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Shao YY, Wang HY, Hsu HW, Wo RR, Cheng AL, Hsu CH. Downregulation of PD-L1 expression by Wnt pathway inhibition to enhance PD-1 blockade efficacy in hepatocellular carcinoma. Biol Direct 2025; 20:49. [PMID: 40211365 PMCID: PMC11987266 DOI: 10.1186/s13062-025-00645-8] [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: 02/21/2025] [Accepted: 03/28/2025] [Indexed: 04/13/2025] Open
Abstract
BACKGROUND Immunotherapy targeting the programmed death-ligand 1 (PD-L1) pathway is a standard treatment for advanced hepatocellular carcinoma (HCC). The Wnt signaling pathway, often upregulated in HCC, contributes to an immunosuppressive tumor microenvironment. This study investigated the impact of Wnt pathway inhibition on PD-L1 expression in HCC and evaluated the potential therapeutic benefit of combining Wnt pathway inhibition with PD-L1 blockade. METHODS The effects of Wnt pathway inhibitors XAV939 and IWR-1 on PD-L1 expression were examined in human HCC cell lines HuH7 and Hep3B. Beta-catenin overexpression and knockdown experiments confirmed these findings. For in vivo efficacy, the BNL 1ME A.7R.1 mouse HCC cell line was orthotopically implanted in mice, which were subsequently treated with XAV939, anti-PD-L1 antibodies, or both. RESULTS Wnt pathway inhibitors XAV939 and IWR-1 significantly reduced PD-L1 protein expression in a dose-dependent manner in HuH7 and Hep3B cells, without affecting mRNA levels. CTNNB1 knockdown produced similar results, and beta-catenin overexpression reversed the effects of Wnt pathway inhibitors on PD-L1 expression. Wnt pathway inhibition did not promote PD-L1 protein degradation but instead increased the level of unphosphorylated 4EBP1, which could prevent the translation function of eIF-4E. In vivo, mice treated with a combination of XAV939 and an anti-PD-L1 antibody had significantly smaller tumors compared to those treated with either agent alone. The combination treatment also enhanced multiple immune-related pathways in harvested tumors. CONCLUSION Inhibition of the Wnt pathway reduced PD-L1 expression in HCC cells and enhanced the efficacy of PD-L1 blockade, supporting its potential as HCC treatment.
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Affiliation(s)
- Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, 1, Sec. 1, Ren'ai Rd, Taipei City, 10051, Taiwan
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, 57, Ln. 155, Sec. 3, Keelung Rd, Taipei City, Taiwan
| | - Han-Yu Wang
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan
| | - Hung-Wei Hsu
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan
| | - Rita Robin Wo
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, 1, Sec. 1, Ren'ai Rd, Taipei City, 10051, Taiwan
- Department of Internal Medicine, National Taiwan University College of Medicine, 1, Sec. 1, Ren'ai Rd, Taipei City, Taiwan
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, 57, Ln. 155, Sec. 3, Keelung Rd, Taipei City, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, 1, Sec. 1, Ren'ai Rd, Taipei City, 10051, Taiwan.
- Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S. Rd, Taipei, Taiwan.
- Department of Medical Oncology, National Taiwan University Cancer Center, 57, Ln. 155, Sec. 3, Keelung Rd, Taipei City, Taiwan.
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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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Zhang H, Zhang G, Lu S, Zhang X, Yu J. Integrated analysis of ncRNA in hepatocellular carcinoma with CTNNB1 mutations reveals miR-205-5p and miR-3940-3p Axes. Dig Liver Dis 2025; 57:51-61. [PMID: 38918127 DOI: 10.1016/j.dld.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 05/27/2024] [Accepted: 06/05/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Catenin beta 1 (CTNNB1) mutations are one of the most common mutations involved in hepatocellular carcinoma (HCC) progression. However, the association between CTNNB1 mutations and HCC remains controversial. METHODS Five tumor samples with wild-type CTNNB1 and three tumor samples with CTNNB1 mutations were collected from patients with HCC for whole transcriptome sequencing. Selected ncRNAs and mRNAs were validated by qPCR in 48 HCC tumors. Selected ncRNA regulatory axes were verified in HCC cells by transfecting mimics and inhibitors of miRNA. RESULTS A network of differentially expressed (DE) lncRNA/circRNA-miRNA-mRNA was constructed to explore the effects of CTNNB1 mutations on ncRNA regulation. TXNRD1, CES1, MATN2, SERPINA5, lncRNA STAT4-210, hsa_circ_0007824, hsa_circ_0008234, hsa-miR-205-5p and hsa-miR-199a-5p were verified at the RNA expression level to validate the sequencing results. The down-up-down axes GLIS3-209/circ_0085440-miR-205-5p-GHRHR and WNK2-213-miR-3940-3p-LY6E were verified at the expression level, and proved to inhibit and promote cell proliferation, respectively. CONCLUSION This study demonstrated CTNNB1 mutations associated ncRNA regulatory axes playing different roles in HCC cell proliferation, providing novel insights into the controversial role of CTNNB1 in HCC.
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Affiliation(s)
- Haibin Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
| | - Guoqing Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
| | - Siyu Lu
- Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China
| | - Xiaolu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
| | - Jingya Yu
- Department of Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
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Dantzer C, Dif L, Vaché J, Basbous S, Billottet C, Moreau V. Specific features of ß-catenin-mutated hepatocellular carcinomas. Br J Cancer 2024; 131:1871-1880. [PMID: 39261716 PMCID: PMC11628615 DOI: 10.1038/s41416-024-02849-7] [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: 07/29/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024] Open
Abstract
CTNNB1, encoding the ß-catenin protein, is a key oncogene contributing to liver carcinogenesis. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in adult, representing the third leading cause of cancer-related death. Aberrant activation of the Wnt/ß-catenin pathway, mainly due to mutations of the CTNNB1 gene, is observed in a significant subset of HCC. In this review, we first resume the major recent advances in HCC classification with a focus on CTNNB1-mutated HCC subclass. We present the regulatory mechanisms involved in β-catenin stabilisation, transcriptional activity and binding to partner proteins. We then describe specific phenotypic characteristics of CTNNB1-mutated HCC thanks to their unique gene expression patterns. CTNNB1-mutated HCC constitute a full-fledged subclass of HCC with distinct pathological features such as well-differentiated cells with low proliferation rate, association to cholestasis, metabolic alterations, immune exclusion and invasion. Finally, we discuss therapeutic approaches to target ß-catenin-mutated liver tumours and innovative perspectives for future drug developments.
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Affiliation(s)
| | - Lydia Dif
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
| | - Justine Vaché
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
| | - Sara Basbous
- University Bordeaux, INSERM, BRIC, U1312, Bordeaux, France
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Xue Y, Ruan Y, Wang Y, Xiao P, Xu J. Signaling pathways in liver cancer: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:20. [PMID: 38816668 PMCID: PMC11139849 DOI: 10.1186/s43556-024-00184-0] [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: 01/04/2024] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.
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Affiliation(s)
- Yangtao Xue
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yeling Ruan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yali Wang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Peng Xiao
- Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China.
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
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Matsumoto S, Kikuchi A. Wnt/β-catenin signaling pathway in liver biology and tumorigenesis. In Vitro Cell Dev Biol Anim 2024; 60:466-481. [PMID: 38379098 DOI: 10.1007/s11626-024-00858-7] [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: 11/13/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024]
Abstract
The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.
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Affiliation(s)
- Shinji Matsumoto
- Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
| | - Akira Kikuchi
- Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
- Center of Infectious Disease Education and Research (CiDER), Osaka University, 2-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan
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Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
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Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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Tang Y, Sun Z, Wu S, Zhang C, Zhang Y, Cao Y. Jin-Fu-An decoction manipulation of macrophage polarization via β-catenin (CTNNB1) synergizes with cisplatin in lung cancer. Biomed Pharmacother 2023; 168:115828. [PMID: 37925939 DOI: 10.1016/j.biopha.2023.115828] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/20/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023] Open
Abstract
Previous studies have demonstrated that tumor-associated macrophages (TAMs) exhibiting an M2 phenotype contribute significantly to the pathogenesis of various cancer types, including lung cancer. Therapeutic approaches targeting TAMs have the potential to complement and synergize with conventional chemotherapy and immunotherapy. Through database analysis, it has become evident that the expression of CTNNB1 (β-catenin) is predominantly localized in macrophages, and its presence is associated with unfavorable outcomes in the absence of CD8+ cells. Jin-Fu-An decoction (JFAD) has been utilized as an adjunct to augment current clinical interventions. By conducting a network pharmacological analysis, we discovered that CTNNB1 is a significant target of JFAD. Experiments were conducted to examine the impact of JFAD on macrophage polarization both in vitro and in vivo. Furthermore, the study investigated the combined effect of JFAD and cisplatin (CDDP) on mitigating adverse reactions and prolonging survival in subcutaneously transplanted tumor models and orthotopic lung cancer models. The percentage of M1 and M2 macrophages in the tumor and spleen were measured using flow cytometry. Additionally, the levels of β-catenin, M1, and M2 macrophage markers were measured by Western blotting and qPCR, while CD8 and iNOS protein expression was analyzed via immunohistochemistry. Our research findings indicate that JFAD has the ability to modulate the transformation of M2 macrophages into M1 macrophages, augment the anticancer efficacy of CDDP, and diminish the expression of cell-related markers in M2 cells. This regulatory effect may potentially be associated with the downregulation of β-catenin expression.
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Affiliation(s)
- Yang Tang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Zhe Sun
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Siqi Wu
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
| | - Chengyu Zhang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China; Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - Yanling Zhang
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The Forth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
| | - Yang Cao
- The First Clinical School of Guangzhou University of Chinese Medicine, Guangzhou 510000, China; Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
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Seo SH, Cho KJ, Park HJ, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Cheon JH, Yook JI, Kim MD, Joo DJ, Kim SU. Inhibition of Dickkopf-1 enhances the anti-tumor efficacy of sorafenib via inhibition of the PI3K/Akt and Wnt/β-catenin pathways in hepatocellular carcinoma. Cell Commun Signal 2023; 21:339. [PMID: 38012711 PMCID: PMC10680194 DOI: 10.1186/s12964-023-01355-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/14/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC. METHODS HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing. RESULTS DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active β-catenin (all P < 0.05) and phospho-GSK-3β (Ser9) expression levels, while increasing the phospho-GSK-3β (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models. CONCLUSIONS Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/β-catenin pathways via regulation of GSK3β activity, suggesting a novel therapeutic strategy for HCC. Video Abstract.
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Affiliation(s)
- Sang Hyun Seo
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kyung Joo Cho
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Jung Park
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Won Lee
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Beom Kyung Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jun Yong Park
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Do Young Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Sang Hoon Ahn
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jong In Yook
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea
| | - Man-Deuk Kim
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University of College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea.
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea.
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Tsai HW, Cheng SW, Chen CC, Chen IW, Ho CL. A combined bioinformatics and experimental approach identifies RMI2 as a Wnt/β-catenin signaling target gene related to hepatocellular carcinoma. BMC Cancer 2023; 23:1025. [PMID: 37875822 PMCID: PMC10594864 DOI: 10.1186/s12885-023-10655-2] [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: 08/10/2022] [Accepted: 02/15/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway plays an important role in embryogenesis and tumorigenesis. In human cancer, abnormal activity of Wnt/β-catenin signaling pathway induces overexpressed of downstream genes, and initiate oncogene. There are several target genes known to be key players in tumorigenesis, such as c-myc, cyclin D1, MMPs or survivin. Therefore, identifying the target genes of Wnt/β-catenin signaling pathway is important to understanding Wnt/β-catenin-mediated carcinogenesis. In this study, we developed a combined bioinformatics and experimental approach to find potential target genes. METHODS Luciferase reporter assay was used to analyze the promoter activity of RMI2. WST1 cell proliferation assays and transwell assays were performed to determine the proliferation and migration capacities of RMI2 overexpressing or knockdown stable hepatic cells. Finally, xenograft experiments were performed to measure the tumor formation capacity in vivo. RESULTS The results showed that RMI2 mRNA was upregulated after LiCl treatment and Wnt3a-conditioned medium in a culture of SK-hep-1 cell lines. A chromatin immunoprecipitation (ChIP) assay showed that the β-catenin/T cell-specific factor (TCF) complex binds to the putative TCF binding site of the RMI2 promoter. We then found a TCF binding site at - 333/- 326 of the RMI2 promoter, which is crucial for β-catenin responsiveness in liver cell lines. RMI2 was overexpressed in hepatoma tissue and cell lines, and it promoted the migration and invasion of HCC cells. Moreover, RMI2 upregulated the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt3a/β-catenin-related genes, but silencing RMI2 had the opposite effects. Notably, the expression of RMI2 was positively correlated with the clinical data of HCC patients who had significantly shorter overall survival (OS) and disease-free survival (DFS) (Both: P < 0.05). In addition, a total of 373 HCC patients' data from the Caner Genome Atlas project (TCGA) were used to validate our findings. CONCLUSIONS Taking all these findings together, we determined that RMI2 was a new target gene of the Wnt/β-catenin signaling pathway. We also found that RMI2 promotes EMT markers, HCC cell invasion, and metastasis, which indicated that RMI2 is a potential target for preventing or at least mitigating the progression of HCC.
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Affiliation(s)
- Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Shu-Wen Cheng
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Chou-Cheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Business Management, CTBC Business School, Tainan, Taiwan
| | - I-Wen Chen
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan City, 704, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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11
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Lu G, Lin J, Song G, Chen M. Prognostic significance of CTNNB1 mutation in hepatocellular carcinoma: a systematic review and meta-analysis. Aging (Albany NY) 2023; 15:9759-9778. [PMID: 37733676 PMCID: PMC10564414 DOI: 10.18632/aging.205047] [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: 05/12/2023] [Accepted: 08/21/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUNDS Hepatocellular Carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. In recent years, researchers have verified that the Wnt/β-catenin signaling pathway affects the clinicopathological features and prognosis of patients with HCC. Although many studies have investigated the relationship between Wnt/β-catenin signaling pathway and HCC, the prognostic value of β-catenin in HCC remains inconclusive. CTNNB1 (Catenin Beta-1) is an important factor in the Wnt/β-catenin signaling pathway. However, no consensus has been reached on the clinical and prognostic significance of CTNNB1 mutations in HCCs. METHODS Eligible studies and relevant data were obtained from PubMed, Web of Science, Elsevier, Cochrane Library, Ovid, and Embase databases. The correlation between CTNNB1 mutations and clinical/prognosis of patients were evaluated. A fixed- or random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). RESULTS Seventeen studies matched the selection criteria, and 1828 patients were included. This meta-analysis demonstrated that patients with HCC with CTNNB1 mutations had favorable clinicopathological features and survival. The combined ORs of 1-, 3- and 5-year overall survival were0.52 (n = 6 studies, 95% CI: 0.34-0.81, Z = 2.89, P =0.004, 0.28 (n =6 studies, 95% CI: 0.18-0.42, Z = 6.03, P<0.00001), -0.22 (n = 6 studies, 95% CI: 0.37-0.06, Z = 2.78, P = 0.005), respectively. Additionally, CTNNB1 mutation might be significantly associated with differentiation (OR = 0.54, 95% CI:0.36-0.81, Z = 2.98, P = 0.003), TMN stages (Tumor, Node, Metastasis staging classification) (OR = -0.25, 95% CI:-0.33--0.18, Z = 6.60, P<0.00001), liver cirrhosis (OR = 0.21, 95% CI:0.11-0.39, Z = 4.94, P< = 0.00001), and HBV (Hepatitis B Virus) infection (OR = 0.44, 95% CI:0.31-0.64, Z = 4.37, P<0.0001), but not with tumor size, metastasis, vascular invasion, and HCV infection. CONCLUSIONS CTNNB1 mutation can serve as an indicator of favorable prognosis as well as a novel target for treatment in HCC.
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Affiliation(s)
- Genlin Lu
- Department of General Surgery, Longyou People’s Hospital Affiliated with Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Quzhou 324400, China
| | - Jian Lin
- Department of General Surgery, Longyou People’s Hospital Affiliated with Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Quzhou 324400, China
| | - Guoqiang Song
- Department of Pulmonary, Department of Cancer Center, Changxing Hospital of Traditional Chinese Medicine, Huzhou 313100, China
| | - Min Chen
- Department of General Surgery, Longyou People’s Hospital Affiliated with Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Quzhou 324400, China
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12
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Fang G, Fan J, Ding Z, Zeng Y. Application of biological big data and radiomics in hepatocellular carcinoma. ILIVER 2023; 2:41-49. [DOI: 10.1016/j.iliver.2023.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
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13
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Revamping the innate or innate-like immune cell-based therapy for hepatocellular carcinoma: new mechanistic insights and advanced opportunities. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2023; 40:84. [PMID: 36680649 DOI: 10.1007/s12032-023-01948-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/02/2023] [Indexed: 01/22/2023]
Abstract
A cancerous tumour termed hepatocellular carcinoma (HCC) is characterized by inflammation and subsequently followed by end-stage liver disease and necrosis of the liver. The liver's continuous exposure to microorganisms and toxic molecules affects the immune response because normal tissue requires some immune tolerance to be safeguarded from damage. Several innate immune cells are involved in this process of immune system activation which includes dendritic cells, macrophages, and natural killer cells. The liver is an immunologic organ with vast quantities of innate and innate-like immune cells subjected to several antigens (bacteria, fungal or viral) through the gut-liver axis. Tumour-induced immune system engagement may be encouraged or suppressed through innate immunological systems, which are recognized promoters of liver disease development in pre-HCC conditions such as fibrosis or cirrhosis, ultimately resulting in HCC. Immune-based treatments containing several classes of drugs have transformed the treatment of several types of cancers in recent times. The effectiveness of such immunotherapies relies on intricate interactions between lymphocytes, tumour cells, and neighbouring cells. Even though immunotherapy therapy has already reported to possess potential effect to treat HCC, a clear understanding of the crosstalk between innate and adaptive immune cell pathways still need to be clearly understood for better exploitation of the same. The identification of predictive biomarkers, understanding the progression of the disease, and the invention of more efficient combinational treatments are the major challenges in HCC immunotherapy. The functions and therapeutic significance of innate immune cells, which have been widely implicated in HCC, in addition to the interplay between innate and adaptive immune responses during the pathogenesis, have been explored in the current review.
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Leung RWH, Lee TKW. Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14215468. [PMID: 36358885 PMCID: PMC9656505 DOI: 10.3390/cancers14215468] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/30/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Simple Summary Aberrant Wnt/β-catenin signaling has been reported to play crucial role in pathogenesis of hepatocellular carcinoma (HCC). In this review, we focus on the regulatory role of Wnt/β-catenin signaling in cancer stemness and metabolic reprogramming, which are two emerging hallmarks of cancer. Understanding the role of Wnt/β-catenin signaling in regulation of the above processes reveals novel therapeutic strategy against this deadly disease. Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide due to its high rates of tumor recurrence and metastasis. Aberrant Wnt/β-catenin signaling has been shown to play a significant role in HCC development, progression and clinical impact on tumor behavior. Accumulating evidence has revealed the critical involvement of Wnt/β-catenin signaling in driving cancer stemness and metabolic reprogramming, which are regarded as emerging cancer hallmarks. In this review, we summarize the regulatory mechanism of Wnt/β-catenin signaling and its role in HCC. Furthermore, we provide an update on the regulatory roles of Wnt/β-catenin signaling in metabolic reprogramming, cancer stemness and drug resistance in HCC. We also provide an update on preclinical and clinical studies targeting Wnt/β-catenin signaling alone or in combination with current therapies for effective cancer therapy. This review provides insights into the current opportunities and challenges of targeting this signaling pathway in HCC.
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Affiliation(s)
- Rainbow Wing Hei Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China
- Correspondence: ; Tel.: +852-3400-8799; Fax: +852-2364-9932
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15
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Xiao Q, Werner J, Venkatachalam N, Boonekamp KE, Ebert MP, Zhan T. Cross-Talk between p53 and Wnt Signaling in Cancer. Biomolecules 2022; 12:453. [PMID: 35327645 PMCID: PMC8946298 DOI: 10.3390/biom12030453] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 11/16/2022] Open
Abstract
Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction.
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Affiliation(s)
- Qiyun Xiao
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
| | - Johannes Werner
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), and Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, D-69120 Heidelberg, Germany; (J.W.); (K.E.B.)
| | - Nachiyappan Venkatachalam
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
| | - Kim E. Boonekamp
- Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ), and Department Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, D-69120 Heidelberg, Germany; (J.W.); (K.E.B.)
| | - Matthias P. Ebert
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
| | - Tianzuo Zhan
- Department of Medicine II, Mannheim University Hospital, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany; (Q.X.); (N.V.); (M.P.E.)
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
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16
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Abstract
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
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Affiliation(s)
- Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhong Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA
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17
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Ahn KS, O'Brien DR, Kim YH, Kim TS, Yamada H, Park JW, Park SJ, Kim SH, Zhang C, Li H, Kang KJ, Roberts LR. Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma. Liver Cancer 2021; 10:593-605. [PMID: 34950182 PMCID: PMC8647136 DOI: 10.1159/000516957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/29/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy-pro-thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. METHODS From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. RESULTS Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-β-catenin signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF-β and VEGF signaling were activated in ↑AFP&L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. CONCLUSIONS Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment.
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Affiliation(s)
- Keun Soo Ahn
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Daniel R. O'Brien
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Yong Hoon Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Tae-Seok Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hiroyuki Yamada
- Global Clinical Research Management, FUJIFILM Wako Pure Chemical Corporation, Tokyo, Japan
| | - Joong-Won Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Sang-Jae Park
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Seoung Hoon Kim
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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CTNNB1 p.L31P mutation in an ovarian endometrioid carcinoma with synchronous uterine endometrioid carcinoma. Pathol Res Pract 2020; 216:153260. [PMID: 33120166 DOI: 10.1016/j.prp.2020.153260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/09/2020] [Accepted: 10/09/2020] [Indexed: 11/20/2022]
Abstract
We performed next generation sequencing of DNA extracted from the neoplastic tissues obtained from a patient who underwent surgery for a large right ovarian carcinoma (OC) of endometrioid type associated with endometrial cancer (EC). This was done in order to ascertain whether the tumors were synchronous endometrial/ovarian cancers or an advanced metastatic stage from either the ovary or the uterus. Pathologic criteria favoured synchronous EC/OC. We identified a PTEN c.959 T > G (p.L320X) truncating mutation occurring with similar allele frequency in both neoplastic tissues (ovary: 88 %, endometrium 89 %) and a CTNNB1 c.100C > G (p.S37C) activating mutation, with a comparable allelic frequency in both tumor tissues (ovary 51 %, endometrium 52 %). The shared genetic mutations, and the presence of PTEN c.959 T > G (p.L320X) truncating mutation, albeit at low allelic frequency (6 %), in the healthy peritumoral endometrial tissue, appear to confirm the recent literature on a primary endometrial origin for synchronous EC/OC. A third mutation was CTNNB1 c.92 T > C (p.L31 P), a missense mutation occurring with a low allele frequency (3.7 %) only in the ovarian cancer tissue. This mutation is only occasionally described in hepatocellular carcinomas.
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19
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He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother 2020; 132:110851. [PMID: 33080466 DOI: 10.1016/j.biopha.2020.110851] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/27/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
The WNT/β-catenin signaling pathway is a highly conserved and tightly controlled molecular mechanism that regulates embryonic development, cellular proliferation and differentiation. Of note, accumulating evidence has shown that the aberrant of WNT/β-catenin signaling promotes the development and/or progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults. There are two different WNT signaling pathways have been identified, which were termed non-canonical and canonical pathways, the latter involving the activation of β-catenin. β-catenin, acting as an intracellular signal transducer in the WNT signaling pathway, is encoded by CTNNB1 and plays a critical role in tumorigenesis. In the past research, most liver tumors have mutations in genes encoding key components of the WNT/β-catenin signaling pathway. In addition, several of other signaling pathways also can crosswalk with β-catenin. In this review, we discuss the most relevant molecular mechanisms of action and regulation of WNT/β-catenin signaling in the development and pathophysiology of liver cancers, as well as in the development of therapeutics.
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Affiliation(s)
- Shuai He
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China
| | - Shilei Tang
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
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20
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Osman NAA, Khalil AI, Yousef RK. The Clinical and Prognostic Implications of Pluripotent Stem Cell Markers Expression and Their Correlation with the WNT signal pathway in Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2020; 21:2961-2970. [PMID: 33112555 PMCID: PMC7798175 DOI: 10.31557/apjcp.2020.21.10.2961] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Indexed: 12/12/2022] Open
Abstract
Objectives: This study aimed to investigate the expression of SOX2, SOX9, p53, and β-catenin in hepatocellular carcinoma (HCC) and their correlation with clinicopathological parameters of prognostic importance. Materials and Methods: Seventy-five patients were enrolled in this study. All patients had full clinical and follow-up data and available paraffin blocks. Immunohistochemical analysis was performed and correlated with clinicopathological factors and patient survival. Results: We detected the positive expression of SOX2, SOX9, p53, and β-catenin in 76%, 50.7%, 50.7%, and 77.9% of HCC specimens respectively. All studied markers showed a significant increase in the expression in tumor tissue specimens compared to non-tumor tissue. Both SOX2 and SOX9 expressions were significantly associated with adverse prognostic factors in HCC. Significant positive correlations were found between SOX2 and SOX9 and both p53 and β-catenin expression (r= 0.528, 0.485 and; r = 0.253, 0.327, respectively; p< 0.0001 for both of them). Regarding survival, we found that HCC patients with positive SOX2 and SOX9 expressions had significantly shorter overall survival (p=0.0001, each). Additionally, larger tumor size, tumor grade, high stage, tumor multiplicity, presence of cirrhosis, tumor necrosis, high p53 expression, and positive β-catenin expression were independent predictors of worse survival. A multivariate Cox analysis revealed that tumor grade, stage, p53, and SOX2 expression were independent predictors of unfavorable prognosis in overall survival (p=0.0001, p=0.0001,p=0.033; and p=0.003, respectively). Conclusions: Our findings might provide an insight into SOX2 and SOX9’s role in HCC and suggest that SOX2 might be targeted for HCC therapy.
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Affiliation(s)
- Nisreen A A Osman
- Department of Pathology, Faculty of Medicine, Minia University, Egypt
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Howell J, Atkinson SR, Pinato DJ, Knapp S, Ward C, Minisini R, Burlone ME, Leutner M, Pirisi M, Büttner R, Khan SA, Thursz M, Odenthal M, Sharma R. Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma. Eur J Cancer 2019; 116:56-66. [PMID: 31173963 DOI: 10.1016/j.ejca.2019.04.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/03/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.
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Affiliation(s)
- Jessica Howell
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK; Centre for Population Health, Macfarlane-Burnet Institute, 85 Commercial Rd, Melbourne, 3004, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, 55 Victoria Pde, Fitzroy, 3065, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, 85 Commercial Rd, Melbourne 3004, Australia
| | - Stephen R Atkinson
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Susanne Knapp
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK; Department of Women's Cancer, Institute for Women's Health, University College London, 72 Huntley St, London, WC1C6DD, UK
| | - Caroline Ward
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Rosalba Minisini
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Michela E Burlone
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Monica Leutner
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100, Novara, Italy
| | - Reinhard Büttner
- Institute for Pathology, University Hospital of Cologne and Center of Integrative Oncology, University Clinic of Cologne and Bonn, Kerpener Str. 62, 50924, Cologne, Germany; The Center of Molecular Medicine, The Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Mark Thursz
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK
| | - Margarete Odenthal
- Institute for Pathology, University Hospital of Cologne and Center of Integrative Oncology, University Clinic of Cologne and Bonn, Kerpener Str. 62, 50924, Cologne, Germany; The Center of Molecular Medicine, The Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS, London, UK.
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22
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Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD, Elsayes KM. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma 2018; 5:61-73. [PMID: 29984212 PMCID: PMC6027703 DOI: 10.2147/jhc.s156701] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/β-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the β-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway.
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Affiliation(s)
- Ahmed M Khalaf
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Fuentes
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ali I Morshid
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,
| | - Mata R Burke
- Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal Hassan
- Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John D Hazle
- Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,
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Qinglin L, Xin W, Zhong L, Fang L, Cao G, Huang P. A study on the anti-tumor mechanism of total flavonoids from Radix Tetrastigmae against additional cell line based on COX-2-mediated Wnt/β-catenin signaling pathway. Oncotarget 2017; 8:54304-54319. [PMID: 28903343 PMCID: PMC5589582 DOI: 10.18632/oncotarget.16876] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 03/09/2017] [Indexed: 01/18/2023] Open
Abstract
This study is to explore the effect of total flavonoids from Radix Tetrastigmae (TF) against hepatic cancer and discuss the acting mechanism. Proliferation of HepG2 cells was promoted by PGE2 and Butaprost. Using AH6809 as the positive control, the inhibitory effect of TF on additional cell line was detected through a CCK-8 assay, the apoptosis rate was detected by flow cytometry, and the nuclear morphology of cells were observed by Hochest33258 staining. Then PCR was applied to determine the mRNA expression. The corresponding Protein expression were determined by Western Blot. The effects of TF on the body weight, tumor growth volume and tumor inhibition rate were observed in nude mice model of human hepatocellular carcinoma by vivo experiments. The results showed TF had an obvious inhibitory effect on HepG2 cells with a significant dose-dependent manner (P<0.01). Pyknosis was found under the fluorescence microscope after TF treatment for 24h by Hochest33258 staining. Typical features of apoptosis were observed in HepG2 cells treated with TF and the apoptosis rate increased with increase of concentration of the TF. mRNA expression levels of GSK-3β, Akt, VEGF, COX-2 and β-catenin were down regulated greatly by the TF in HepG2 cells. Moderate and high concentrations of TF led to an obvious down regulation of GSK-3β, p-GSK-3β, Akt, p-Akt, VEGF, COX-2 and β-catenin in HepG2 cells, while p-β-catenin was up regulated. The tumor inhibition rates with high, medium and low dose of TF were 64.07%, 53.64%, 46.69%, respectively. The inhibitory effect of total flavonoids on tumor growth in mice was better than that of CTX, and the inhibitory effect of TF on tumor growth was less than CTX. TF exhibited a significant inhibitory effect on HepG2 cells, promoting the apoptosis of HepG2 cells in a dose-dependent manner. TF was also regulatory of the COX-2-Wnt/β-catenin signaling pathway, which was presumed to be the working mechanism of Tetrastigmae.
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Affiliation(s)
- Li Qinglin
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
| | - Wenxiu Xin
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
| | - Like Zhong
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
| | - Luo Fang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
| | - Gang Cao
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ping Huang
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
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24
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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25
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Liu LJ, Xie SX, Chen YT, Xue JL, Zhang CJ, Zhu F. Aberrant regulation of Wnt signaling in hepatocellular carcinoma. World J Gastroenterol 2016; 22:7486-7499. [PMID: 27672271 PMCID: PMC5011664 DOI: 10.3748/wjg.v22.i33.7486] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/07/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as "canonical") and CTNNB1-independent (often referred to as "non-canonical") pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca(2+) pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.
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Yang Z, Xie C, Xu W, Liu G, Cao X, Li W, Chen J, Zhu Y, Luo S, Luo Z, Lu N. Phosphorylation and inactivation of PTEN at residues Ser380/Thr382/383 induced by Helicobacter pylori promotes gastric epithelial cell survival through PI3K/Akt pathway. Oncotarget 2016; 6:31916-26. [PMID: 26376616 PMCID: PMC4741650 DOI: 10.18632/oncotarget.5577] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 08/19/2015] [Indexed: 02/07/2023] Open
Abstract
Phosphorylation of PTEN at residues Ser380/Thr382/383 leads to loss of phosphatase activity and tumor suppressor function. Here, we found that phosphorylation of PTEN at residues Ser380/Thr382/383 was increased with gastric carcinogenesis, and more importantly, Helicobacter pylori was a trigger of this modification in chronic non-atrophic gastritis. H. pylori could phosphorylate and inactivate PTEN in vivo and in vitro, resulting in survival of gastric epithelial cells. Furthermore, stable expression of dominant-negative mutant PTEN or inhibition of Akt prevented the enhanced survival induced by H. pylori. These results indicate that PTEN phosphorylation at residues Ser380/Thr382/383 is a novel mechanism of PTEN inactivation in gastric carcinogenesis, and H. pylori triggers this modification, resulting in activation of the PI3K/Akt pathway and promotion of cell survival.
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Affiliation(s)
- Zhen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wenting Xu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Gongmeizi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ximei Cao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wei Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shiwen Luo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.,Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhijun Luo
- The Medical College of Nanchang University, Nanchang, Jiangxi, China.,Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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27
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Mao J, Wang D, Wang Z, Tian W, Li X, Duan J, Wang Y, Yang H, You L, Cheng Y, Bian J, Chen Z, Yang Y. Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway. Cancer Lett 2016; 380:134-43. [PMID: 27349166 DOI: 10.1016/j.canlet.2016.06.020] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 02/07/2023]
Abstract
Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3β activation, Wnt/β-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3β-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-β and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic.
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Affiliation(s)
- Jie Mao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Duowei Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Zhuo Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Tian
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Xianjing Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Jingjing Duan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Yun Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Hongbao Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Linjun You
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Yan Cheng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China
| | - Jinsong Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Zhen Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
| | - Yong Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
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28
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Pan LH, Yao M, Cai Y, Gu JJ, Yang XL, Wang L, Yao DF. Oncogenic Wnt3a expression as an estimable prognostic marker for hepatocellular carcinoma. World J Gastroenterol 2016; 22:3829-3836. [PMID: 27076768 PMCID: PMC4814746 DOI: 10.3748/wjg.v22.i14.3829] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 01/06/2016] [Accepted: 01/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate member 3a of Wingless-type MMTV integration site family (Wnt3a) expression in cancerous and surrounding tissues and the relationship between clinicopathologic features of hepatocellular carcinoma (HCC) and Wnt3a expression. METHODS Wnt3a expression and cellular distribution and clinicopathologic characteristics in cancerous tissue and matched surrounding tissues were analyzed in 80 HCC patients from January 2006 to August 2008 by tissue microarrays and immunohistochemistry. The overall and disease-free survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with univariate and multivariate Cox regressions models. RESULTS The incidence of oncogenic Wnt3a expression in the cancerous group was up to 96.25% (77 of 80), which was significantly higher (χ(2) = 48.818, P < 0.001) than that in the surrounding group (46.25%, 37 of 80). Brown Wnt3a staining gradually increased with clinical staging that showed very strong staining in advanced HCC. The clinicopathologic features of high Wnt3a expression in HCC were related to poorly-differentiated grade (χ(2) = 20.211, P < 0.001), liver cirrhosis (χ(2) = 8.467, P < 0.004), hepatitis B virus (HBV) infection (χ(2) = 12.957, P < 0.001), higher tumor-node-metastasis stage (χ(2) = 22.960, P < 0.001), and 5-year survival rate (χ(2) = 15.469, P < 0.001). CONCLUSION Oncogenic Wnt3a expression associated with HBV infection and cirrhotic liver might be an independent prognostic factor for HCC.
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29
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Guo Y, Wang J, Zhang L, Shen S, Guo R, Yang Y, Chen W, Wang Y, Chen G, Shuai X. Theranostical nanosystem-mediated identification of an oncogene and highly effective therapy in hepatocellular carcinoma. Hepatology 2016; 63:1240-55. [PMID: 26680504 DOI: 10.1002/hep.28409] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 12/09/2015] [Indexed: 12/24/2022]
Abstract
UNLABELLED Because the primary surgical treatment options for hepatocellular carcinoma (HCC)-including hepatic resection and liver transplantation-often fail due to recurrence and metastasis, identifying early prognostic biomarkers and therapeutic targets for HCC is of great importance. This study shows that transducin β-like protein 1-related protein (TBLR1) is a key HCC oncogene that plays important roles in HCC proliferation, antiapoptosis, and angiogenesis by regulating the Wnt/β-catenin pathway. The folate-targeted theranostic small interfering RNA (siRNA) nanomedicine Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 effectively silences the TBLR1 gene in different human HCC cell lines in vitro and in human HCC samples in vivo, resulting in the simultaneous suppression of HCC cell proliferation, antiapoptosis, and angiogenesis. Because of its multi-anticancer functions against HCC, intravenous injection of the folate-targeted siRNA nanomedicine into nude mice bearing intrahepatic or subcutaneous xenografts of human HCC has a significant therapeutic effect. Tumor growth in those animals was almost completely inhibited by treatment with Fa-PEG-g-PEI-SPION/psiRNA-TBLR1. Moreover, the SPION-encapsulated polyplexes possess high magnetic resonance imaging (MRI) detection sensitivity, which makes tumor-targeted siRNA delivery easily trackable using the clinical MRI technique. CONCLUSION The theranostic siRNA nanomedicine examined here possesses great theranostic potential for combined gene therapy and MRI diagnosis of HCC.
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Affiliation(s)
- Yu Guo
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China
- Experimental Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jing Wang
- Experimental Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lu Zhang
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China
| | - Shunli Shen
- Experimental Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ruomi Guo
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenjie Chen
- Hepatology Laboratory, Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, China
| | - Yiru Wang
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China
| | - Guihua Chen
- Hepatology Laboratory, Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, China
| | - Xintao Shuai
- PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China
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K.M. Ip C, Yin J, K.S. Ng P, Lin SY, B. Mills G. Genomic-Glycosylation Aberrations in Tumor Initiation, Progression and Management. AIMS MEDICAL SCIENCE 2016. [DOI: 10.3934/medsci.2016.4.386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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31
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Tsujikawa H, Masugi Y, Yamazaki K, Itano O, Kitagawa Y, Sakamoto M. Immunohistochemical molecular analysis indicates hepatocellular carcinoma subgroups that reflect tumor aggressiveness. Hum Pathol 2015; 50:24-33. [PMID: 26997435 DOI: 10.1016/j.humpath.2015.10.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 10/15/2015] [Accepted: 10/21/2015] [Indexed: 12/14/2022]
Abstract
Histopathologic parameters and molecular markers are widely accepted as useful predictors of tumor aggressiveness in hepatocellular carcinoma (HCC). However, few studies have analyzed immunohistochemical profiles comprehensively in one series, a fact that has resulted in fragmentation of information that could be applied in clinical practice. We conducted immunohistochemical expression analysis of biliary/stem cell markers (cytokeratin 19, sal-like protein 4, epithelial cell adhesion molecule, and CD133), Wnt/β-catenin signaling-related molecules (β-catenin and glutamine synthetase), p53, and cell proliferation markers (Ki-67 and mitosis) in 162 HCCs surgically resected from 142 patients and analyzed the results with respect to clinicopathological features. Immunohistochemical analysis broadly identified 3 groups: the biliary/stem cell marker-positive group, the Wnt/β-catenin signaling-related marker-positive group, and the biliary/stem cell marker-negative and Wnt/β-catenin signaling-related marker-negative group. p53 was frequently positive in the biliary/stem cell marker-positive group, but it was rarely positive in the Wnt/β-catenin signaling-related marker-positive group. The biliary/stem cell marker-positive group exhibited poor tumor differentiation, increased frequency of portal vein invasion and/or intrahepatic metastasis, and highly proliferative activity. In contrast, the biliary/stem cell marker-negative and Wnt/β-catenin signaling-related marker-negative group exhibited better tumor differentiation, a decreased frequency of portal vein invasion and/or intrahepatic metastasis, and less proliferative activity. The Wnt/β-catenin signaling-related marker-positive group showed neither tendency. The biliary/stem cell marker-positive group had the shortest time to recurrence among the 3 groups. Immunohistochemical profiling of HCC reflects tumor aggressiveness and suggests the potential efficacy of immunohistochemistry-based subclassification of HCC.
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Affiliation(s)
- Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Ken Yamazaki
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Osamu Itano
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
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Chiu SH, Wu CC, Fang CY, Yu SL, Hsu HY, Chow YH, Chen JY. Epstein-Barr virus BALF3 mediates genomic instability and progressive malignancy in nasopharyngeal carcinoma. Oncotarget 2015; 5:8583-601. [PMID: 25261366 PMCID: PMC4226706 DOI: 10.18632/oncotarget.2323] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer prevalent throughout Southern China and Southeast Asia. Patient death following relapse after primary treatment remains all too common but the cause of NPC relapse is unclear. Clinical and epidemiological studies have revealed the high correlation among NPC development, Epstein-Barr virus (EBV) reactivation and host genomic instability. Previously, recurrent EBV reactivation was shown to cause massive genetic alterations and enhancement of tumor progression in NPC cells and these may be required for NPC relapse. Here, EBV BALF3 has the ability to induce micronuclei and DNA strand breaks. After recurrent expression of BALF3 in NPC cells, genomic copy number aberrations, determined by array-based comparative genomic hybridization, had accumulated to a significant extent and tumorigenic features, such as cell migration, cell invasion and spheroid formation, increased with the rounds of induction. In parallel experiments, cells after highly recurrent induction developed into larger tumor nodules than control cells when inoculated into NOD/SCID mice. Furthermore, RNA microarrays showed that differential expression of multiple cancer capability-related genes and oncogenes increased with recurrent BALF3 expression and these changes correlated with genetic aberrations. Therefore, EBV BALF3 is a potential factor that mediates the impact of EBV on NPC relapse.
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Affiliation(s)
- Shih-Hsin Chiu
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Chung-Chun Wu
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Chih-Yeu Fang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Shu-Ling Yu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Hui-Yu Hsu
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Yen-Hung Chow
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Jen-Yang Chen
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
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