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Sayilan Ozgun G, Ozgun E, Karabas T, Suer Gokmen S, Eskiocak S. Piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma: an in-vitro study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024:10.1007/s00210-024-03725-0. [PMID: 39708099 DOI: 10.1007/s00210-024-03725-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024]
Abstract
We aimed to determine the effects of piperine on cell viability, cellular stresses, and apoptosis first, then the relationship of piperine's effects with the c-Jun N-terminal kinase (JNK) signaling pathway, and also the interaction of piperine with sorafenib in hepatocellular carcinoma. Hepatocellular carcinoma (HepG2 and Hep3B) and non-cancerous hepatocyte (AML12) cell lines were used. The cell viability was determined by using MTT assay. Cellular stresses, apoptosis, and JNK signaling markers were measured by Western blotting. Cells were pre-treated with SP600125 as a JNK inhibitor. The inhibitory concentration 50% (IC50) values and interaction of piperine with sorafenib were calculated by using CompuSyn software. IC50 values of piperine were 97 µM for HepG2, 58 µM for Hep3B, and 184 µM for AML12 with incubation for 48 h. Piperine caused a significant concentration-dependent increase in cellular stresses, apoptosis, and activated JNK signaling in hepatocellular carcinoma cells. Pre-treatment with a JNK inhibitor significantly reduced piperine-induced cellular stresses, apoptosis, and cytotoxicity. Piperine had concentration-dependent additive or synergistic effects when combined with sorafenib in both HepG2 and Hep3B cells. We found that piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma.
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Affiliation(s)
- Gulben Sayilan Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey.
| | - Eray Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Tugce Karabas
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Selma Suer Gokmen
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Sevgi Eskiocak
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
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2
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Vij P, Hussain MS, Satapathy SK, Cobos E, Tripathi MK. The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3904. [PMID: 39682093 DOI: 10.3390/cancers16233904] [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: 09/11/2024] [Revised: 11/01/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC), a liver cancer originating from hepatocytes, is a major health concern and among the most common malignancies worldwide. Sorafenib, approved by the U.S. F.D.A., is the primary first-line treatment for patients with advanced HCC. While the preferred first-line systemic regimen for HCC is immunotherapy with Atezolizumab plus bevacizumab or Tremelimumab-actl + durvalumab, Sorafenib is still an alternative recommended regimen. While some patients with advanced HCC may benefit from Sorafenib treatment, most eventually develop resistance, leading to poor prognosis. Long noncoding RNAs (lncRNAs) have been found to play a critical role in tumorigenesis and the development of HCC, as well as other cancers. They are also key players in tumor drug resistance, though the mechanisms of lncRNAs in Sorafenib resistance in HCC remain poorly understood. This review summarizes the molecular mechanisms contributing to Sorafenib resistance in HCC with their potential correlation with lncRNAs, including the roles of transporters, receptors, cell death regulation, and other influencing factors.
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Affiliation(s)
- Puneet Vij
- Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA
| | - Mohammad Shabir Hussain
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Sanjaya K Satapathy
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health Center for Liver Diseases & Transplantation, Northshore University Hospital, Manhasset, NY 11030, USA
| | - Everardo Cobos
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Manish K Tripathi
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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3
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Bakiri L, Hasenfuss SC, Guío-Carrión A, Thomsen MK, Hasselblatt P, Wagner EF. Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc. Proc Natl Acad Sci U S A 2024; 121:e2404188121. [PMID: 38657045 PMCID: PMC11067056 DOI: 10.1073/pnas.2404188121] [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: 02/28/2024] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.
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Affiliation(s)
- Latifa Bakiri
- Laboratory Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Sebastian C. Hasenfuss
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Ana Guío-Carrión
- Genes, Development and Disease Group, National Cancer Research Centre, 28029, Madrid, Spain
| | - Martin K. Thomsen
- Department of Biomedicine, University of Aarhus, 8000, Aarhus, Denmark
| | - Peter Hasselblatt
- Department of Medicine II, University Hospital and Faculty of Medicine, 79106, Freiburg, Germany
| | - Erwin F. Wagner
- Laboratory Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
- Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna, 1090, Vienna, Austria
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4
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Ladd AD, Duarte S, Sahin I, Zarrinpar A. Mechanisms of drug resistance in HCC. Hepatology 2024; 79:926-940. [PMID: 36680397 DOI: 10.1097/hep.0000000000000237] [Citation(s) in RCA: 66] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/21/2022] [Indexed: 01/22/2023]
Abstract
HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
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Affiliation(s)
- Alexandra D Ladd
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Sergio Duarte
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ilyas Sahin
- Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
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5
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Liu Y, Sui A, Sun J, Wu Y, Liu F, Yang Y. c-Jun-mediated JMJD6 restoration enhances resistance of liver cancer to radiotherapy through the IL-4-activated ERK pathway. Cell Biol Int 2023; 47:1392-1405. [PMID: 37070787 DOI: 10.1002/cbin.12026] [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: 11/10/2022] [Revised: 03/17/2023] [Accepted: 04/01/2023] [Indexed: 04/19/2023]
Abstract
Radiotherapy is widely used in the treatment of liver cancer, but the efficacy can be limited by radioresistance. In this study, we attempt to delineate the possible molecular mechanism of c-Jun-regulated Jumonji domain-containing protein 6/interleukin 4/extracellular signal-regulated kinase (JMJD6/IL-4/ERK) axis in radioresistance of liver cancer. The expression of c-Jun was quantified in liver cancer tissues and cell lines, and the results indicated that c-Jun was upregulated in liver cancer tissues and cells. We further illustrated the role of c-Jun following gain- and loss-of-function strategies in malignant phenotypes of liver cancer cells. It was established that c-Jun elevated JMJD6 expression and augmented the malignancy and aggressiveness of liver cancer cells. The in vivo effects of c-Jun on radioresistance in liver cancer were validated in nude mice, in response to IL-4 knockdown or the ERK pathway inhibitor, PD98059. In the presence of JMJD6 upregulation, the expression of IL-4 was elevated in mice with liver cancer, which enhanced the radiation resistance. Moreover, knockdown of IL-4 inactivated the ERK pathway, thereby reversing the radiation resistance caused by overexpressed JMJD6 in tumor-bearing mice. Taken together, c-Jun augments the radiation resistance in liver cancer by activating the ERK pathway through JMJD6-upregulated IL-4 transcription.
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Affiliation(s)
- Yong Liu
- Department of Interventional Therapy, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing, People's Republic of China
- Department of Oncology, Baoding First Central Hospital, Baoding, People's Republic of China
| | - Aixia Sui
- The First Department of Oncology, Hebei Provincial People's Hospital, Shijiazhuang, People's Republic of China
| | - Jirui Sun
- Key Laboratory of Molecular Pathology & Early Diagnosis of Tumor (Hebei province), Baoding First Central Hospital, Baoding, People's Republic of China
| | - Yifan Wu
- Department of Interventional Therapy, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing, People's Republic of China
| | - Fuquan Liu
- Department of Interventional Therapy, Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing, People's Republic of China
| | - Yang Yang
- Health Science Center, Hebei University, Baoding, People's Republic of China
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6
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Zhou S, Xu H, Wei T. Inhibition of stress proteins TRIB3 and STC2 potentiates sorafenib sensitivity in hepatocellular carcinoma. Heliyon 2023; 9:e17295. [PMID: 37389061 PMCID: PMC10300369 DOI: 10.1016/j.heliyon.2023.e17295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 07/01/2023] Open
Abstract
Sorafenib resistance is one of the main obstacles to the treatment of advanced hepatocellular carcinoma (HCC). Stress proteins TRIB3 and STC2 confer cell resistance to a variety of stresses, including hypoxia, nutritional deprivation, and other perturbations, which induce endoplasmic reticulum stress. However, the role of TRIB3 and STC2 in sorafenib sensitivity to HCC remains unclear. In this study, our results indicated that the common differentially expressed genes (DEGs) in sorafenib-treated HCC cells obtained from the NCBI-GEO database (Huh7 and Hep3B cells; GSE96796) included TRIB3, STC2, HOXD1, C2orf82, ADM2, RRM2, and UNC93A. The most significantly upregulated DEGs were TRIB3 and STC2, which were both stress protein genes. Bioinformatic analysis in NCBI public databases indicated that TRIB3 and STC2 were highly expressed in HCC tissues and closely associated with poor prognoses in HCC patients. Further investigation showed that inhibition of TRIB3 or STC2 with siRNA could enhance the anti-cancer effect of sorafenib in HCC cell lines. In conclusion, our study showed that stress proteins TRIB3 and STC2 are closely associated with sorafenib resistance in HCC. The combination of TRIB3 or STC2 inhibition and sorafenib may be a promising therapeutic strategy for HCC.
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Affiliation(s)
- Sheng Zhou
- Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, China
| | - Huanji Xu
- Department of Abdominal Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Tianhong Wei
- Department of Ultrasound, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, China
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7
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Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
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Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
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8
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Hagiwara S, Nishida N, Kudo M. Advances in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:2070. [PMID: 37046727 PMCID: PMC10093619 DOI: 10.3390/cancers15072070] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) aim to induce immune responses against tumors and are less likely to develop drug resistance than molecularly targeted drugs. In addition, they are characterized by a long-lasting antitumor effect. However, since its effectiveness depends on the tumor's immune environment, it is essential to understand the immune environment of hepatocellular carcinoma to select ICI therapeutic indications and develop biomarkers. A network of diverse cellular and humoral factors establishes cancer immunity. By analyzing individual cases and classifying them from the viewpoint of tumor immunity, attempts have been made to select the optimal therapeutic drug for immunotherapy, including ICIs. ICI treatment is discussed from the viewpoints of immune subclass of HCC, Wnt/β-catenin mutation, immunotherapy in NASH-related HCC, the mechanism of HPD onset, and HBV reactivation.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
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9
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Zhou XH, Li JR, Zheng TH, Chen H, Cai C, Ye SL, Gao B, Xue TC. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis 2023; 40:5-32. [PMID: 36318440 DOI: 10.1007/s10585-022-10188-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
Abstract
Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.
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Affiliation(s)
- Xing-Hao Zhou
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Jing-Ru Li
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Tang-Hui Zheng
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Hong Chen
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Chen Cai
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Sheng-Long Ye
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Medical College, Shanghai, 200032, China.
| | - Tong-Chun Xue
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China. .,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China. .,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
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10
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Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches. Essays Biochem 2022; 66:371-386. [PMID: 35818992 DOI: 10.1042/ebc20220001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/24/2022]
Abstract
The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.
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11
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Chen VL, Huang Q, Harouaka R, Du Y, Lok AS, Parikh ND, Garmire LX, Wicha MS. A Dual-Filtration System for Single-Cell Sequencing of Circulating Tumor Cells and Clusters in HCC. Hepatol Commun 2022; 6:1482-1491. [PMID: 35068084 PMCID: PMC9134808 DOI: 10.1002/hep4.1900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/07/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Identification and sequencing of circulating tumor (CT) cells and clusters may allow for noninvasive molecular characterization of HCC, which is an unmet need, as many patients with HCC do not undergo biopsy. We evaluated CT cells and clusters, collected using a dual-filtration system in patients with HCC. We collected and filtered whole blood from patients with HCC and selected individual CT cells and clusters with a micropipette. Reverse transcription, polymerase chain reaction, and library preparation were performed using a SmartSeq2 protocol, followed by single-cell RNA sequencing (scRNAseq) on an Illumina MiSeq V3 platform. Of the 8 patients recruited, 6 had identifiable CT cells or clusters. Median age was 64 years old; 7 of 8 were male; and 7 of 8 had and Barcelona Clinic Liver Cancer stage C. We performed scRNAseq of 38 CT cells and 33 clusters from these patients. These CT cells and clusters formed two distinct groups. Group 1 had significantly higher expression than group 2 of markers associated with epithelial phenotypes (CDH1 [Cadherin 1], EPCAM [epithelial cell adhesion molecule], ASGR2 [asialoglycoprotein receptor 2], and KRT8 [Keratin 8]), epithelial-mesenchymal transition (VIM [Vimentin]), and stemness (PROM1 [CD133], POU5F1 [POU domain, class 5, transcription factor 1], NOTCH1, STAT3 [signal transducer and activator of transcription 3]) (P < 0.05 for all). Patients with identifiable group 1 cells or clusters had poorer prognosis than those without them (median overall survival 39 vs. 384 days; P = 0.048 by log-rank test). Conclusion: A simple dual-filtration system allows for isolation and sequencing of CT cells and clusters in HCC and may identify cells expressing candidate genes known to be involved in cancer biology. Presence of CT cells/clusters expressing candidate genes is associated with poorer prognosis in advanced-stage HCC.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Qianhui Huang
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Ramdane Harouaka
- Division of Hematology and OncologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Yuheng Du
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Anna S. Lok
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Neehar D. Parikh
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
| | - Lana X. Garmire
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMIUSA
| | - Max S. Wicha
- Division of Hematology and OncologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMIUSA
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12
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Anti-Cancer Activity of Buthus occitanus Venom on Hepatocellular Carcinoma in 3D Cell Culture. Molecules 2022; 27:molecules27072219. [PMID: 35408621 PMCID: PMC9000837 DOI: 10.3390/molecules27072219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/12/2022] [Accepted: 03/28/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most dominant primary liver cancer, which can be caused by chronic hepatitis virus infections and other environmental factors. Resection, liver transplantation, and local ablation are only a few of the highly effective and curative procedures presently accessible. However, other complementary treatments can reduce cancer treatment side effects. In this present work, we evaluated the activity of Moroccan scorpion venom Buthus occitanus and its fractions obtained by chromatography gel filtration against HCC cells using a 3D cell culture model. The venom was fractionated by gel filtration chromatography, each fraction and the crude venom was tested on normal hepatocytes (Fa2N-4 cells). Additionally, the fractions and the crude venom were tested on MCTSs (multicellular tumor spheroids), and this latter was generated by cultivate Huh7.5 cancer cell line with WI38 cells, LX2 cells, and human endothelial cells (HUVEC). Our results indicate that Buthus occitanus venom toxin has no cytotoxic effects on normal hepatocytes. Moreover, it is reported that F3 fraction could significantly inhibit the MCTS cells. Other Protein Separation Techniques (High-performance liquid chromatography) are needed in order to identify the most active molecule.
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13
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Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition. Cancers (Basel) 2022; 14:cancers14040910. [PMID: 35205659 PMCID: PMC8869973 DOI: 10.3390/cancers14040910] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.
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14
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Zhou M, Chen X, Bai H, Sun Y, Zhang Z, Li S, Wang X, Zeng M. RABL2A-CCDC34 Axis Promotes Sorafenib Resistance in Hepatocellular Carcinoma. DNA Cell Biol 2021; 40:1418-1427. [PMID: 34767735 DOI: 10.1089/dna.2021.0473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
In this study, we examined the regulatory role of CCDC34 in the sorafenib sensitivity of hepatocellular carcinoma (HCC) and its functional partners. Wide-type Huh7 and Hep3B and induced sorafenib-resistant (SR) Huh7/SR and Hep3B/SR cells were used as in vitro cell models. Immunofluorescent staining and coimmunoprecipitation were performed to check protein-protein interaction. Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL), PI/Annexin V staining, and western blot analysis were performed to assess cell response to sorafenib. The results showed that CCDC34 upregulation in HCC was associated with poor survival. Huh7/SR and Hep3B/SR cells had significantly higher CCDC34 expression than the parental cell lines. RABL2A expression was significantly upregulated in SR HCC cells and interacted with CCDC34 in its GTP-bound state in Huh7/SR and Hep3B/SR cells. RABL2A depletion sensitized Huh7/SR and Hep3B/SR cells to sorafenib. RABL2A Q80L mutant (GTP-bound state locked), but not S35N mutant (GDP-bound state locked) overexpression increased sorafenib IC50 of Huh7 and Hep3B cells. CCDC34 depletion nearly abrogated the protective effects of RABL2A Q80L overexpression both in vitro and in vivo. RABL2A Q80L overexpression significantly increased the expression of p-p38 and p-JNK, the effects of which were significantly attenuated by CCDC34 depletion. In summary, we infer that the RABL2A-CCDC34 axis plays an important role in mediating p38/MAPK and JNK/MAPK signaling, thereby contributing to acquired sorafenib resistance in HCC.
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Affiliation(s)
- Mingxiu Zhou
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xue Chen
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hansong Bai
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuemei Sun
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China
| | - Zican Zhang
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China
| | - Simin Li
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiaoshan Wang
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China
| | - Ming Zeng
- Cancer Center, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.,School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Cancer Center, Chengdu BOE Hospital, Chengdu, China
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15
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Guan X, Wu Y, Zhang S, Liu Z, Fan Q, Fang S, Qiao S, Sun F, Liang C. Activation of FcRn Mediates a Primary Resistance Response to Sorafenib in Hepatocellular Carcinoma by Single-Cell RNA Sequencing. Front Pharmacol 2021; 12:709343. [PMID: 34421602 PMCID: PMC8379008 DOI: 10.3389/fphar.2021.709343] [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: 05/13/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC.
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Affiliation(s)
| | - Yi Wu
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | | | | | | | | | | | | | - Chongyang Liang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
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16
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Hu X, Zhu H, Shen Y, Zhang X, He X, Xu X. The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:696705. [PMID: 34367979 PMCID: PMC8340683 DOI: 10.3389/fonc.2021.696705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.
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Affiliation(s)
- Xinyao Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Shen
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoyu Zhang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoqin He
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.,Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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17
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Dahiya M, Dureja H. Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms. J Chemother 2021; 34:286-301. [PMID: 34291704 DOI: 10.1080/1120009x.2021.1955202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most widespread typical therapy-resistant, unresectable type of malignant solid tumour with a high death rate constituting huge medical concern. Sorafenib is a small molecule oral multi-target kinase potent inhibitor that acts by suppressing/blocking the multiplication of the tumour cells, angiogenesis, and encouraging apoptosis of the tumour cells. Though, the precise mechanism of tumour cell death induction by sorafenib is yet under exploration. Furthermore, genetic heterogeneity plays a critical role in developing sorafenib resistance, which leads the way to identify the need for predictive biomarkers responsible for drug resistance. Therefore, it is essential to find out the fundamental resistance mechanisms to expand therapeutic plans. The authors summarize the molecular concepts of resistance, progression, potential molecular targets, HCC management therapies, and discussion on the advancements expected in the coming future, inclusive of biomarker-driven treatment strategies, which may provide the prospects to design innovative therapeutically targeted strategies for the HCC treatment and the clinical implementation of emerging targeted agents.
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Affiliation(s)
- Mandeep Dahiya
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
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18
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Zeng Z, Lu Q, Liu Y, Zhao J, Zhang Q, Hu L, Shi Z, Tu Y, Xiao Z, Xu Q, Huang D. Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma. Front Oncol 2021; 11:641522. [PMID: 34307125 PMCID: PMC8292964 DOI: 10.3389/fonc.2021.641522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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Affiliation(s)
- Zhi Zeng
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Qiliang Lu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Yang Liu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Junjun Zhao
- Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.,Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qian Zhang
- The Medical College of Qingdao University, Qingdao, China
| | - Linjun Hu
- The Medical College of Qingdao University, Qingdao, China.,Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Zhan Shi
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yifeng Tu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zunqiang Xiao
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiuran Xu
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
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19
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Shrestha R, Bridle KR, Cao L, Crawford DHG, Jayachandran A. Dual Targeting of Sorafenib-Resistant HCC-Derived Cancer Stem Cells. ACTA ACUST UNITED AC 2021; 28:2150-2172. [PMID: 34208001 PMCID: PMC8293268 DOI: 10.3390/curroncol28030200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/09/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022]
Abstract
Sorafenib, an oral multi-tyrosine kinase inhibitor, has been the first-line therapy for the treatment of patients with advanced HCC, providing a survival benefit of only three months in approximately 30% of patients. Cancer stem cells (CSCs) are a rare tumour subpopulation with self-renewal and differentiation capabilities, and have been implicated in tumour growth, recurrence and drug resistance. The process of epithelial-to-mesenchymal transition (EMT) contributes to the generation and maintenance of the CSC population, resulting in immune evasion and therapy resistance in several cancers, including HCC. The aim of this study is to target the chemoresistant CSC population in HCC by assessing the effectiveness of a combination treatment approach with Sorafenib, an EMT inhibitor and an immune checkpoint inhibitor (ICI). A stem-cell-conditioned serum-free medium was utilised to enrich the CSC population from the human HCC cell lines Hep3B, PLC/PRF/5 and HepG2. The anchorage independent spheres were characterised for CSC features. The human HCC-derived spheres were assessed for EMT status and expression of immune checkpoint molecules. The effect of combination treatment with SB431542, an EMT inhibitor, and siRNA-mediated knockdown of programmed cell death protein ligand-1 (PD-L1) or CD73 along with Sorafenib on human HCC-derived CSCs was examined with cell viability and apoptosis assays. The three-dimensional spheres enriched from human HCC cell lines demonstrated CSC-like features. The human HCC-derived CSCs also exhibited the EMT phenotype along with the upregulation of immune checkpoint molecules. The combined treatment with SB431542 and siRNA-mediated PD-L1 or CD73 knockdown effectively enhanced the cytotoxicity of Sorafenib against the CSC population compared to Sorafenib alone, as evidenced by the reduced size and proliferation of spheres. Furthermore, the combination treatment of Sorafenib with SB431542 and PD-L1 or CD73 siRNA resulted in an increased proportion of an apoptotic population, as evidenced by flow cytometry analysis. In conclusion, the combined targeting of EMT and immune checkpoint molecules with Sorafenib can effectively target the CSC tumour subpopulation.
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Affiliation(s)
- Ritu Shrestha
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (R.S.); (K.R.B.); (L.C.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Kim R. Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (R.S.); (K.R.B.); (L.C.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Lu Cao
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (R.S.); (K.R.B.); (L.C.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Darrell H. G. Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (R.S.); (K.R.B.); (L.C.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
| | - Aparna Jayachandran
- Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia; (R.S.); (K.R.B.); (L.C.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- Correspondence: ; Tel.: +61-4-2424-8058
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20
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Liang Z, Wu B, Ji Z, Liu W, Shi D, Chen X, Wei Y, Jiang J. The binding of LDN193189 to CD133 C-terminus suppresses the tumorigenesis and immune escape of liver tumor-initiating cells. Cancer Lett 2021; 513:90-100. [PMID: 33984420 DOI: 10.1016/j.canlet.2021.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/16/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
The tumor-initiating cell (TIC) marker CD133 promotes TIC self-renewal and tumorigenesis through the tyrosine phosphorylation of its c-terminal domain. Therefore, finding compounds that target the phosphorylation of CD133 will provide an effective method for inhibiting TICs characteristics. Here, through small molecule microarray screening, compound LDN193189 was found to bind to the c-terminus of CD133 and influenced its tyrosine phosphorylation. LDN193189 inhibited the interaction between CD133 and p85, accompanied by a reduction in the self-renewal and tumorigenicity of liver TIC. In addition, LDN193189 inhibited the expression and transcription of Galectin-3 by reducing the tyrosine phosphorylation of CD133. Galectin-3 secreted by liver TICs inhibited the proliferation of activated CD8+ T cells by binding to PD-1. LDN193189 suppressed the immune escape ability of liver TICs by downregulating Galectin-3. Taken together, LDN193189 suppressed the tumorigenesis and immune escape of liver CSCs by targeting the CD133-Galectin-3 axis.
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Affiliation(s)
- Ziwei Liang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Bingrui Wu
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Zhi Ji
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Weitao Liu
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Danfang Shi
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Xiaoning Chen
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Yuanyan Wei
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China.
| | - Jianhai Jiang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China.
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21
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Abstract
Cancer stem cells (CSCs) represent a small subpopulation of cells found within tumors that exhibit properties of self-renewal, like normal stem cells. CSCs have been defined as a crucial factor involved in driving cancer relapse, chemoresistance and metastasis. Prominin-1 (CD133) is one of the most well-characterized markers of CSCs in various tumor types, including hepatocellular carcinoma (HCC). CD133+ cells have been demonstrated to be involved in metastasis, tumorigenesis, tumor recurrence, and resistance to treatment in HCC. CD133-related clinical prognosis prediction, and targeted therapy have highlighted the clinical significance of CD133 in HCC. However, there remains controversy over the role of CD133 in experimental and clinical research involving HCC. In this article, we summarize the fundamental cell biology of CD133 in HCC cells and discuss the important characteristics of CD133+ in HCC cells. Furthermore, the prognostic value of CD133, and therapeutic strategies for its targeting in HCC, is also reviewed.
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Affiliation(s)
- Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanzhi Qian
- Department of Gastroenterology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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22
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Selective Anti-Cancer Effects of Plasma-Activated Medium and Its High Efficacy with Cisplatin on Hepatocellular Carcinoma with Cancer Stem Cell Characteristics. Int J Mol Sci 2021; 22:ijms22083956. [PMID: 33921230 PMCID: PMC8069277 DOI: 10.3390/ijms22083956] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/26/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major histological subtype of primary liver cancer. Ample evidence suggests that the pathological properties of HCC originate from hepatic cancer stem cells (CSCs), which are responsible for carcinogenesis, recurrence, and drug resistance. Cold atmospheric-pressure plasma (CAP) and plasma-activated medium (PAM) induce apoptosis in cancer cells and represent novel and powerful anti-cancer agents. This study aimed to determine the anti-cancer effect of CAP and PAM in HCC cell lines with CSC characteristics. We showed that the air-based CAP and PAM selectively induced cell death in Hep3B and Huh7 cells with CSC characteristics, but not in the normal liver cell line, MIHA. We observed both caspase-dependent and -independent cell death in the PAM-treated HCC cell lines. Moreover, we determined whether combinatorial PAM therapy with various anti-cancer agents have an additive effect on cell death in Huh7. We found that PAM highly increased the efficacy of the chemotherapeutic agent, cisplatin, while enhanced the anti-cancer effect of doxorubicin and the targeted-therapy drugs, trametinib and sorafenib to a lesser extent. These findings support the application of CAP and PAM as anti-cancer agents to induce selective cell death in cancers containing CSCs, suggesting that the combinatorial use of PAM and some specific anti-cancer agents is complemented mechanistically.
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23
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Li W, Liu K, Chen Y, Zhu M, Li M. Role of Alpha-Fetoprotein in Hepatocellular Carcinoma Drug Resistance. Curr Med Chem 2021; 28:1126-1142. [PMID: 32729413 DOI: 10.2174/0929867327999200729151247] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 07/04/2020] [Accepted: 07/11/2020] [Indexed: 01/30/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and a major cause of cancer-related deaths worldwide because of its high recurrence rate and poor prognosis. Surgical resection is currently the major treatment measure for patients in the early and middle stages of the disease. Because due to late diagnosis, most patients already miss the opportunity for surgery upon disease confirmation, conservative chemotherapy (drug treatment) remains an important method of comprehensive treatment for patients with middle- and late-stage liver cancer. However, multidrug resistance (MDR) in patients with HCC severely reduces the treatment effect and is an important obstacle to chemotherapeutic success. Alpha-fetoprotein (AFP) is an important biomarker for the diagnosis of HCC. The serum expression levels of AFP in many patients with HCC are increased, and a persistently increased AFP level is a risk factor for HCC progression. Many studies have indicated that AFP functions as an immune suppressor, and AFP can promote malignant transformation during HCC development and might be involved in the process of MDR in patients with liver cancer. This review describes drug resistance mechanisms during HCC drug treatment and reviews the relationship between the mechanism of AFP in HCC development and progression and HCC drug resistance.
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Affiliation(s)
- Wei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Kun Liu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Yi Chen
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
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24
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Luong AB, Do HQ, Tarchi P, Bonazza D, Bottin C, Cabral LKD, Tran LDC, Doan TPT, Crocè LS, Pham HLT, Tiribelli C, Sukowati CHC. The mRNA Distribution of Cancer Stem Cell Marker CD90/Thy-1 Is Comparable in Hepatocellular Carcinoma of Eastern and Western Populations. Cells 2020; 9:E2672. [PMID: 33322687 PMCID: PMC7764111 DOI: 10.3390/cells9122672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
Epidemiology of hepatocellular carcinoma (HCC) showed a correlation between incidence and geographical-relevant risk factors. This study aims to compare the distributions of cancer stem cells (CSC) in two distant populations in Asia and Europe. We analyzed 52 and 43 selected HCC patients undergoing hepatectomy in Ho Chi Minh City (Vietnam) and Trieste (Italy). Each patient sample consisted of HCC, peri-HCC, and non-tumoral (distal) tissue. Demographic data were recorded together with clinical findings. The protocol for the collection of tissue samples and RNA was standardized in both laboratories and gene expression analysis was performed in a single laboratory with identical PCR conditions. Baseline data showed comparable laboratory findings between the two cohorts. mRNA distribution showed a comparable pattern of all CSC markers analyzed with the expression of CD90 progressively increasing from distal and peri-HCC to be highest in HCC (p < 0.001), confirmed by immunofluorescence data. CD90 mRNA distribution was related to HBV-related HCC and a tumor diameter less than 5 cm. Patients with high tumoral CD90 mRNA had a shorter time (p < 0.05) to tumor recurrence compared to patients with lower CD90. This comparative study showed that CD90 mRNA expressions are comparable between Eastern and Western HCC cases.
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Affiliation(s)
- An B. Luong
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam
| | - Huy Q. Do
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Laboratory of Stem Cell Research and Application, VNUHCM-University of Science, Ho Chi Minh City 700000, Vietnam
| | - Paola Tarchi
- Clinical Surgery Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Deborah Bonazza
- Surgical Pathology Unit, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), 34148 Trieste, Italy;
| | - Cristina Bottin
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | - Long D. C. Tran
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Thao P. T. Doan
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam;
| | - Lory S. Crocè
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy;
| | - Hoa L. T. Pham
- University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh, Ho Chi Minh City 700000, Vietnam; (L.D.C.T.); (H.L.T.P.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, 34149 Trieste, Italy; (A.B.L.); (H.Q.D.); (L.K.D.C.); (L.S.C.); (C.T.)
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Studying the Role and Molecular Mechanisms of MAP4K3 in Sorafenib Resistance of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4965670. [PMID: 33204699 PMCID: PMC7665914 DOI: 10.1155/2020/4965670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/16/2020] [Accepted: 08/24/2020] [Indexed: 12/12/2022]
Abstract
Sorafenib is the first FDA-approved therapeutic drug for molecular target medication on advanced-stage hepatocellular carcinoma. It is reported that sorafenib could improve the survival of progression-free patients for 4 to 6 months; however, most of the patients developed drug resistance. Thus, it is critical to reveal the biological mechanisms behind sorafenib resistance. In this study, a sorafenib-resistant model was developed by exposing HepG2 cells to sorafenib with gradient increasing concentration, and the resistance-related genes were screened by microarray. Real-time qPCR was used to validate selected gene expression of the resistance model, and lentivirus vector-mediated RNA interference was applied for specific gene knockdown. In addition, high-throughput High Celigo Select (HCS) and flow cytometry were used to measure the effect on cellular proliferation and apoptosis. As a result, our study established a sorafenib-resistant model with IC50 of 9.988 μM. The Affymetrix expression profile of the sorafenib-resistant model showed 35 resistant-related genes, and 91.4% of the resistant genes showed upregulation in HepG2 resistance cells. In addition, 20 genes were knocked down to measure cell proliferation, and MAP4K3 with high proliferation inhibiting phenotype was chosen for further study. Meanwhile, the HCS results revealed that shMAP4K3 transfection could downregulate resistant cell proliferation, and the flow cytometry results showed that cell apoptosis was significantly increased in the MAP4K3 knockdown group. In summary, MAP4K3 is a novel molecular marker for improving the drug sensitivity of sorafenib treatment in hepatocellular carcinoma.
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Fang L, Gao C, Bai RX, Wang HF, Du SY. Overexpressed sFRP3 exerts an inhibitory effect on hepatocellular carcinoma via inactivation of the Wnt/β-catenin signaling pathway. Cancer Gene Ther 2020; 28:875-891. [DOI: 10.1038/s41417-020-0201-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 07/07/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022]
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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Mossenta M, Busato D, Dal Bo M, Toffoli G. Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies. Cancers (Basel) 2020; 12:E1668. [PMID: 32585931 PMCID: PMC7352479 DOI: 10.3390/cancers12061668] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/12/2020] [Accepted: 06/20/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid-lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.
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Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
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Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity. Cancers (Basel) 2020; 12:E1576. [PMID: 32549224 PMCID: PMC7352671 DOI: 10.3390/cancers12061576] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.
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Affiliation(s)
| | | | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato (Italian Liver Foundation), AREA Science Park, Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
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31
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The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5:87. [PMID: 32532960 PMCID: PMC7292831 DOI: 10.1038/s41392-020-0187-x] [Citation(s) in RCA: 610] [Impact Index Per Article: 122.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/14/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
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Sasaki R, Kanda T, Fujisawa M, Matsumoto N, Masuzaki R, Ogawa M, Matsuoka S, Kuroda K, Moriyama M. Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines. Int J Mol Sci 2020; 21:ijms21093349. [PMID: 32397371 PMCID: PMC7246870 DOI: 10.3390/ijms21093349] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/26/2020] [Accepted: 05/08/2020] [Indexed: 02/07/2023] Open
Abstract
Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.
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Seitz T, Freese K, Dietrich P, Thasler WE, Bosserhoff A, Hellerbrand C. Fibroblast Growth Factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma. Sci Rep 2020; 10:4546. [PMID: 32161315 PMCID: PMC7066162 DOI: 10.1038/s41598-020-61510-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 02/25/2020] [Indexed: 01/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is closely associated with liver fibrosis. Hepatic stellate cells (HSC) and cancer-associated myofibroblasts are key players in liver fibrogenesis and hepatocarcinogenesis. Overexpression of fibroblast growth factor (FGF) receptors contributes to HCC development and progression. This study aimed to elucidate the role of FGFs in the HSC-HCC crosstalk. Analysis of the expression of the fifteen paracrine FGF-members revealed that FGF9 was only expressed by HSC but not by HCC cells. Also in human HCC tissues, HSC/stromal myofibroblasts were identified as cellular source of FGF9. High expression levels of FGF9 significantly correlated with poor patient survival. Stimulation with recombinant FGF9 induced ERK- and JNK-activation combined with significantly enhanced proliferation, clonogenicity, and migration of HCC cells. Moreover, FGF9 significantly reduced the sensitivity of HCC cells against sorafenib. Protumorigenic effects of FGF9 on HCC cells were almost completely abrogated by the FGFR1/2/3 inhibitor BGJ398, while the selective FGFR4 inhibitor BLU9931 had no significant effect. In conclusion, these data indicate that stroma-derived FGF9 promotes tumorigenicity and sorafenib resistance of HCC cells and FGF9 overexpression correlates with poor prognosis in HCC patients. Herewith, FGF9 appears as potential prognostic marker and novel therapeutic target in HCC.
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Affiliation(s)
- Tatjana Seitz
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Kim Freese
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Medical Clinic 1, Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen, Germany
| | | | - Anja Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. .,Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany.
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Feng YH, Tung CL, Su YC, Tsao CJ, Wu TF. Proteomic Profile of Sorafenib Resistance in Hepatocellular Carcinoma; GRP78 Expression Is Associated With Inferior Response to Sorafenib. Cancer Genomics Proteomics 2020; 16:569-576. [PMID: 31659110 DOI: 10.21873/cgp.20159] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIM The outcome of patients with advanced hepatocellular carcinoma (HCC) remains poor and therapeutic options, including sorafenib, the first anti-cancer drug proved to prolong survival in patients with advanced HCC, are limited. However, no clinically useful predictive biomarker for sorafenib has been reported. MATERIALS AND METHODS We exploited two-dimensional gel electrophoresis coupled with mass spectrometry to find de-regulated proteins by using conditioning of a sorafenib-resistant HCC cell line, Huh7. Tumor samples from 60 patients with HCC treated with sorafenib were analyzed and correlated with survival outcome. RESULTS Comparative proteomics indicated three proteins including, 78 kDa glucose related protein (GRP78), 14-3-3ε, and heat shock protein 90β (HSP90β). The three proteins were over-expressed in sorafenib-resistant Huh7 cells. In HCC tumor samples from patients treated with sorafenib, 73% of tumor samples had a high expression of GRP78, 18% had high 14-3-3ε expression and 85% had high HSP90β expression. Among these, GRP78 was associated with the shortest progression-free survival of HCC patients treated with sorafenib. CONCLUSION GRP78 can be a predictive biomarker in HCC patients treated with sorafenib. Strategies designed to inhibit the GRP78-related pathway may overcome sorafenib resistance.
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Affiliation(s)
- Yin-Hsun Feng
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C. .,Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan, R.O.C
| | - Chao-Ling Tung
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan, R.O.C
| | - Yu-Chu Su
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.,Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C
| | - Chao-Jung Tsao
- Department of Hematology and Oncology, Chi-Mei Medical Center, Liouying Campus, Tainan, Taiwan, R.O.C
| | - Ting-Feng Wu
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan, R.O.C.
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Kim BH, Park JW, Kim JS, Lee SK, Hong EK. Stem Cell Markers Predict the Response to Sorafenib in Patients with Hepatocellular Carcinoma. Gut Liver 2020; 13:342-348. [PMID: 30600675 PMCID: PMC6529171 DOI: 10.5009/gnl18345] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/18/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Sorafenib remains the only approved molecular targeted agent for hepatocellular carcinoma (HCC); however, reliable biomarkers that predict its efficacy are still lacking. The aim of this study was to explore whether cancer stem cell (CSC) markers have a predictive role with regard to the sorafenib response in HCC patients. Methods We enrolled 47 patients with HCC for whom tumor samples obtained before starting sorafenib treatment were available. RNA was extracted from formalin-fixed, paraffin-embedded samples, and real-time polymerase chain reaction was used to quantify mRNA expression of the CSC genes EpCAM, CD13, CK8, CD24, CD44, CD90, CD133, SALL4, ALDH1A1, ALB, and AFP. Results Of 47 patients, 14.9% and 74.5% had vascular invasion and extrahepatic spread, respectively. Patients with low CD133 expression tended to have longer progression-free survival (PFS) than those with high CD133 expression (5.5 months vs 4.0 months), although without statistical significance. The expression levels of other markers were not associated with PFS. When examining markers in combination, patients with high CD133 and CD90 expression had shorter PFS rates than those with low expression (2.7 months vs 5.5 months; p=0.04). Patients with low CD133 and EpCAM expression demonstrated better PFS than those with high expression (7.0 months vs 4.2 months; p=0.04). Multivariable analysis indicated that an Eastern Cooperative Oncology Group performance status score of 1 and high CD133/CD90 expression were significantly associated with shorter PFS. Conclusions Overexpression of the CSC markers CD133 and CD90 in HCC was associated with poorer response to sorafenib. These two genes may serve as predictive biomarkers for sorafenib therapy.
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Affiliation(s)
- Bo Hyun Kim
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Joong-Won Park
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea.,Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Jin Sook Kim
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Sook-Kyung Lee
- Common Cancer Branch, Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
| | - Eun Kyung Hong
- Center for Liver Cancer,Division of Clinical Research, Research Institute, National Cancer Center, Goyang, Korea
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Cai S, Bi Z, Bai Y, Zhang H, Zhai D, Xiao C, Tang Y, Yang L, Zhang X, Li K, Yang R, Liu Y, Chen S, Sun T, Liu H, Yang C. Glycyrrhizic Acid-Induced Differentiation Repressed Stemness in Hepatocellular Carcinoma by Targeting c-Jun N-Terminal Kinase 1. Front Oncol 2020; 9:1431. [PMID: 31998631 PMCID: PMC6962306 DOI: 10.3389/fonc.2019.01431] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/02/2019] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. Cancer stem cells play a vital role in tumor initiation and malignancy. The degree of differentiation of HCC is closely related to its stemness. Glycyrrhizic acid (GA) plays a critical role in inhibiting the degree of malignancy of HCC. At present, the effect of GA on the differentiation and stemness of HCC has not been reported, and its pharmacological mechanism remains to be elucidated. This study evaluated the effect of GA on the stemness of HCC and investigated its targets through proteomics and chemical biology. Results showed that GA can repress stemness and induce differentiation in HCC in vitro. GEO analysis revealed that cell differentiation and stem cell pluripotency were up-regulated and down-regulated after GA administration, respectively. Virtual screening was used to predict the c-Jun N-terminal kinase 1 (JNK1) as a direct target of GA. Moreover, chemical biology was used to verify the interaction of JNK1 and GA. Experimental data further indicated that JNK1 inhibits stemness and induces differentiation of HCC. GA exerts its function by targeting JNK1. Clinical data analysis from The Cancer Genome Atlas also revealed that JNK1 can aggravate the degree of malignancy of HCC. The results indicated that, by targeting JNK1, GA can inhibit tumor growth through inducing differentiation and repressing stemness. Furthermore, GA enhanced the anti-tumor effects of sorafenib in HCC treatment. These results broadened our insight into the pharmacological mechanism of GA and the importance of JNK1 as a therapeutic target for HCC treatment.
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Affiliation(s)
- Shijiao Cai
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Zhun Bi
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Yunpeng Bai
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Heng Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Denghui Zhai
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Cui Xiao
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Yuanhao Tang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Lan Yang
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Xiaoyun Zhang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
| | - Kun Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Ru Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Yanrong Liu
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Shuang Chen
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Tao Sun
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Huijuan Liu
- Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.,College of Life Sciences, Nankai University, Tianjin, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
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Caputo F, Dadduzio V, Tovoli F, Bertolini G, Cabibbo G, Cerma K, Vivaldi C, Faloppi L, Rizzato MD, Piscaglia F, Celsa C, Fornaro L, Marisi G, Conti F, Silvestris N, Silletta M, Lonardi S, Granito A, Stornello C, Massa V, Astara G, Delcuratolo S, Cascinu S, Scartozzi M, Casadei-Gardini A. The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib. PLoS One 2020; 15:e0232449. [PMID: 32379785 PMCID: PMC7205300 DOI: 10.1371/journal.pone.0232449] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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Affiliation(s)
- Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Dadduzio
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Francesco Tovoli
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Krisida Cerma
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Luca Faloppi
- Medical Oncology Unit, Macerata General Hospital, Macerata, Italy
| | - Mario Domenico Rizzato
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabio Piscaglia
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | - Ciro Celsa
- Section of Gastroenterology & Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | | | - Giorgia Marisi
- Medical Oncology Unit IRCSS-IRST Meldola, Meldola, Italy
| | - Fabio Conti
- Department of Internal Medicine, Degli Infermi Hospital, Faenza, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Marianna Silletta
- Medical Oncology Department, Campus Biomedico, University of Rome, Rome, Italy
| | - Sara Lonardi
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Alessandro Granito
- Azienda Ospedaliera Universitaria S.Orsola-Malpighi Bologna, Bologna, Italy
| | | | | | - Giorgio Astara
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Sabina Delcuratolo
- Medical Oncology Unit, IRCCS Giovanni Paolo II Cancer Center, Bari, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
- * E-mail:
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Song S, Sun K, Dong J, Zhao Y, Liu F, Liu H, Sha Z, Mao J, Ding G, Guo W, Fu Z. microRNA-29a regulates liver tumor-initiating cells expansion via Bcl-2 pathway. Exp Cell Res 2019; 387:111781. [PMID: 31857112 DOI: 10.1016/j.yexcr.2019.111781] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/12/2019] [Accepted: 12/13/2019] [Indexed: 12/26/2022]
Abstract
MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that miR-29a is downregulated in tumor-initiating cells (T-ICs) and has an important function in liver T-ICs. Functional studies revealed that miR-29a knockdown promotes liver T-ICs self-renewal and tumorigenesis. Conversely, a forced miR-29a expression inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, we find that miR-29a downregulates Bcl-2 via binding its mRNA 3'UTR in liver T-ICs. The correlation between miR-29a and Bcl-2 is validated in human HCC tissues. Furthermore, the miR-29a expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-29a high patients are more sensitive to sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-29a in liver T-ICs expansion and sorafenib response, rendering miR-29a as an optimal target for the prevention and intervention of HCC.
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Affiliation(s)
- Shaohua Song
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Keyan Sun
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Junfeng Dong
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Yuanyu Zhao
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Fang Liu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Hao Liu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Zhilin Sha
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Jiaxi Mao
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Guoshan Ding
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Wenyuan Guo
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
| | - Zhiren Fu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
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Nazmy EA, El-Khouly OA, Zaki MMA, Elsherbiny NM, Said E, Al-Gayyar MMH, Salem HA. Targeting p53/TRAIL/caspase-8 signaling by adiponectin reverses thioacetamide-induced hepatocellular carcinoma in rats. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2019; 72:103240. [PMID: 31421311 DOI: 10.1016/j.etap.2019.103240] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/23/2019] [Accepted: 08/02/2019] [Indexed: 06/10/2023]
Abstract
Given the enormous impact of HCC on the patients' quality of life and healthcare economics, the current study was conducted to investigate the potential ability of adiponectin to reverse established HCC and to investigate the underlying mechanisms which control the chemotherapeutic and hepatoprotective effects. HCC was induced in Male Sprague Dawely rats by I.P. injection of thioacetamide(200 mg/kg) 3 times/week for 14 weeks.HCC development was confirmed by histopathological examination and assessment of serum levels of α-fetoprotein (AFP). Adiponectin was administered (5 μg/kg, I.P.) starting from week 13 of the experiment and for further 4 weeks. Adiponectinadministration revealed a significant antitumor activity with significant improvement in liver functions and oxidative status. Nevertheless, pathological features as cirrhosis, dysplastic changes, and tumoral nodules were significantly attenuated with significant enhancement in hepatic caspase-3 immunostaining. Mechanistically, adiponectin administration was associated with significant restoration of p53 activity; which increased by 133%, with a reduction in HCC-induced expression of-JNK which decreased by 53%as well as a significant enhancement of hepatic TRAIL and caspase-8 activities which increased by 27% and 20% respectively. In conclusion; Adiponectin can be proposed as a promising therapy for HCC. Adiponectin's tumoricidal activity can be partially mediated by blocking HCC-induced reduction in p53 expression as well as reactivation of TRAIL signaling and induction of apoptotic pathway providing more protection for the body against the tumor.
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Affiliation(s)
- Entsar A Nazmy
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Omar A El-Khouly
- Dep. of Pharmaceutical Organic Chemistry, Faculty of Pharmacy,Mansoura University, Mansoura, Egypt
| | - Marwa M A Zaki
- Dep. of Pathology, Faculty of Medicine, Mansoura University, Egypt
| | - Nehal M Elsherbiny
- Dep. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Eman Said
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
| | - Mohammed M H Al-Gayyar
- Dep. of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Dep. of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Hatem A Salem
- Dep. of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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40
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Gao X, Jiang P, Zhang Q, Liu Q, Jiang S, Liu L, Guo M, Cheng Q, Zheng J, Yao H. Peglated-H1/pHGFK1 nanoparticles enhance anti-tumor effects of sorafenib by inhibition of drug-induced autophagy and stemness in renal cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:362. [PMID: 31426831 PMCID: PMC6699135 DOI: 10.1186/s13046-019-1348-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 07/29/2019] [Indexed: 12/19/2022]
Abstract
Background Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles—PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC). Methods We produced a novel cationic polymer—PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro. Results We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo. Conclusions HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1348-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Pin Jiang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Qian Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Qian Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Shuangshuang Jiang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Ling Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Maomao Guo
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Qian Cheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China. .,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.
| | - Hong Yao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China. .,Department of Cancer Biotherapy Center, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650118, People's Republic of China.
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Zeng X, Wang S, Gui P, Wu H, Li Z. Expression and significance of Annexin A3 in the osteosarcoma cell lines HOS and U2OS. Mol Med Rep 2019; 20:2583-2590. [PMID: 31524248 PMCID: PMC6691243 DOI: 10.3892/mmr.2019.10513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 04/17/2019] [Indexed: 12/21/2022] Open
Abstract
Annexin A3 (ANXA3) is highly expressed in different types of cancers, but the impact of ANXA3 in bone tumors is still not clear. In the present study, the expression of ANXA3 in osteosarcoma cells was first confirmed by cellular immunofluorescence. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were used to detect the expression of ANXA3 in osteoblasts in the osteosarcoma cell lines U2OS and HOS. Furthermore, small interfering (si)‑RNA were transfected into U2OS and HOS cells via a liposome‑mediated method. Then once ANXA3 had been successfully downregulated in U2OS and HOS cells, the cells were collected and total protein was extracted after 48 h of transfection. Western blot analysis was used to confirm successful ANXA3 transfection into osteosarcoma cells and the apoptotic rate of HOS and U2OS was detected by flow cytometry. The expression of ANXA3 in the osteosarcoma cell lines HOS and U2OS were first observed by confocal laser scanning microscopy, and was then detected by RT‑qPCR and western blotting. The mRNA and protein levels of ANXA3 in the osteosarcoma cell lines HOS and U2OS were significantly increased compared with osteoblasts, particularly in HOS cells. When siRNA was transfected into HOS and U2OS cells, the protein expression level of ANXA3 was measured via western blotting. The results indicated that the expression of ANXA3 was significantly decreased. In addition, to determine whether ANXA3 knockdown induced cell apoptosis, the present study analyzed the apoptotic rate by flow cytometry. The results revealed that ANXA3 knockdown markedly increased HOS and U2OS cell apoptosis. To the best of our knowledge, the present study is the first to confirm that ANXA3 is highly expressed in the osteosarcoma cell lines HOS and U2OS. In addition, downregulation of ANXA3 expression in HOS and U2OS cells could increase apoptotic ability.
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Affiliation(s)
- Xinxin Zeng
- Department of Orthopaedics, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Shengtao Wang
- Department of Emergency and Trauma Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Peng Gui
- Department of Orthopaedics, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Hao Wu
- Department of Orthopaedics, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, P.R. China
| | - Zhaoxu Li
- Department of Orthopaedics, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi 541002, P.R. China
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Marisi G, Cucchetti A, Ulivi P, Canale M, Cabibbo G, Solaini L, Foschi FG, De Matteis S, Ercolani G, Valgiusti M, Frassineti GL, Scartozzi M, Casadei Gardini A. Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers? World J Gastroenterol 2018; 24:4152-4163. [PMID: 30271080 PMCID: PMC6158485 DOI: 10.3748/wjg.v24.i36.4152] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/06/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma (HCC) since 2007 and numerous studies have investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology, DI.BI.M.I.S., University of Palermo, Palermo 35628, Italy
| | - Leonardo Solaini
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Francesco G Foschi
- Department of Internal Medicine, Degli Infermi Hospital, Faenza 48018, Italy
| | - Serena De Matteis
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
| | - Giovanni L Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University of Cagliari, Cagliari 45698, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola 47014, Italy
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Saeki I, Yamasaki T, Maeda M, Hisanaga T, Iwamoto T, Fujisawa K, Matsumoto T, Hidaka I, Marumoto Y, Ishikawa T, Yamamoto N, Suehiro Y, Takami T, Sakaida I. Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy. World J Hepatol 2018; 10:571-584. [PMID: 30310535 PMCID: PMC6177565 DOI: 10.4254/wjh.v10.i9.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 07/30/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.
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Affiliation(s)
- Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Masaki Maeda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takuro Hisanaga
- Department of Medical Education, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Koichi Fujisawa
- Center of Research and Education for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, 755-8505, Japan
| | - Toshihiko Matsumoto
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Isao Hidaka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Yoshio Marumoto
- Center for Clinical Research, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan
| | - Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Naoki Yamamoto
- Yamaguchi University Health Administration Center, Yamaguchi 753-8511, Japan
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
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Gao X, Shan W, Liu X, Zhang J, Zheng J, Yao H. JNK1/2 and ERK1/2 provides vital clues about tumor recurrence and survival in hepatocellular carcinoma patients. Future Oncol 2018; 14:2471-2481. [PMID: 29714074 DOI: 10.2217/fon-2018-0171] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM To explore JNK1/2 and ERK1/2 activation in hepatocellular carcinoma (HCC) patients. PATIENTS & METHODS Phosphorylated-JNK1/2 and -ERK1/2 (p-JNK1/2 and p-ERK1/2) expressions were determined and analyzed in 104 unique HCC tissue specimens. RESULTS Expression of p-JNK1/2 and p-ERK1/2 was not correlated with clinicopathological characteristics. High p-JNK1/2 and low p-ERK1/2 expressions predicated significantly lower tumor recurrence for HCC patients. However, HCC patients with low p-JNK1/2 and high p-ERK1/2 had higher tumor recurrence. Moreover, p-JNK1/2 positively, but p-ERK1/2 negatively, associated with overall survival (OS) and recurrence-free survival (RFS) in HCC patients. In addition, HCC patients with simultaneous low p-JNK1/2 and high p-ERK1/2 had poorer OS and RFS. On the contrary, patients with high p-JNK1/2 and low p-ERK1/2 presented better OS and RFS. CONCLUSION HCC patients with low p-JNK1/2 and high p-ERK1/2 either independently or simultaneously, had significantly higher tumor recurrence and worse OS.
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Affiliation(s)
- Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Wenhua Shan
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Xiangye Liu
- Jiangsu Key Laboratory of Immunity & Metabolism, Department of Pathogenic Biology & Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province 221004, PR China
| | - Jian Zhang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China.,Jiangsu Center for the Collaboration & Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China
| | - Hong Yao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, PR China.,Instituteof Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Provience, 518055, PR China
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45
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Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer 2017; 1868:564-570. [PMID: 29054475 DOI: 10.1016/j.bbcan.2017.10.002] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/04/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.
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Affiliation(s)
- Leilei Niu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Liping Liu
- Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China
| | - Shengli Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianwei Ren
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China.
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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46
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Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis. Sci Rep 2017; 7:10440. [PMID: 28874700 PMCID: PMC5585302 DOI: 10.1038/s41598-017-10570-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 08/11/2017] [Indexed: 02/08/2023] Open
Abstract
Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV-related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of β-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis.
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47
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Sakurai T, Yada N, Hagiwara S, Arizumi T, Minaga K, Kamata K, Takenaka M, Minami Y, Watanabe T, Nishida N, Kudo M. Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma. Cancer Sci 2017; 108:1996-2003. [PMID: 28777492 PMCID: PMC5623735 DOI: 10.1111/cas.13341] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 07/24/2017] [Accepted: 07/30/2017] [Indexed: 12/24/2022] Open
Abstract
Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation‐induced tumorigenesis in the colon. Although the in vitro function of gankyrin is well known, its role in vivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell‐specific gankyrin ablation (Alb‐Cre;gankyrinf/f) and gankyrin deletion both in liver parenchymal and non‐parenchymal cells (Mx1‐Cre;gankyrinf/f). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP‐1), mainly expressed in liver non‐parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non‐parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)‐6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression‐free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.
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Affiliation(s)
- Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Norihisa Yada
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Tadaaki Arizumi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
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48
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Hu K, Huang P, Luo H, Yao Z, Wang Q, Xiong Z, Lin J, Huang H, Xu S, Zhang P, Liu B. Mammalian-enabled (MENA) protein enhances oncogenic potential and cancer stem cell-like phenotype in hepatocellular carcinoma cells. FEBS Open Bio 2017; 7:1144-1153. [PMID: 28781954 PMCID: PMC5537062 DOI: 10.1002/2211-5463.12254] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 05/08/2017] [Accepted: 05/23/2017] [Indexed: 01/19/2023] Open
Abstract
Mammalian-enabled (MENA) protein is an actin-regulatory protein that influences cell motility and adhesion. It is known to play a role in tumorigenicity of hepatocellular carcinoma (HCC) but the underlying molecular mechanism remains unknown. This study aimed to investigate the oncogenic potential of MENA and its capacity to regulate cancer stem cell (CSC)-like phenotypes in HCC cells. Real-time-PCR and western blot were used to assess mRNA and protein levels of target genes in human HCC tissue specimens and HCC cell lines, respectively. Stable MENA-overexpressing HCC cells were generated from HCC cell lines. Transwell cell migration and colony formation assays were employed to evaluate tumorigenicity. Ectopic expression of MENA significantly enhanced cell migration and colony-forming ability in HCC cells. Overexpression of MENA upregulated several hepatic progenitor/stem cell markers in HCC cells. A high MENA protein level was associated with high mRNA levels of MENA, CD133, cytokeratin 19 (CK19), and epithelial cell adhesion molecule (EpCAM) in human HCC tissues. Overexpression of MENA enhanced epithelial-to-mesenchymal transition (EMT) markers, extracellular signal-regulated kinases (ERK) phosphorylation, and the level of β-catenin in HCC cells. This study demonstrated that overexpression of MENA in HCC cells promoted stem cell markers, EMT markers, and tumorigenicity. These effects may involve, at least partially, the ERK and β-catenin signaling pathways.
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Affiliation(s)
- Kunpeng Hu
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Pinzhu Huang
- Department of Gastrointestinal Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Hui Luo
- Department of Operating Room The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Zhicheng Yao
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Qingliang Wang
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Zhiyong Xiong
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Jizong Lin
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - He Huang
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Shilei Xu
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Peng Zhang
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
| | - Bo Liu
- Department of General Surgery The Third Affiliated Hospital Sun Yat-sen University Guangzhou China
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49
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Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin 2017; 38:614-622. [PMID: 28344323 PMCID: PMC5457690 DOI: 10.1038/aps.2017.5] [Citation(s) in RCA: 490] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/19/2017] [Indexed: 12/13/2022]
Abstract
Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.
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Affiliation(s)
- Yan-Jing Zhu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Bo Zheng
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
| | - Hong-Yang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
- National Center for Liver Cancer, Shanghai 201805, China
| | - Lei Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China
- National Center for Liver Cancer, Shanghai 201805, China
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50
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Jariwala N, Rajasekaran D, Mendoza RG, Shen XN, Siddiq A, Akiel MA, Robertson CL, Subler MA, Windle JJ, Fisher PB, Sanyal AJ, Sarkar D. Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma. Cancer Res 2017; 77:3306-3316. [PMID: 28428278 DOI: 10.1158/0008-5472.can-17-0298] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 03/29/2017] [Accepted: 04/14/2017] [Indexed: 12/22/2022]
Abstract
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306-16. ©2017 AACR.
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Affiliation(s)
- Nidhi Jariwala
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Devaraja Rajasekaran
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Rachel G Mendoza
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Xue-Ning Shen
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Ayesha Siddiq
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Maaged A Akiel
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Chadia L Robertson
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Mark A Subler
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Jolene J Windle
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.,VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.,VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia
| | - Arun J Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. .,VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.,VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia
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