu BB. Gas7 attenuates hepatocellular carcinoma progression and chemoresistance through the PI3K/Akt signaling pathway. Cell Signal 2023; 112:110908. [PMID: 37769891 DOI: 10.1016/j.cellsig.2023.110908] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/01/2023] [Accepted: 09/25/2023] [Indexed: 10/03/2023]
Abstract
Growth arrest-specific gene 7 (Gas7) was involved in various cellular functions, although its specific roles and molecular mechanisms in hepatocellular carcinoma (HCC) remained unclear. So the current study was to investigate the role of Gas7 in HCC. Our findings revealed that Gas7 was downregulated in various HCC cell lines and low Gas7 expression was associated with decreased overall survival in patients with HCC. Additionally, our functional assays showed that Gas7 inhibited cell proliferation and migration, induced cell cycle arrest, apoptosis, and autophagy, and enhanced oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway. We also observed that transcription factorSp1 was responsible for inhibiting Gas7. These findings provide insights into the role and elucidated a potential mechanism of Gas7 in HCC progression and metastasis. It was also observed that the Sp1/Gas7/PI3K/Akt axis was critical for malignant phenotype and oxaliplatin sensitivity in HCC. Therefore, Gas7 can be considered as a prognostic predictor and therapeutic target for HCC.
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Affiliation(s)
- Wen-Feng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qi-Wei Zhang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Bing Quan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Feng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Shen-Xin Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| | - Bin-Bin Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Mangiapane G, Pascut D, Dalla E, Antoniali G, Degrassi M, Crocè LS, De Sanctis V, Piazza S, Canarutto G, Tiribelli C, Tell G. Clinical Significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 and MicroRNA Axis in Hepatocellular Carcinoma. J Clin Transl Hepatol 2023; 11:1291-1307. [PMID: 37719963 PMCID: PMC10500290 DOI: 10.14218/jcth.2022.00179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 05/10/2023] [Accepted: 06/07/2023] [Indexed: 09/19/2023] Open
Abstract
Background and Aims Identification of prognostic factors for hepatocellular carcinoma (HCC) opens new perspectives for therapy. Circulating and cellular onco-miRNAs are noncoding RNAs which can control the expression of genes involved in oncogenesis through post-transcriptional mechanisms. These microRNAs (miRNAs) are considered novel prognostic and predictive factors in HCC. The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) contributes to the quality control and processing of specific onco-miRNAs and is a negative prognostic factor in several tumors. The present work aims to: a) define APE1 prognostic value in HCC; b) identify miRNAs regulated by APE1 and their relative target genes and c) study their prognostic value. Methods We used The Cancer Genome Atlas (commonly known as TCGA) data analysis to evaluate the expression of APE1 in HCC. To identify differentially-expressed miRNAs (DEmiRNAs) upon APE1 depletion through specific small interfering RNA, we used NGS and nanostring approaches in the JHH-6 HCC tumor cell line. Bioinformatics analyses were performed to identify signaling pathways involving APE1-regulated miRNAs. Microarray analysis was performed to identify miRNAs correlating with serum APE1 expression. Results APE1 is considerably overexpressed in HCC tissues compared to normal liver, according to the TCGA-liver HCC (known as LIHC) dataset. Enrichment analyses showed that APE1-regulated miRNAs are implicated in signaling and metabolic pathways linked to cell proliferation, transformation, and angiogenesis, identifying Cyclin Dependent Kinase 6 and Lysosomal Associated Membrane Protein 2 as targets. miR-33a-5p, miR-769, and miR-877 are related to lower overall survival in HCC patients. Through array profiling, we identified eight circulating DE-miRNAs associated with APE1 overexpression. A training phase identified positive association between sAPE1 and miR-3180-3p and miR-769. Conclusions APE1 regulates specific miRNAs having prognostic value in HCC.
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Affiliation(s)
- Giovanna Mangiapane
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Devis Pascut
- Fondazione Italiana Fegato - ONLUS, Liver Cancer Unit, Trieste, Italy
| | - Emiliano Dalla
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Giulia Antoniali
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Monica Degrassi
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
| | - Lory Saveria Crocè
- Fondazione Italiana Fegato - ONLUS, Liver Cancer Unit, Trieste, Italy
- Department of Medical Sciences, University of Trieste, Trieste, Italy
- Clinica Patologie Fegato, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy
| | | | - Silvano Piazza
- Computational Biology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy
| | - Giulia Canarutto
- Computational Biology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy
| | - Claudio Tiribelli
- Fondazione Italiana Fegato - ONLUS, Liver Cancer Unit, Trieste, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Wang S, Yi W, Xu Z, Shi M. PYCR2 promotes growth and aerobic glycolysis in human liver cancer by regulating the AKT signaling pathway. Biochem Biophys Res Commun 2023; 680:15-24. [PMID: 37708598 DOI: 10.1016/j.bbrc.2023.09.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023]
Abstract
Hepatocellular carcinoma (HCC) is the world's third most fatal cancer. Because metabolic rewiring is a hallmark of HCC, studies into the causes of aberrant glycolysis could provide insight into novel HCC therapeutic strategies. Pyrroline-5-carboxylate reductase 2 (PYCR2), a key enzyme of proline synthesis, has previously been found to play vital roles in various malignancies regarding amino acid metabolism and oxidative stress response. Our study investigated the mechanistic function of PYCR2 in HCC. We used Gene Expression Profiling Interactive Analysis to perform bioinformatics analysis of PYCR2 expression and survival in human HCC patients based on the Cancer Genome Atlas database. The function of PYCR2 in cell viability and glycolysis was assessed using CCK-8 and ECAR assays. Transducing shRNA or overexpression vectors into the HCC cell line altered the expression status of PYCR2. PYCR2 expression was validated using quantitative real-time PCR and Western blot. In mouse xenograft models, the role of PYCR2 in HCC tumor formation was confirmed. PYCR2 was overexpressed in human HCC tumor tissue and was associated with a poor prognosis. The functional assay revealed that silencing PYCR2 inhibited cell viability, glycolysis, and AKT activation. Furthermore, the xenograft experiment demonstrated that silencing PYCR2 significantly inhibited tumor growth and Ki67 expression. On the other hand, PYCR2 overexpression significantly promoted cell viability and glycolysis, which could be inhibited by either a glycolysis inhibitor or an AKT inhibitor, indicating that PYCR2 may function via glycolysis and the AKT pathway. Moreover, despite the overexpression of PYCR2 in vivo, treatment with a glycolysis inhibitor may considerably suppress tumor growth. Our findings suggest that PYCR2 may play an oncogenic role in HCC growth by promoting glycolysis and activating AKT, emphasizing PYCR2's clinical relevance in HCC management as a novel potential therapeutic target.
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Affiliation(s)
- Shaoyan Wang
- Department of Infectious Diseases, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Wenyan Yi
- Department of Emergency Internal Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Zhenyu Xu
- Department of Emergency Internal Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Minyu Shi
- Department of Infectious Diseases, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
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Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
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Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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Lu N, Min J, Peng L, Huang S, Chai X, Wang S, Wang J. MiR-297 inhibits tumour progression of liver cancer by targeting PTBP3. Cell Death Dis 2023; 14:564. [PMID: 37633911 PMCID: PMC10460384 DOI: 10.1038/s41419-023-06097-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/11/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
Whereas increasing evidences demonstrate that miR-297 contributes to the tumour development and progression, the role of miR-297 and its underlying molecular mechanisms in hepatocellular carcinoma (HCC) was still unclear. Here, we reported that the expression of miR-297 increased significantly in hepG2 cells after the treatment of the conditioned medium of human amniotic epithelial cells(hAECs) which can inhibit the proliferation and migration of hepG2. And the overexpression of miR-297 inhibits the cell proliferation, migration and invasion of HCC cell lines in vitro and suppressed the tumorigenesis of HCC in vivo. Polypyrimidine tract-binding protein 3 (PTBP3) was identified as a direct target gene of miR-297 in HCC cell lines, and mediated the function of miR-297 in HCC cells. In clinical samples, miR-297 levels have a tendency to decrease, but there are no statistically significant differences. Furthermore, in vitro cell experiments confirmed that overexpression of miR-297 could inhibit the PI3K/AKT signaling pathway by down-regulating PTBP3 expression, thereby inhibiting the proliferation, migration and invasion of HCC cells. In conclusion, our results revealed that miR-297 could down-regulate the expression of PTBP3 and inhibit the activation of PI3K/AKT signaling pathway, thereby preventing HCC growth, migration and invasion.
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Affiliation(s)
- Na Lu
- The Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
| | - Jiali Min
- The Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Lin Peng
- Changsha Hospital for Maternal and Child Health Care of Hunan Normal University, Changsha, China
| | - Shengjian Huang
- Hunan Guangxiu Hi-tech Life Technology Co., Ltd., Changsha, China
| | - Xiahua Chai
- The Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Susu Wang
- The Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jian Wang
- The Institute of Reproduction and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha, China.
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
- National Engineering and Research Center of Human Stem Cells, Changsha, China.
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Chen R, Zhao M, An Y, Liu D, Tang Q. GBAP1 functions as a tumor promotor in hepatocellular carcinoma via the PI3K/AKT pathway. BMC Cancer 2023; 23:628. [PMID: 37407932 DOI: 10.1186/s12885-023-11107-7] [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: 10/08/2022] [Accepted: 06/23/2023] [Indexed: 07/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is common worldwide, and novel therapeutic targets and biomarkers are needed to improve outcomes. In this study, bioinformatics analyses combined with in vitro and in vivo assays were used to identify the potential therapeutic targets. Differentially expressed genes (DEG) in HCC were identified by the intersection between The Cancer Genome Atlas and International Cancer Genome Consortium data. The DEGs were evaluated by a gene set enrichment analysis as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A protein interaction network, univariate Cox regression, and Lasso regression were used to screen out hub genes correlated with survival. Increased expression of the long noncoding RNA GBAP1 in HCC was confirmed in additional datasets and its biological function was evaluated in HCC cell lines and nude mice. Among 121 DEGs, GBAP1 and PRC1 were identified as hub genes with significant prognostic value. Overexpression of GBAP1 in HCC was confirmed in 21 paired clinical tissues and liver cancer or normal cell lines. The inhibition of GBAP1 expression reduced HCC cell proliferation and promoted apoptosis by inactivating the PI3K/AKT pathway in vitro and in vivo. Therefore, GBAP1 has a pro-oncogenic function in HCC and is a candidate prognostic biomarker and therapeutic target.
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Affiliation(s)
- Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Meng Zhao
- Medical college, Henan University of Traditional Chinese Medicine, 450001, Henan Province, China
| | - Yanli An
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Dongfang Liu
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Qiusha Tang
- Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
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Niture S, Gadi S, Lin M, Qi Q, Niture SS, Moore JT, Bodnar W, Fernando RA, Levine KE, Kumar D. Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways. ENVIRONMENTAL TOXICOLOGY 2023; 38:783-797. [PMID: 36602393 DOI: 10.1002/tox.23731] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 06/17/2023]
Abstract
Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure to low concentrations of Cd increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in a human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines. Acute exposure of Cd increased Jagged-1 expression and activated Notch signaling in HepaRG and HCC cells HepG2 and SK-Hep1. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Chronic exposure to low concentrations of Cd-activated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNF-α-Induced Protein 8 (TNFAIP8). RNA-Seq data revealed that chronic exposure to low concentrations of Cd modulated the expression of several fatty liver disease-related genes involved in cell steatosis/fibrosis in HepaRG and HepG2 cells. Collectively, our data suggest that low concentrations of Cd modulate steatosis along with fibrogenic and oncogenic signaling in HCC cells by activating Notch and AKT/mTOR pathways.
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Affiliation(s)
- Suryakant Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Sashi Gadi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Minghui Lin
- The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Qi Qi
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Samiksha S Niture
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - John T Moore
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
| | - Wanda Bodnar
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Reshan A Fernando
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Keith E Levine
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
| | - Deepak Kumar
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA
- NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA
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Zhao R, Xu X, Sun L, Zhang G. Long-term effect of anesthesia choice on patients with hepatocellular carcinoma undergoing open liver resection. Front Oncol 2023; 12:960299. [PMID: 36713494 PMCID: PMC9880263 DOI: 10.3389/fonc.2022.960299] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 12/28/2022] [Indexed: 01/14/2023] Open
Abstract
Clinical and experimental evidence suggested that anesthesia choice can influence cancer progression and patients' outcomes by modulating tumor microenvironment and tumorigenic pathways. Curative resection is the mainstay of therapy for hepatocellular carcinoma (HCC), which is an intractable disease due to high recurrence and poor prognosis. However, different anesthetics may play different roles in alleviating surgery-induced stress response and inflammatory cytokines release that are considered to be closely associated with proliferation, invasion and metastasis of tumor cells. Propofol, sevoflurane, non-steroidal anti-inflammatory drugs and local anesthetics have shown to exert anti-tumor effect on HCC mainly through regulating microRNAs or signaling pathways, while other inhalational agents, dexmedetomidine and opioids have the potential to promote tumor growth. In terms of anesthetic methods and analgesia strategies, propofol based total intravenous anesthesia and thoracic epidural analgesia could be preferred for HCC patients undergoing open liver resection rather than inhalational anesthesia. Local anesthesia techniques have great potential to attenuate perioperative stress response, hence they may contribute to more favorable outcomes. This review summarized the relations between different anesthesia choices and HCC patients' long-term outcomes as well as their underlying mechanisms. Due to the complexity of molecules interactions and signaling pathways, further studies are warranted to confirm these results so as to optimize anesthesia strategy for HCC patients.
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Affiliation(s)
- Runzhi Zhao
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiyuan Xu
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Sun
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China,*Correspondence: Li Sun, ; Guohua Zhang,
| | - Guohua Zhang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, China,*Correspondence: Li Sun, ; Guohua Zhang,
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Zhang Y, Pan Q, Shao Z. Extracellular vesicles derived from cancer-associated fibroblasts carry tumor-promotive microRNA-1228-3p to enhance the resistance of hepatocellular carcinoma cells to sorafenib. Hum Cell 2023; 36:296-311. [PMID: 36424471 DOI: 10.1007/s13577-022-00800-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022]
Abstract
Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) can promote tumor progression by delivering microRNA (miRNA). Whether EVs could transfer miR-1228-3p into hepatocellular carcinoma (HCC) cells to affect chemoresistance was discussed in this study. Normal fibroblasts (NFs) and CAFs were isolated from tissue samples of HCC patients. We assessed the functions of HCC cells after co-culturing with NFs and CAFs. miR-1228-3p gain-of-function experiments were conducted. Next, functional assays were carried out to determine the binding of miR-1228-3p to placenta associated 8 (PLAC8). In vivo models were constructed for validation. CAFs-derived EVs exerted promoting effect on proliferative, migrating, invading potential of HCC cells and their resistance to sorafenib. PLAC8 was demonstrated as a direct target of miR-1228-3p. By targeting PLAC8, miR-1228-3p activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In addition, the transfer of miR-1228-3p from CAFs-derived EVs into HCC cells boosted chemoresistance of HCC cells, which was reversed by restoring PLAC8. All in all, CAF-EV-carried miR-1228-3p strengthens the chemoresistance of HCC through activating PLAC8-mediated PI3K/AKT pathway. This finding contributes to the development of EV-based therapies overcoming the chemoresistance of HCC.
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Affiliation(s)
- Yijie Zhang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110000, Liaoning Province, People's Republic of China
- The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang, 110000, Liaoning Province, People's Republic of China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110000, Liaoning Province, People's Republic of China
- The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang, 110000, Liaoning Province, People's Republic of China
| | - Zigong Shao
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, 110000, Liaoning Province, People's Republic of China.
- The Key Laboratory of Organ Transplantation of Liaoning Province, Shenyang, 110000, Liaoning Province, People's Republic of China.
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21
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Abu-Shahba N, Hegazy E, Khan FM, Elhefnawi M. In Silico Analysis of MicroRNA Expression Data in Liver Cancer. Cancer Inform 2023; 22:11769351231171743. [PMID: 37200943 PMCID: PMC10185868 DOI: 10.1177/11769351231171743] [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: 11/30/2022] [Accepted: 04/04/2023] [Indexed: 05/20/2023] Open
Abstract
Abnormal miRNA expression has been evidenced to be directly linked to HCC initiation and progression. This study was designed to detect possible prognostic, diagnostic, and/or therapeutic miRNAs for HCC using computational analysis of miRNAs expression. Methods: miRNA expression datasets meta-analysis was performed using the YM500v2 server to compare miRNA expression in normal and cancerous liver tissues. The most significant differentially regulated miRNAs in our study undergone target gene analysis using the mirWalk tool to obtain their validated and predicted targets. The combinatorial target prediction tool; miRror Suite was used to obtain the commonly regulated target genes. Functional enrichment analysis was performed on the resulting targets using the DAVID tool. A network was constructed based on interactions among microRNAs, their targets, and transcription factors. Hub nodes and gatekeepers were identified using network topological analysis. Further, we performed patient data survival analysis based on low and high expression of identified hubs and gatekeeper nodes, patients were stratified into low and high survival probability groups. Results: Using the meta-analysis option in the YM500v2 server, 34 miRNAs were found to be significantly differentially regulated (P-value ⩽ .05); 5 miRNAs were down-regulated while 29 were up-regulated. The validated and predicted target genes for each miRNA, as well as the combinatorially predicted targets, were obtained. DAVID enrichment analysis resulted in several important cellular functions that are directly related to the main cancer hallmarks. Among these functions are focal adhesion, cell cycle, PI3K-Akt signaling, insulin signaling, Ras and MAPK signaling pathways. Several hub genes and gatekeepers were found that could serve as potential drug targets for hepatocellular carcinoma. POU2F1 and PPARA showed a significant difference between low and high survival probabilities (P-value ⩽ .05) in HCC patients. Our study sheds light on important biomarker miRNAs for hepatocellular carcinoma along with their target genes and their regulated functions.
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Affiliation(s)
- Nourhan Abu-Shahba
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
- Stem Cell Research Group, Medical Research Center of Excellence, National Research Centre, Cairo, Egypt
| | - Elsayed Hegazy
- School of Information Technology and Computer Science, Nile University, Giza, Egypt
| | - Faiz M. Khan
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Mahmoud Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt
- Mahmoud Elhefnawi, Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, 33, elbohouth street, Cairo 11211, Egypt.
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Tümen D, Heumann P, Gülow K, Demirci CN, Cosma LS, Müller M, Kandulski A. Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma. Biomedicines 2022; 10:3202. [PMID: 36551958 PMCID: PMC9775527 DOI: 10.3390/biomedicines10123202] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation and progression are favored by different etiological risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, non-/and alcoholic fatty liver disease (N/AFLD), and tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, etc.), and dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute to the development of HCC. The multitude and complexity of different pathomechanisms also reflect the difficulties in tailored medical therapy of HCC. Treatment options for HCC are strictly dependent on tumor staging and liver function, which are structured by the updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, and liver transplantation are valid and curative therapeutic options for early tumor stages. For multifocal and metastatic diseases, systemic therapy is recommended. While Sorafenib had been the standalone HCC first-line therapy for decades, recent developments had led to the approval of new treatment options as first-line as well as second-line treatment. Anti-PD-L1 directed combination therapies either with anti-VEGF directed agents or with anti-CTLA-4 active substances have been implemented as the new treatment standard in the first-line setting. However, data from clinical trials indicate different responses on specific therapeutic regimens depending on the underlying pathogenesis of hepatocellular cancer. Therefore, histopathological examinations have been re-emphasized by current international clinical guidelines in addition to the standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. In this review, we emphasize the current knowledge on molecular pathogenesis of hepatocellular carcinoma. On this occasion, the treatment sequences for early and advanced tumor stages according to the recently updated Barcelona Clinic Liver Cancer classification system and the current algorithm of systemic therapy (first-, second-, and third-line treatment) are summarized. Furthermore, we discuss novel precautional and pre-therapeutic approaches including therapeutic vaccination, adoptive cell transfer, locoregional therapy enhancement, and non-coding RNA-based therapy as promising treatment options. These novel treatments may prolong overall survival rates in regard with quality of life and liver function as mainstay of HCC therapy.
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Affiliation(s)
| | | | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases University Hospital Regensburg Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
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23
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Chi Y, Gong Z, Xin H, Wang Z, Liu Z. microRNA-206 prevents hepatocellular carcinoma growth and metastasis via down-regulating CREB5 and inhibiting the PI3K/AKT signaling pathway. Cell Cycle 2022; 21:2651-2663. [PMID: 36003063 PMCID: PMC9704407 DOI: 10.1080/15384101.2022.2108275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 04/22/2022] [Accepted: 07/26/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and has continued to increase in incidence worldwide. Moreover, the involvement of microRNAs (miRs) has been reported in the development and progression of HCC. Here, we investigated the role of miR-206 in HCC growth and metastasis. HCC-related microarray datasets were harvested to screen differentially expressed miRNAs in HCC samples followed by prediction of downstream target genes. The dual-luciferase reporter assay verified the target-binding relationship between miR-206 and CREB5. The human HCC cell line MHCC97-H was cultured in vitro and transfected with miR-206 mimic/inhibitor or sh-/oe-CREB5 for analyzing MHCC97-H cell biological functions. The orthotopic xenograft model of HCC mice was constructed to observe the tumorigenic ability of HCC cells in vivo. Bioinformatics analysis found that miR-206 may be involved in HCC growth and metastasis by targeting CREB5 and regulating PI3K/AKT signaling pathway. In vivo animal experiments found that CREB5 was significantly overexpressed in mouse HCC tissues. In HCC cells, miR-206 can target down-regulate the expression of CREB5, thereby inhibiting the activation of PI3K/AKT signaling pathway. Furthermore, in vitro cell experiments confirmed that overexpression of miR-206 could inhibit the PI3K/AKT signaling pathway by down-regulating CREB5 expression, thereby inhibiting the proliferation, migration and invasion of HCC cells. In conclusion, our results revealed that miR-206 could down-regulate the expression of CREB5 and inhibit the activation of PI3K/AKT signaling pathway, thereby preventing HCC growth and metastasis.Abbreviations: HCC: hepatocellular carcinoma; HBV or HCV: hepatitis B or C virus; miRNAs: microRNAs; CREB: cAMP response element-binding protein; CRE: cAMP response elements.
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Affiliation(s)
- Yuan Chi
- Department of Radiology, Shengjing Hospital of China Medical University, ShenyangP.R. China
| | - Zheng Gong
- Department of Radiology, Shengjing Hospital of China Medical University, ShenyangP.R. China
| | - He Xin
- Department of Radiology, Shengjing Hospital of China Medical University, ShenyangP.R. China
| | - Ziwen Wang
- Department of Radiology, Shengjing Hospital of China Medical University, ShenyangP.R. China
| | - Zhaoyu Liu
- Department of Radiology, Shengjing Hospital of China Medical University, ShenyangP.R. China
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24
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Lee KT, Chen LY, Li WS, Lee HZ. Transcriptome analysis revealed the role of mTOR and MAPK signaling pathways in the white strain of Hypsizygus marmoreus extracts-induced cell death of human hepatoma Hep3B cells. Front Pharmacol 2022; 13:1039376. [PMID: 36506551 PMCID: PMC9732266 DOI: 10.3389/fphar.2022.1039376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/17/2022] [Indexed: 11/27/2022] Open
Abstract
The aim of this study was to investigate the anticancer mechanisms of white genius mushroom (WGM). WGM is a popular edible mushroom in Taiwan and has been demonstrated to mediate potent antiproliferation effects against human Hep3B liver cancer cells in our previous study. According to next generation sequencing technology and KEGG pathway enrichment analysis, mTOR and MAPK signaling pathways were markedly changed during treatment with WGM extracts in Hep3B cells. Therefore, this study examined the effects of WGM extracts on the expression of mTOR and MAPK signaling pathway-related proteins, such as PI3K, Akt, mTOR, Ras, Raf, MEK, ERK, p38 and JNK in Hep3B cells. According to the results of immunoblotting, we demonstrated that the protein expression of the members of PI3K/Akt/mTOR and MAPK signaling pathways were involved in WGM extracts-induced cell death. Furthermore, the inhibitors of PI3K/Akt/mTOR and MAPK signaling pathways such as rapamycin, MK2206, LY3214996 and SB202190, blocked the induction of cell death and vacuoles formation induced by WGM extracts. This study also demonstrated that WGM extracts is able to inhibit Hep3B cell migration and colony formation in a dose-dependent manner. In addition to being a very popular food, WGM should be a pharmacologically safe natural agent for cancer treatment. Therefore, WGM might be designed to develop into a dietary chemopreventive agent for the cancer treatment.
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Affiliation(s)
- Kun-Tsung Lee
- Department of Oral Hygiene, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan,Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Li-Yun Chen
- School of Pharmacy, China Medical University, Taichung, Taiwan
| | - Wei-Sung Li
- Plant Pathology Division, Taiwan Agricultural Research Institute, Council of Agriculture, Executive Yuan, Taichung, Taiwan
| | - Hong-Zin Lee
- School of Pharmacy, China Medical University, Taichung, Taiwan,*Correspondence: Hong-Zin Lee,
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25
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Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, Wang C. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 20:203-222. [PMID: 36369487 DOI: 10.1038/s41575-022-00704-9] [Citation(s) in RCA: 348] [Impact Index Per Article: 116.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2022] [Indexed: 11/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hailin Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linmeng Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Boston, MA, USA. .,Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
| | - René Bernards
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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26
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Nagy G, Gerlei Z, Haboub-Sandil A, Görög D, Szabó J, Kóbori L, Huszty G, Bihari L, Rózsa B, Pőcze B, Máthé Z, Piros L. Optimizing Survival for Hepatocellular Carcinoma After Liver Transplantation: A Single-Center Report and Current Perspectives. Transplant Proc 2022; 54:2593-2597. [DOI: 10.1016/j.transproceed.2022.10.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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27
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Kung ML, Huang ST, Tsai KW, Chu TH, Hsieh S. Nanosized zingerone-triggered anti-angiogenesis contributes to tumor suppression in human hepatocellular carcinoma. Colloids Surf A Physicochem Eng Asp 2022. [DOI: 10.1016/j.colsurfa.2022.130697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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28
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Razpotnik R, Vidmar R, Fonović M, Rozman D, Režen T. Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:4524. [PMID: 36139684 PMCID: PMC9497178 DOI: 10.3390/cancers14184524] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/11/2022] [Accepted: 09/11/2022] [Indexed: 11/23/2022] Open
Abstract
Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced colony formation, migration, cell proliferation, sorafenib sensitivity, and additionally induced morphological changes in cell lines, indicating an important role of hsa_circ_0062682 in oncogenesis. Pathway enrichment analysis and gene set enrichment analysis of the transcriptome data from hsa_circ_0062682 knockdown explained the observed phenotypes and exposed transcription factors E2F1, Sp1, HIF-1α, and NFκB1 as potential downstream targets. Biotinylated oligonucleotide pulldown combined with proteomic analyses identified protein interaction partners of which YBX1, a known oncogene, was confirmed by RNA immunoprecipitation. Furthermore, we discovered a complex cell-type-specific phenotype in response to the oncogenic potential of hsa_circ_0062682. This finding is in line with different classes of HCC tumours, and more studies are needed to shed a light on the molecular complexity of liver cancer.
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Affiliation(s)
- Rok Razpotnik
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Robert Vidmar
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia
| | - Marko Fonović
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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29
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Up-Regulation of RACGAP1 Promotes Progressions of Hepatocellular Carcinoma Regulated by GABPA via PI3K/AKT Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3034150. [PMID: 35958019 PMCID: PMC9363186 DOI: 10.1155/2022/3034150] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 11/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the dominating tumors causing death due to lack of timely discovery and valid treatment. Abnormal increase of Rac GTPase activating protein 1 (RACGAP1) has been verified to be an oncogene in plenty tumors. The profound mechanism of RACGAP1 was rarely reported in HCC. In this study, we explored the function and mechanism of RACGAP1 in HCC through multiple analysis and experiments. RACGAP1 expression was up-regulated in HCC samples and the high expression of RACGAP1 was an independent prognostic risk factor for HCC patients. Meanwhile, RACGAP1 promoted developments of HCC both in vitro and in vivo. We verified that RACGAP1 promoted proliferation of HCC via PI3K/AKT/CDK2 and PI3K/AKT/GSK3β/Cyclin D1 signaling pathway. RACGAP1 accelerated the invasion and metastasis of HCC via phosphorylation of GSK3β and nuclear translocation of β-catenin. Furthermore, by luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay, we confirmed Recombinant GA Binding Protein Transcription Factor Alpha (GABPA) regulated the transcription of RACGAP1. All these findings revealed that RACGAP1 promotes the progression of HCC through a novel mechanism, which might be a new therapeutic target for HCC patients.
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Pavlek G, Romic I, Juzbasic K, Alduk AM, Petrovic I, Radojkovic R, Grbavac D, Silovski H. Case report: Urgent liver pathologies: All in one. Front Surg 2022; 9:940856. [PMID: 35937607 PMCID: PMC9346066 DOI: 10.3389/fsurg.2022.940856] [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: 05/10/2022] [Accepted: 06/29/2022] [Indexed: 11/24/2022] Open
Abstract
Ruptured hepatocellular carcinoma (HCC) is a well-known serious complication of this most common primary liver malignancy. However, when HCC rupture is associated with other focal liver lesions, the diagnosis and therapy may be very challenging. Correct differentiation of focal liver lesions is of paramount importance for successful treatment. The aim of this report is to present a unique case of HCC rupture complicated with liver abscess, hematoma and portal vein thrombosis. We discuss possible pathophysiological mechanisms and radiologic findings of such clinical scenarios and review literature related to the management of HCC rupture.
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Affiliation(s)
| | - Ivan Romic
- Department of Surgery, University Hospital Centre Zagreb, Zagreb, Croatia
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Huang L, Guan S, Feng L, Wei J, Wu L. Integrated analysis identified NPNT as a potential key regulator in tumor metastasis of hepatocellular carcinoma. Gene 2022; 825:146436. [PMID: 35304239 DOI: 10.1016/j.gene.2022.146436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/12/2022] [Accepted: 03/11/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the lethal malignancies worldwide. Tumor metastasis is the main cause of HCC related death. Although progress has been made in the mechanism study of HCC in the past decades, the underlying mechanism of HCC metastasis has not been fully illustrated. In the present study, bioinformatic analysis including weighted gene co-expression network analysis (WGCNA), differentially expressed gene analysis, and gene enrichment analysis were applied to discover genes correlated with HCC metastasis. Immunohistochemistry (IHC) assays were applied to detect the expression of NPNT in HCC samples. Cell transfection, wound healing, matrigel transwell assays, and western blot assays were utilized to evaluate the effects of NPNT on cell migration and invasion and signaling pathway variation. We found that NPNT was up-regulated in HCC tumor tissues compared with normal tissues. Especially, NPNT was highly expressed in metastatic tumor compared with non-metastatic HCC tumors. Down-regulation of NPNT via siRNA transfection inhibited cell migration, invasion, and FAK/PI3K/AKT signaling pathway in HCC. Our results demonstrate that NPNT is a potential key regulator in HCC metastasis.
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Affiliation(s)
- Lingkun Huang
- Medical College, Guangxi University, Nanning 530004, China
| | - Shuzhen Guan
- Medical College, Guangxi University, Nanning 530004, China
| | - Lin Feng
- Department of Pathology, the first Medical Center of PLA General Hospital, Beijing, China
| | - Jinrui Wei
- Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Lichuan Wu
- Medical College, Guangxi University, Nanning 530004, China.
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PI3K/AKT/mTOR Pathway-Associated Genes Reveal a Putative Prognostic Signature Correlated with Immune Infiltration in Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:7545666. [PMID: 35592706 PMCID: PMC9112180 DOI: 10.1155/2022/7545666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/09/2022] [Accepted: 03/29/2022] [Indexed: 11/26/2022]
Abstract
Background The dysregulated PI3K/AKT/mTOR pathway acts as the main regulator of tumorigenesis in hepatocellular carcinoma (HCC). Aim Here, we identify the prognostic significance of PI3K/AKT/mTOR pathway-associated genes (PAGs) as well as their putative signature based on PAGs in an HCC patient's cohort. Methods The transcriptomic data and clinical feature sets were queried to extract the putative prognostic signature. Results We identified nine PAGs with different expressions. GO and KEGG indicated that these differentially expressed genes were associated with various carcinogenic pathways. Based on the signature-computed median risk score, we categorized the patients into groups of low risk and high risk. The survival time for the low-risk group is longer than that of the high-risk group in Kaplan-Meier (KM) curves. The prognostic value of risk score (ROC = 0.736) of receiver operating characteristic (ROC) curves performed better in comparison to that of other clinicopathological features. In both the GEO database and ICGC database, these outcomes were verified. The predictions of the overall survival rates in HCC patients of 1 year, 3 years, and 5 years can be obtained separately from the nomogram. The risk score was associated with the immune infiltrations of CD8 T cells, activated CD4 memory T cells, and follicular helper T cells, and the expression of immune checkpoints (PD-1, TIGIT, TIM-3, BTLA, LAG-3, and CTLA4) was positively relevant to the risk score. The sensitivity to several chemotherapeutic drugs can also be revealed by the signature. CDK1, PITX2, PRKAA2, and SFN were all upregulated in the tumor tissue of clinical samples. Conclusion A putative and differential dataset-validated prognostic signature on the basis of integrated bioinformatic analysis was established in our study, providing the immunotherapeutic targets as well as the personalized treatment in HCC with neoteric insight.
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Teng YJ, Deng Z, Ouyang ZG, Zhou Q, Mei S, Fan XX, Wu YR, Long HP, Fang LY, Yin DL, Zhang BY, Guo YM, Zhu WH, Huang Z, Zheng P, Ning DM, Tian XF. Xihuang pills induce apoptosis in hepatocellular carcinoma by suppressing phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin pathway. World J Gastrointest Oncol 2022; 14:872-886. [PMID: 35582102 PMCID: PMC9048534 DOI: 10.4251/wjgo.v14.i4.872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/30/2021] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phosphoinositide 3-kinase/protein kinase-B/mechanistic target of rapamycin (PI3K/Akt/mTOR) signalling pathway is crucial for cell survival, differentiation, apoptosis and metabolism. Xihuang pills (XHP) are a traditional Chinese preparation with antitumour properties. They inhibit the growth of breast cancer, glioma, and other tumours by regulating the PI3K/Akt/mTOR signalling pathway. However, the effects and mechanisms of action of XHP in hepatocellular carcinoma (HCC) remain unclear. Regulation of the PI3K/Akt/mTOR signalling pathway effectively inhibits the progression of HCC. However, no study has focused on the XHP-associated PI3K/Akt/mTOR signalling pathway. Therefore, we hypothesized that XHP might play a role in inhibiting HCC through the PI3K/Akt/mTOR signalling pathway.
AIM To confirm the effect of XHP on HCC and the possible mechanisms involved.
METHODS The chemical constituents and active components of XHP were analysed using ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Cell-based experiments and in vivo xenograft tumour experiments were utilized to evaluate the effect of XHP on HCC tumorigenesis. First, SMMC-7721 cells were incubated with different concentrations of XHP (0, 0.3125, 0.625, 1.25, and 2.5 mg/mL) for 12 h, 24 h and 48 h. Cell viability was assessed using the CCK-8 assay, followed by an assessment of cell migration using a wound healing assay. Second, the effect of XHP on the apoptosis of SMMC-7721 cells was evaluated. SMMC-7721 cells were stained with fluorescein isothiocyanate and annexin V/propidium iodide. The number of apoptotic cells and cell cycle distribution were measured using flow cytometry. The cleaved protein and mRNA expression levels of caspase-3 and caspase-9 were detected using Western blotting and quantitative reverse-transcription polymerase chain reaction (RT-qPCR), respectively. Third, Western blotting and RT–qPCR were performed to confirm the effects of XHP on the protein and mRNA expression of components of the PI3K/Akt/mTOR signalling pathway. Finally, the effects of XHP on the tumorigenesis of subcutaneous hepatocellular tumours in nude mice were assessed.
RESULTS The following 12 compounds were identified in XHP using high-resolution mass spectrometry: Valine, 4-gingerol, myrrhone, ricinoleic acid, glycocholic acid, curzerenone, 11-keto-β-boswellic acid, oleic acid, germacrone, 3-acetyl-9,11-dehydro-β-boswellic acid, 5β-androstane-3,17-dione, and 3-acetyl-11-keto-β-boswellic acid. The cell viability assay results showed that treatment with 0.625 mg/mL XHP extract decreased HCC cell viability after 12 h, and the effects were dose- and time-dependent. The results of the cell scratch assay showed that the migration of HCC cells was significantly inhibited in a time-dependent manner by the administration of XHP extract (0.625 mg/mL). Moreover, XHP significantly inhibited cell migration and resulted in cell cycle arrest and apoptosis. Furthermore, XHP downregulated the PI3K/Akt/mTOR signalling pathway, which activated apoptosis executioner proteins (e.g., caspase-9 and caspase-3). The inhibitory effects of XHP on HCC cell growth were determined in vivo by analysing the tumour xenograft volumes and weights.
CONCLUSION XHP inhibited HCC cell growth and migration by stimulating apoptosis via the downregulation of the PI3K/Akt/mTOR signalling pathway, followed by the activation of caspase-9 and caspase-3. Our findings clarified that the antitumour effects of XHP on HCC cells are mediated by the PI3K/Akt/mTOR signalling pathway, revealing that XHP may be a potential complementary therapy for HCC.
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Affiliation(s)
- Yong-Jie Teng
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhe Deng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhao-Guang Ouyang
- Department of Preventive Dentistry, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510132, Guangdong Province, China
| | - Qing Zhou
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xing-Xing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
| | - Yong-Rong Wu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Hong-Ping Long
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Le-Yao Fang
- The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Dong-Liang Yin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Bo-Yu Zhang
- College of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yin-Mei Guo
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Wen-Hao Zhu
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhen Huang
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Piao Zheng
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Di-Min Ning
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Xue-Fei Tian
- College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
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Bao ZM, Yao D, Qian X, Zhang HG, Yang M, Guo YH, Qin L. Activating transcription factor 2 promotes the progression of hepatocellular carcinoma by inducing the activation of the WHSC1-mediated TOP2A/PI3K/AKT axis. Kaohsiung J Med Sci 2022; 38:662-674. [PMID: 35394699 DOI: 10.1002/kjm2.12536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
Activating transcription factor 2 (ATF2) is a tumor driver gene implicated in several human malignancies. This study aimed to determine the roles of ATF2 and its related molecules in the tumorigenesis of hepatocellular carcinoma (HCC). According to the Pan-cancer bioinformatics system, ATF2 is highly expressed in HCC. An increase in the expression of ATF2 was identified in clinically collected tumor tissues and procured HCC cells. The silencing of ATF2 reduced the viability, colony formation, invasion, and death resistance of HepG2 and SNU-398 cells in vitro. ATF2 promoted the transcription of Wolf-Hirschhorn syndrome candidate 1 (WHSC1) by binding to its promoter. WHSC1 further increased the expression of DNA topoisomerase II alpha (TOP2A) in HCC by inducing the dimethylation of histone H3 lysine 36 (H3K36me2) in the TOP2A promoter region. TOP2A activated the oncogenic PI3K/AKT signaling pathway. Further overexpression of WHSC1 activated the TOP2A/PI3K/AKT axis and restored the malignant behaviors of HCC cells suppressed by ATF2 silencing in vitro. In summary, this study demonstrated that, depending on WHSC1, ATF2 can activate the TOP2A/PI3K/AKT signaling cascade to promote the tumorigenesis of HCC. ATF2, WHSC1, and TOP2A may serve as potential targets in managing HCC.
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Affiliation(s)
- Zhong-Ming Bao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.,Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Dan Yao
- Department of Gastrointestinal Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Jiangsu, P. R. China
| | - Xu Qian
- Department of Thyroid and Breast Surgery, Huai'an Second People's Hospital, Jiangsu, P. R. China
| | - Hua-Guo Zhang
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Ming Yang
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Yun-Hu Guo
- Department of Hepatobiliary Surgery, Huaiyin People's Hospital (Huai'an Fifth People's Hospital), Jiangsu, P. R. China
| | - Lei Qin
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China
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El-Mahdy HA, Sallam AAM, Ismail A, Elkhawaga SY, Elrebehy MA, Doghish AS. miRNAs inspirations in hepatocellular carcinoma: Detrimental and favorable aspects of key performers. Pathol Res Pract 2022; 233:153886. [PMID: 35405621 DOI: 10.1016/j.prp.2022.153886] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. HCC initiation, progression, and therapy failure are all influenced by various variables, including microRNAs (miRNAs). miRNAs are short non-coding RNA sequences that modulate target mRNA expression by deteriorating or repressing translation. miRNAs play an imperative role in HCC pathogenesis by triggering the induction of cancer stem cells (CSCs) and their proliferation, while also delaying apoptosis, sustaining the cell cycle, and inspiring angiogenesis, invasion, and metastasis. Additionally, miRNAs modulate crucial HCC-related molecular pathways such as the p53 pathway, the Wnt/β-catenin pathway, VEGFR2, and PTEN/PI3K/AKT pathway. Consequently, the goal of this review was to give an up-to-date overview of oncogenic and tumor suppressor (TS) miRNAs, as well as their potential significance in HCC pathogenesis and treatment responses, highlighting their underpinning molecular pathways in HCC initiation and progression. Similarly, the biological importance and clinical application of miRNAs in HCC are summarized.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
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Huang L, Yang Q, Chen H, Wang Z, Liu Q, Ai S. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway. Open Med (Wars) 2022; 17:626-637. [PMID: 35434373 PMCID: PMC8976180 DOI: 10.1515/med-2022-0453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 01/05/2022] [Accepted: 02/22/2022] [Indexed: 12/24/2022] Open
Abstract
The activation of signaling pathways induced by Toll-like receptor (TLR) has been demonstrated to play essential roles in multiple liver diseases. Toll-interacting protein (Tollip) acts as an endogenous negative modulator of TLR signaling and is implicated in various cardio-metabolic diseases. However, the effect of Tollip in hepatocellular carcinoma (HCC) remains elusive. In the current study, enhanced Tollip expression was observed in HCC cells and tissues examined by RT-PCR, western blot, and immunohistochemistry staining. Moreover, the co-immunofluorescence staining demonstrated that increased Tollip expression was primarily located in hepatocytes. Functionally, Tollip overexpression significantly increased proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, which ultimately accelerated tumorigenesis. Mechanistically, Tollip overexpression dramatically promoted the activation of PI3K/AKT signaling pathway in HCC cells which was attenuated by Tollip silencing. Importantly, the inhibition of PI3K/AKT axis can abolish the promoted effects of Tollip on proliferation and EMT of HCC cells. Our current study demonstrated that Tollip played an important role in the regulation of HCC development by engaging PI3K/AKT signaling pathway. These evidences suggested that the blockade of Tollip-PI3K/AKT axis was an ideal therapeutic treatment for management of HCC.
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Affiliation(s)
- Lu Huang
- Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan province, China
| | - Qiong Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan province, China
| | - Huihong Chen
- Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan province, China
| | - Zhenggeng Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan province, China
| | - Qi Liu
- Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang City, 421001, Hunan province, China
| | - Shuhua Ai
- Department of Gastroenterology, The Second Affiliated Hospital of University of South China, No. 35 Jiefang Road, Hengyang City, 421001, Hunan province, China
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Zhou J, Che J, Xu L, Yang W, Li Y, Zhou W, Zou S. Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1. Bioengineered 2022; 13:5737-5755. [PMID: 35184652 PMCID: PMC8974146 DOI: 10.1080/21655979.2021.2023792] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Metastasis and chemoresistance are the leading causes of death in patients with hepatocellular carcinoma (HCC). microRNAs (miRNAs or miRs) may be useful as diagnostic, therapeutic and prognostic markers for HCC. In this study, we set out to investigate the possible role of miR-381 in HCC development and chemoresistance along with the related mechanism. Microarray-based gene expression profiling was carried out to analyze the expression of SET domain bifurcated 1 (SETDB1) and histone methyltransferase enhancer of zeste homolog 2 (EZH2) followed by validation in clinical HCC tissues and cells. The potential binding between miR-381 and SETDB1 was found and verified. Then, the role of SETDB1 in HCC in relation to miR-381 and protein kinase B (AKT) pathway was explored through gain- and loss-of-function approaches. After expression determination of EZH2, SETDB1, miR-381, and AKT pathway-related factors, their reactions were analyzed and their functional roles in HCC progression and chemoresistance were investigated in vitro and in vivo. SETDB1 was aberrantly upregulated in clinical HCC tissues and cells. This upregulation activated AKT pathway by promoting its tri-methylation on K64. SETDB1 promoted the proliferation, migration and chemoresistance through the AKT pathway in HCC cells. In a xenograft mouse model, SETDB1 promoted HCC cell tumorigenesis in vivo by activating the AKT pathway. Furthermore, EZH2 suppressed miR-381 by catalyzing the activity of H3K27me3 on its promoter region. In conclusion, EZH2 suppressed miR-381 expression by promoting H3K27me3 activity on its promoter region to facilitate SETDB1 expression, thereby activating the AKT pathway to promote hepatocarcinogenesis and chemoresistance.
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Affiliation(s)
- Jingyang Zhou
- Queen Mary School, Medical Department, Nanchang University, Nanchang, P.R. China
| | - Jinhui Che
- Department of Hepatobillary Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, P.R. China
| | - Lu Xu
- Department of Hepatobillary Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, P.R. China
| | - Weizhong Yang
- Department of Hepatobillary Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, P.R. China
| | - Yunmei Li
- Department of Hepatobillary Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, P.R. China
| | - Wuyuan Zhou
- Department of Hepatopancreatobillary Surgery, Xuzhou Cancer Hospital, Xuzhou, P.R. China
| | - Shubing Zou
- Department of Hepatopancreatobillary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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Karanam G, Arumugam MK. Potential anticancer effects of cyclo(-Pro-Tyr) against N-diethyl nitrosamine induced hepatocellular carcinoma in mouse through PI3K/AKT signaling. ENVIRONMENTAL TOXICOLOGY 2022; 37:256-269. [PMID: 34726822 DOI: 10.1002/tox.23395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 06/13/2023]
Abstract
The oceans are considered as magnificent source of bioactive metabolites, of which marine sponges associated organisms are being the most effective producers of various bioactive molecules. We previously reported that cyclo(-Pro-Tyr) (CPT), a dipeptide from marine sponge Callyspongia fistularis associated Bacillus pumilus AMK1 bacteria for its anti-proliferative activity through down regulating PI3K signaling and inducing mitochondrial mediated apoptosis in HepG2 cells. Further we emphasize to study the role of CPT against hepatocellular carcinoma (HCC) induced by N-diethylnitrosamine (DEN) in male swiss albino mice in vivo. In this study, HCC was induced by the administration of DEN (75 mg/kg b.wt) dissolved in saline once/week for 3 weeks, then 100 mg/kg b.wt for another successive 3 weeks and observed for 18 weeks. CPT (100 mg/kg b.wt) treatment was started after 14 weeks of DEN induction. The obtained results demonstrated that CPT altered DEN induced oxidative stress by decreasing serum SGOT and SGPT followed increment in the antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. This was accompanied by decreased accumulation of glycoconjugates and argyophilic nucleolar organizing regions in the treatment groups. Further, CPT significantly reduced the levels of phospho-PI3Kinase p85 and phospho-AKT and upregulation of PTEN compared with DEN induced group. Besides this, decreased expression of Bcl-2 and increased expression of Bax, Caspase 3, and p53 was observed in CPT treated mice. Therefore, the anticancer mechanism of CPT against DEN induced HCC may be associated with the regulation of the PI3K/AKT signaling pathway, which ultimately stimulates apoptosis.
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Affiliation(s)
- Gayathri Karanam
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Madan Kumar Arumugam
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
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Mo M, Liu B, Luo Y, Tan JHJ, Zeng X, Zeng X, Huang D, Li C, Liu S, Qiu X. Construction and Comprehensive Analysis of a circRNA-miRNA-mRNA Regulatory Network to Reveal the Pathogenesis of Hepatocellular Carcinoma. Front Mol Biosci 2022; 9:801478. [PMID: 35141281 PMCID: PMC8819184 DOI: 10.3389/fmolb.2022.801478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC.Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network.Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa_circRNA_091581, hsa_circRNA_066568, and hsa_circRNA_105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes (ESR1, BUB1, PRC1, LOX, CCT5, YWHAZ, and DDX39B) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells.Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC.
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Affiliation(s)
- Meile Mo
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Bihu Liu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Yihuan Luo
- Department of Acute Care Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jennifer Hui Juan Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xi Zeng
- Department of Occupational and Environmental Health, School of Public Health, Guilin Medical University, Guilin, China
| | - Xiaoyun Zeng
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Dongping Huang
- Department of Sanitary Chemistry, School of Public Health, Guangxi Medical University, Nanning, China
| | - Changhua Li
- Department of Acute Care Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shun Liu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Guangxi Medical University, Nanning, China
- *Correspondence: Xiaoqiang Qiu, ; Shun Liu,
| | - Xiaoqiang Qiu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
- *Correspondence: Xiaoqiang Qiu, ; Shun Liu,
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Gouda G, Gupta MK, Donde R, Behera L, Vadde R. Tumor microenvironment in heptocellular carcinoma. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:109-124. [DOI: 10.1016/b978-0-323-98806-3.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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Ding W, Chen X, Yang L, Chen Y, Song J, Bu W, Feng B, Zhang M, Luo Y, Jia X, Feng L. Combination of ShuangDan Capsule and Sorafenib Inhibits Tumor Growth and Angiogenesis in Hepatocellular Carcinoma Via PI3K/Akt/mTORC1 Pathway. Integr Cancer Ther 2022; 21:15347354221078888. [PMID: 35234063 PMCID: PMC8894619 DOI: 10.1177/15347354221078888] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a high mortality liver cancer. The existing treatments (transplantation, chemotherapy, and individualized treatment) with limitations. However, drug combination provides a viable option for hepatocellular carcinoma treatment. A Chinese patent medicine, ShuangDan Capsules (SDC), has been clinically prescribed to hepatocellular carcinoma patients as adjuvant therapy and has shown good antitumor activity. The purpose of this study was to investigate whether SDC could improve the anti-cancer effect and mitigate adverse reactions of sorafenib on HCC in vivo. Magnetic resonance imaging (MRI), immunohistochemistry, and western blot were executed to reveal the potential mechanisms of the combination of SDC and sorafenib on HCC. Tumors appeared hyperintense on T2 sequence images relative to the adjacent normal liver in MRI. Combination of SDC and sorafenib inhibited the progression of DEN (Diethylnitrosamine)-induced HCC. In the HepG2 xenografts model, sorafenib plus SDC exhibited greater suppression on tumor growth than individual treatment accompanied with decreased expression of VEGF, VEGFA, Ki67, CD31 and increased expression of caspase-3. Furthermore, PI3K/Akt/mTORC1 pathway was inhibited by co-administration. Sorafenib monotherapy elicited hepatotoxicity for specific expression in the up-regulated level of aspartate transaminase (AST) and AST/glutamic-pyruvic transaminase (ALT) ratio, but the co-administration could remedy this adverse effect. These dates indicated that the combination of SDC and sorafenib might offer a potential therapy for HCC.
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Affiliation(s)
- Wenbo Ding
- Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Xiuwei Chen
- Yuhuatai District Maternity and Child Care Clinic, Nanjing, P.R. China
| | - Licheng Yang
- China Pharmaceutical University, Nanjing, P.R. China
| | - Yaping Chen
- China Pharmaceutical University, Nanjing, P.R. China
| | - Jie Song
- Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Weiquan Bu
- Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Bin Feng
- Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Meng Zhang
- China Pharmaceutical University, Nanjing, P.R. China
| | - Yi Luo
- Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Xiaobin Jia
- China Pharmaceutical University, Nanjing, P.R. China
| | - Liang Feng
- China Pharmaceutical University, Nanjing, P.R. China
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Abstract
Hepatocellular carcinoma (HCC) is a very deadly disease. HCC initiation and progression involve multiple genetic events, including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes. Activation of oncogenes stimulates cell growth and survival, while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth. In this review, we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years. These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.
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Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells. Biomedicines 2021; 9:biomedicines9111527. [PMID: 34829756 PMCID: PMC8615277 DOI: 10.3390/biomedicines9111527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/12/2021] [Accepted: 10/20/2021] [Indexed: 12/20/2022] Open
Abstract
Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.
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Sun RJ, Yin DM, Yuan D, Liu SY, Zhu JJ, Shan NN. Quantitative LC-MS/MS uncovers the regulatory role of autophagy in immune thrombocytopenia. Cancer Cell Int 2021; 21:548. [PMID: 34663331 PMCID: PMC8524881 DOI: 10.1186/s12935-021-02249-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 10/07/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is an autoimmune haemorrhagic disease whose pathogenesis is associated with bone marrow megakaryocyte maturation disorder and destruction of the haematopoietic stem cell microenvironment. METHODS In this study, we report the qualitative and quantitative profiles of the ITP proteome. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted to elucidate the protein profiles of clinical bone marrow mononuclear cell (BMMC) samples from ITP patients and healthy donors (controls). Gene Ontology (GO) and Kyoto Encyclopaedia Genes and Genome (KEGG) pathway analyses were performed to annotate the differentially expressed proteins. A protein-protein interaction (PPI) network was constructed with the BLAST online database. Target proteins associated with autophagy were quantitatively identified by parallel reaction monitoring (PRM) analysis. RESULTS Our approaches showed that the differentially expressed autophagy-related proteins, namely, HSPA8, PARK7, YWHAH, ITGB3 and CSF1R, were changed the most. The protein expression of CSF1R in ITP patients was higher than that in controls, while other autophagy-related proteins were expressed at lower levels in ITP patients than in controls. CONCLUSION Bioinformatics analysis indicated that disruption of the autophagy pathway is a potential pathological mechanism of ITP. These results can provide a new direction for exploring the molecular mechanism of ITP.
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Affiliation(s)
- Rui-Jie Sun
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Dong-Mei Yin
- Department of Blood Transfusion, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Dai Yuan
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China
| | - Shu-Yan Liu
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Jing-Jing Zhu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China
| | - Ning-Ning Shan
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China.
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Fang J, Zhu H, Xu P, Jiang R. Zingerone suppresses proliferation, invasion, and migration of hepatocellular carcinoma cells by the inhibition of MTDH-mediated PI3K/Akt pathway. J Recept Signal Transduct Res 2021; 42:409-417. [PMID: 34645355 DOI: 10.1080/10799893.2021.1988970] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE Previous studies have proved that zingerone was a therapeutic agent for many tumors. Metadherin (MTDH) acts as an oncogene and is involved in tumorigenesis. The purpose of this study was to explore the underlying mechanism of zingerone that regulates MTDH to affect hepatocellular carcinoma (HCC) progression. METHODS CCK-8 assay was performed to detect HCC cell proliferation. The invasion and migration abilities of HCC cells were evaluated using Transwell assay. The mRNA and protein levels in cells and tissues were measured using qRT-PCR and Western blot assays. Moreover, we established the HCC xenografts nude mice to evaluate the effect of zingerone on tumor growth. RESULTS We found that zingerone treatment significantly inhibited HCC cell malignant phenotype and tumor growth. Moreover, MTDH was highly expressed in HCC tissues and cell lines and was positively associated with poor overall survival of patients with HCC. Knockdown of MTDH notably suppressed the proliferation, invasion, and migration capacities of HCC cells. Mechanistically, inhibition of MTDH by zingerone impeded the malignant biological behavior of HCC cells by inactivating the PI3K/Akt pathway. CONCLUSION These results suggested that zingerone served as an effective therapeutic agent in HCC via blocking the MTDH-mediated PI3K/Akt pathway.
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Affiliation(s)
- Jian Fang
- Department of Hepatobiliary Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Huifen Zhu
- Department of Hepatobiliary Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Pengcheng Xu
- Department of Hepatobiliary Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Renya Jiang
- Department of Hepatobiliary Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
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El-Hanboshy SM, Helmy MW, Abd-Alhaseeb MM. Catalpol synergistically potentiates the anti-tumour effects of regorafenib against hepatocellular carcinoma via dual inhibition of PI3K/Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways. Mol Biol Rep 2021; 48:7233-7242. [PMID: 34596810 DOI: 10.1007/s11033-021-06715-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 09/23/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer characterized by dysregulation of several crucial cellular signaling pathways such as PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. Novel therapies targeting these pathways have been discovered such as regorafenib which is small molecular multi-kinase inhibitor mainly targets VEGF/VEGFR2. Catalpol is an iridoid glycoside richly found in rehmannia glutinosa which is a fundamental herb used extensively in traditional Chinese medicine. It is evidenced that catalpol has many pharmacological effects on nervous and cardiovascular systems, in addition to exhibiting hypoglycemic, anti-inflammatory, anti-proliferative and anti-tumour activities. However, its effect on HCC isn't clear enough. So, this study aimed to investigate the anti-tumour effects of catalpol either alone or in combination with regorafenib on HCC. METHODS AND RESULTS In vitro experiments were performed using HepG2 and HUH-7 hepatocellular carcinoma cell lines. MTT assays evaluated anti-proliferative effects of catalpol and/or regorafenib. Combination index was calculated via compusyn software to detect synergism. Tumour biomarkers were measured using ELISA technique. Results showed that catalpol has anti-tumour effects against HCC via targeting PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 pathways. In addition, results revealed that our novel combination of catalpol and regorafenib showed potent synergistic anti-tumour effect via suppressing both of PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and their downstreams. CONCLUSION Catalpol and/or regorafenib markedly suppressed PI3K/p-Akt/mTOR/NF-κB and VEGF/VEGFR2 signaling pathways and consequently showed potent anti-tumour effects against HCC. Results encourage further pre-clinical and clinical studies of this novel combination as a promising targeted therapy for HCC management.
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Affiliation(s)
- Sara Muhammad El-Hanboshy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.
| | - Maged Wasfy Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt
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Chen G, Zhang W, Ben Y. Identification of Key Regulators of Hepatitis C Virus-Induced Hepatocellular Carcinoma by Integrating Whole-Genome and Transcriptome Sequencing Data. Front Genet 2021; 12:741608. [PMID: 34567091 PMCID: PMC8460086 DOI: 10.3389/fgene.2021.741608] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/12/2021] [Indexed: 12/23/2022] Open
Abstract
Background: Hepatitis C virus (HCV) infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in the understanding of the biological basis of HCC development, the molecular mechanisms underlying HCV-induced HCC (HCC-HCV) remain unclear. The carcinogenic potential of HCV varies according to the genotype and mutation in its viral sequence. Moreover, regulatory pathways play important roles in many pathogenic processes. Therefore, identifying the pathways by which HCV induces HCC may enable improved HCC diagnosis and treatment. Methods: We employed a systematic approach to identify an important regulatory module in the process of HCV-HCC development to find the important regulators. First, an HCV-related HCC subnetwork was constructed based on the gene expression in HCC-HCV patients and HCC patients. A priority algorithm was then used to extract the module from the subnetworks, and all the regulatory relationships of the core genes of the network were extracted. Integrating the significantly highly mutated genes involved in the HCC-HCV patients, core regulatory modules and key regulators related to disease prognosis and progression were identified. Result: The key regulatory genes including EXO1, VCAN, KIT, and hsa-miR-200c-5p were found to play vital roles in HCV-HCC development. Based on the statistics analysis, EXO1, VCAN, and KIT mutations are potential biomarkers for HCV–HCC prognosis at the genomic level, whereas has-miR-200c-5P is a potential biomarker for HCV–HCC prognosis at the expression level. Conclusion: We identified three significantly mutated genes and one differentially expressed miRNA, all related to HCC prognosis. As potential pathogenic factors of HCC, these genes and the miRNA could be new biomarkers for HCV-HCC diagnosis.
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Affiliation(s)
- Guolin Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yiran Ben
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Zhu H, Liu X. Advances of Tumorigenesis, Diagnosis at Early Stage, and Cellular Immunotherapy in Gastrointestinal Malignancies. Front Oncol 2021; 11:666340. [PMID: 34434889 PMCID: PMC8381364 DOI: 10.3389/fonc.2021.666340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023] Open
Abstract
Globally, in 2018, 4.8 million new patients have a diagnosis of gastrointestinal (GI) cancers, while 3.4 million people died of such disorders. GI malignancies are tightly relevant to 26% of the world-wide cancer incidence and occupies 35% of all cancer-associated deaths. In this article, we principally investigated molecular and cellular mechanisms of tumorigenesis in five major GI cancers occurring at esophagus, stomach, liver, pancreas, and colorectal region that illustrate high morbidity in Eastern and Western countries. Moreover, through this investigation, we not only emphasize importance of the tumor microenvironment in development and treatment of malignant tumors but also identify significance of M2PK, miRNAs, ctDNAs, circRNAs, and CTCs in early detection of GI cancers, as well as systematically evaluate contribution of personalized precision medicine including cellular immunotherapy, new antigen and vaccine therapy, and oncolytic virotherapy in treatment of GI cancers.
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Affiliation(s)
- Haipeng Zhu
- Precision and Personalized Cancer Treatment Center, Division of Cancer Diagnosis & Therapy, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China.,Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical College, Xinxiang, China
| | - Xiaojun Liu
- Division of Cellular & Biomedical Science, Ciming Boao International Hospital, Boao Lecheng International Medical Tourism Pilot Zone, Qionghai, China
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Jin M, Kong L, Han Y, Zhang S. Gut microbiota enhances the chemosensitivity of hepatocellular carcinoma to 5-fluorouracil in vivo by increasing curcumin bioavailability. Phytother Res 2021; 35:5823-5837. [PMID: 34374130 DOI: 10.1002/ptr.7240] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 01/01/2023]
Abstract
5-Fluorouracil (5-Fu) is efficient for hepatocellular carcinoma (HCC) treatment, but fast-emerging resistance limits its usage. Curcumin is being investigated for its potential chemosensitivity, but its low oral bioavailability hinders its chemosensitivity effect in vivo. Gut microbiota modulation is considered to contribute to its bioactivities in vivo. In the current study, we demonstrate that curcumin can enhance 5-Fu chemosensitivity in HCC cells in vitro, increase the apoptosis rate, arrest the cell cycle at G2/M phase, and block the PI3k/AKT/mTOR signalling pathway by inhibiting the phosphorylation of PI3K and its downstream protein kinases. Curcumin also remarkably sensitized H22 cells to 5-Fu, allowing it to inhibit tumour growth in vivo. 16S rDNA sequencing suggests that curcumin in combination with 5-Fu significantly alters the gut microbiota composition based on alpha and beta diversity analysis compared to drug treatment alone. Gut microbiota depletion abolished curcumin's chemosensitivity effect in vivo. A pharmacodynamics study suggested that the gut microbiota increased the oral bioavailability of curcumin (AUC(0-t) 15.24 ± 0.77 μM/h [wt] vs. 3.04 ± 0.18 μM/h [gut microbiota depleted]). In conclusion, curcumin can increase the chemosensitivity of HCC to 5-Fu in vitro and in vivo, and gut microbiota plays a key role in its effect in vivo.
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Affiliation(s)
- Meng Jin
- Department of Traditional Chinese Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Li Kong
- Department of Chinese and Western Medicine Combined with Liver Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ying Han
- Department of Traditional Chinese Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Sen Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union medical college, Beijing, China
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Yang H, Li Q, Su M, Luo F, Liu Y, Wang D, Fan Y. Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition. Bioorg Med Chem 2021; 46:116346. [PMID: 34403956 DOI: 10.1016/j.bmc.2021.116346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/18/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
Abnormal activation of the PI3K/Akt pathway is demonstrated in most of human malignant tumors via regulation of proliferation, cell cycle, and apoptosis. Therefore, drug discovery and development of targeting the PI3K/Akt pathway has attracted great interest of researchers in the development of anticancer drugs. In this study, fifteen 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives were designed and synthesized. Anticancer activities of the synthetic compounds were evaluated and the potential mechanisms were explored. Several compounds showed certain proliferation inhibitory activity against the tested cancer cells including human non-small cell lung cancer (NSCLC) HCC827, human neuroblastoma SH-SY5Y and hepatocellular carcinoma LM3 cells. Among them, compound 7i and 7m showed the best inhibitory activity against all the cancer cell lines and more active against HCC827 cells with IC50 values of 1.12 μM and 1.20 μM, respectively. In addition, 7i and 7m showed lower inhibitory activity against H7702 cells (human normal liver cells) with IC50 values of 8.66 μM and 10.89 μM, respectively, nearly 8-fold lower than that in HCC827 cells. These results suggested that compounds 7i and 7m had certain selectivity to tumor cells, compared to human normal cells. Further biological studies indicated 7i induced G2/M phase arrests and cell apoptosis of HCC827 cells via PI3K/Akt and caspase dependent pathway. Together, these novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives such as compound 7i and 7m might be lead compounds for development of potential anti-cancer drugs.
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Affiliation(s)
- Huarong Yang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China
| | - Qing Li
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Mingzhi Su
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Fang Luo
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China
| | - Yahua Liu
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China.
| | - Daoping Wang
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
| | - Yanhua Fan
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
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