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Nakra T, Jassim M, Yadav R, Agarwala S, Das P, Nilima N, Sreenivas V, Chopra A, Dattagupta S, Iyer VK. Study of WNT and NOTCH Signaling Pathways in Hepatoblastoma: Role in Diagnosis and Prognosis. Int J Surg Pathol 2025:10668969251346938. [PMID: 40491264 DOI: 10.1177/10668969251346938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
Background. Hepatoblastoma has an aggressive course in a subset of children. Studying various markers related to the signaling pathways can aid in understanding its pathogenesis at the molecular level and may pave the way for targeted therapy. We conducted this study to evaluate the immunohistochemical expression of markers related to WNT and NOTCH signaling pathways in hepatoblastoma and to compare them among its histological subtypes. Methods. The specimens of hepatoblastoma diagnosed over a period of 8 years were retrieved. Clinicoradiological data was obtained. Slides were reviewed and detailed histopathological parameters, diagnosis, and subtypes were reevaluated. Immunohistochemistry for β-catenin, CCND1, glutamine synthetase, MYC, AXIN2, NOTCH2, DLK1, and HES1 was performed. Statistical analysis was done. Results. A total of 51 samples of hepatoblastoma were included in the study. Mixed epithelial-mesenchymal hepatoblastoma was the most common histologic subtype. PRETEXT IV, high-risk group, high mitotic index, and less differentiated histologic subtype were associated with worse outcomes. β-catenin, AXIN2, CCND1, expression was more in less differentiated subtypes. MYC, HES1, and glutamine synthetase expression was more common in the fetal component. NOTCH2 and DLK1 expression was seen across all types. A statistically significant association was observed among AXIN2 expression with β-catenin, CCND1, and MYC nuclear expression. Mean overall survival was 66.6 months and mean event-free survival was 54.7 months. Conclusions. The NOTCH pathway converges with the WNT pathway. Differential expression of the immunohistochemical markers of these pathways helps in the semiquantitation of various epithelial components, guides adjuvant treatment, and patient prognostication.
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Affiliation(s)
- Tripti Nakra
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
| | - Mohamed Jassim
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
| | - Rajni Yadav
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Agarwala
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
| | - Nilima Nilima
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | | | - Anita Chopra
- Laboratory Oncology Unit, All India Institute of Medical Sciences, New Delhi, India
| | - S Dattagupta
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
| | - Venkateswaran K Iyer
- Department of Pathology All India Institute of Medical Sciences, New Delhi, India
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Law W, Zheng J, Kim TH, Horvat N, Harding JJ, Sigel C, Arslan ME, Wei A, Do RK, Chernyak V. CT and MRI features of Catenin Beta 1-mutated hepatocellular carcinoma in a Western cohort. Abdom Radiol (NY) 2025:10.1007/s00261-025-05044-1. [PMID: 40493177 DOI: 10.1007/s00261-025-05044-1] [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: 03/31/2025] [Revised: 05/19/2025] [Accepted: 05/29/2025] [Indexed: 06/12/2025]
Abstract
OBJECTIVES Various mutations in hepatocellular carcinoma (HCC) carry prognostic implications. The objective of this study is to assess CT and MRI imaging features associated with Catenin Beta-1 (CTNNB1) mutation in HCC. METHODS This retrospective, IRB- approved multi-reader, single-center study included treatment-naive, pathologic-proven HCC that underwent contrast-enhanced CT, MRI or both, with subsequent targeted tumor sequencing test. Preoperative CT and MRI were reviewed for the Liver Imaging Reporting and Data System (LI-RADS, LR) features and prognostic imaging features. Fisher's exact test and multiple testing adjustment were used to assess the association of imaging features and CTNNB1 mutation status. RESULTS Of the 160 HCCs included (median age 69 [IQR: 62, 75], 125 men), 58 (36%) had CTNNB1 mutation. Compared to wildtype, CTNNB1-mutated HCCs were more likely to be present as solitary lesion (CT: 26/43[60%] vs. 31/80 [40%], p = 0.024), have mosaic appearance (MRI: 9/34[26%] vs. 3/68[4.4%], p = 0.002), blood products in mass (CT: 7/43[16%] vs. 2/80[2.5%], p = 0.009; MRI: 12/34[35%] vs. 8/68[12%], p = 0.008), necrosis (CT: 16/43[37%] vs. 14/80[18]%, p = 0.026), intralesional arteries (CT: 26/43[60%] vs. 32/80[40%], p = 0.038). A subgroup of 98 high risk patients (hepatitis B, morphologic cirrhosis) were assigned LI-RADS categorization; majority of patients were assigned LR-5 (CT: 15/25[60%] vs. 21/52[40%]; MRI: 10/18[56%] vs. 19/44[43%]). No feature was significantly associated with CTNNB1 mutation status after multiple testing adjustment. CONCLUSION Compared to wildtype, CTNNB1-mutated HCCs are more likely to appear as solitary masses with mosaic, heterogeneous appearance containing blood products, necrosis and intralesional arteries. Majority of CTNNB1-mutated tumors were categorized as LR-5 in a subgroup of high risk patients. No imaging feature independently predicted CTNNB1-mutated HCCs.
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Affiliation(s)
- Wyanne Law
- Memorial Sloan Kettering Cancer Center, New York, USA.
| | - Junting Zheng
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - Tae-Hyung Kim
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - Natally Horvat
- Memorial Sloan Kettering Cancer Center, New York, USA
- Mayo Clinic, Rochester, USA
| | - James J Harding
- Memorial Sloan Kettering Cancer Center, New York, USA
- Weill Cornell Medicine, New York, USA
| | - Carlie Sigel
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - Mustafa Erdem Arslan
- Memorial Sloan Kettering Cancer Center, New York, USA
- East Carolina University, Greenville, USA
| | - Alice Wei
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - Richard K Do
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - Victoria Chernyak
- Memorial Sloan Kettering Cancer Center, New York, USA
- Columbia University, New York, USA
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Liang Z, Li S, Wang Z, Zhou J, Huang Z, Li J, Bao H, Yam JWP, Xu Y. Unraveling the Role of the Wnt Pathway in Hepatocellular Carcinoma: From Molecular Mechanisms to Therapeutic Implications. J Clin Transl Hepatol 2025; 13:315-326. [PMID: 40206274 PMCID: PMC11976435 DOI: 10.14218/jcth.2024.00401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/13/2024] [Accepted: 12/23/2024] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and its incidence and mortality have increased year by year. HCC research has increasingly focused on understanding its pathogenesis and developing treatments.The Wnt signaling pathway, a complex and evolutionarily conserved signal transduction system, has been extensively studied in the genesis and treatment of several malignant tumors. Recent investigations suggest that the pathogenesis of HCC may be significantly influenced by dysregulated Wnt/β-catenin signaling. This article aimed to examine the pathway that controls Wnt signaling in HCC and its mechanisms. In addition, we highlighted the role of this pathway in HCC etiology and targeted treatment.
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Affiliation(s)
- Zixin Liang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shanshan Li
- School of Pharmacy, Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical University, Bengbu, Anhui, China
| | - Zhiyu Wang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Junting Zhou
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziyue Huang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Jiehan Li
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Haolin Bao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- School of Pharmacy, Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu Medical University, Bengbu, Anhui, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
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Akarca FG, Grenert JP, Kakar S. Role of genomic analysis in the classification of well differentiated hepatocellular lesions. Hum Pathol 2025; 158:105794. [PMID: 40374146 DOI: 10.1016/j.humpath.2025.105794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND The distinction of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) from well-differentiated hepatocellular carcinoma (WD-HCC) in noncirrhotic liver can be challenging. High-grade dysplastic nodule (HGDN) in cirrhosis can have overlapping features with WD-HCC. In some cases, HCA diagnosis is evident but glutamine synthetase (GS) staining is indeterminate for β-catenin activation, which does not allow reliable risk assessment. This study examines the role of genomic analysis in better categorization of WD hepatocellular lesions (WDHL). DESIGN Genomic analysis using capture-based NGS assay was done in 23 WDHLs that could not be definitely classified based on morphology, reticulin stain and IHC, and were designated as 'atypical hepatocellular neoplasms' (AHNs). GS staining was classified as diffuse homogeneous (moderate to strong staining in >90 % of tumor cells), diffuse heterogeneous (50-90 %), not diffuse (<50 %) and borderline (not clear if more or less than 50 %). RESULTS The genomic profile provided additional information for the diagnosis and/or risk assessment enabling a benign diagnosis in 15/23 cases (66 %) and HCC in 4/23 cases (17 %), while the diagnosis remained as atypical in the remaining 4 cases. Of the 4 cases with final HCC diagnosis, findings were suspicious but not diagnostic based on morphology/IHC; additional changes like TERT promoter mutation (n = 2), AXIN mutation (n = 1), CDKN2A loss (n = 2) and copy number alterations (n = 3) helped to support HCC. Of the 15 cases with a final benign diagnosis, the status of β-catenin activation was unclear based on GS stain in 8 cases, 2 of which showed CTNNB1 exon 7 mutation, 1 showed CTNNB1 exon 8 mutation, while genomic changes in 5 cases did not show any evidence of Wnt activation. FNH-like features were seen in 2 cases, but the genomic changes excluded FNH (CTNNB1 and ARID1A mutation). The final diagnosis was unchanged from the initial diagnosis of AHN in 4/23 cases (17 %) as the molecular findings did not favor HCC. CONCLUSION Genomic changes were helpful in characterization of WDHLs, supporting HCC in 17 % of cases and clarifying β-catenin activation status in all 7 cases with borderline GS staining. Genomic changes are not specific but can provide diagnostic clues in selected challenging cases that cannot be classified on morphology and IHC. Given the significant treatment implications of distinguishing between HCC and benign/premalignant entities, routine use of genomic analysis in diagnostically challenging settings should be considered.
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MESH Headings
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/classification
- Liver Neoplasms/diagnosis
- Liver Neoplasms/chemistry
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/classification
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/diagnosis
- Adenoma, Liver Cell/genetics
- Adenoma, Liver Cell/pathology
- Adenoma, Liver Cell/classification
- Adenoma, Liver Cell/diagnosis
- Adenoma, Liver Cell/chemistry
- Male
- Middle Aged
- Female
- Aged
- Focal Nodular Hyperplasia/genetics
- Focal Nodular Hyperplasia/pathology
- Focal Nodular Hyperplasia/diagnosis
- Focal Nodular Hyperplasia/classification
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/analysis
- Adult
- Genomics/methods
- Diagnosis, Differential
- Glutamate-Ammonia Ligase/analysis
- beta Catenin/genetics
- Mutation
- High-Throughput Nucleotide Sequencing
- Predictive Value of Tests
- Cell Differentiation
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Desterke C, Fu Y, Bonifacio-Mundaca J, Monge C, Pineau P, Mata-Garrido J, Francés R. Single-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma. Curr Oncol 2025; 32:35. [PMID: 39851951 PMCID: PMC11763369 DOI: 10.3390/curroncol32010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 01/26/2025] Open
Abstract
(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types. In medulloblastoma, LEF1 upregulation is associated with the WNT-subtype. The analysis of LEF1 genome binding occupancy in H1 embryonic stem cells identified 141 LEF1 proximal targets activated in WNT medulloblastoma, 13 of which are involved in Wnt pathway regulation: RNF43, LEF1, NKD1, AXIN2, DKK4, DKK1, LGR6, FGFR2, NXN, TCF7L1, STK3, YAP1, and NFATC4. The ROC curve analysis of the combined expression of these 13 WNT-related LEF1 targets yielded an area under the curve (AUC) of 1.00, indicating 100% specificity and sensitivity for predicting the WNT subtype in the PBTA medulloblastoma cohort. An expression score based on these 13 WNT-LEF1 targets accurately predicted the WNT subtype in two independent medulloblastoma transcriptome cohorts. At the single-cell level, the WNT-LEF1 expression score was exclusively positive in WNT-medulloblastoma tumor cells. This WNT-LEF1-dependent signature was also confirmed as activated in the hepatoblastoma tumor transcriptome. At the single-cell level, the WNT-LEF1 expression score was higher in tumor cells from both human hepatoblastoma samples and a hepatoblastoma patient-derived xenotransplant model; (4) Discussion: This study uncovered a shared transcriptional activation of a LEF1-dependent embryonic program, which orchestrates the regulation of the Wnt signaling pathway in tumor cells from both hepatoblastoma and medulloblastoma.
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Affiliation(s)
- Christophe Desterke
- Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, INSERM UMRS-1310, 94805 Villejuif, France;
| | - Yuanji Fu
- Institut Necker Enfants Malades, INSERM, CNRS, Université Paris Cité, 75015 Paris, France;
| | - Jenny Bonifacio-Mundaca
- National Tumor Bank, Department of Pathology, National Institute of Neoplastic Diseases, Lima 15024, Peru;
| | - Claudia Monge
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, France; (C.M.); (P.P.)
| | - Pascal Pineau
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, France; (C.M.); (P.P.)
| | - Jorge Mata-Garrido
- Institut Pasteur, Université Paris Cité, Unité Organisation Nucléaire et Oncogenèse, INSERM U993, 75015 Paris, France; (C.M.); (P.P.)
| | - Raquel Francés
- Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75006 Paris, France
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Rahman MA, Rakib-Uz-Zaman SM, Chakraborti S, Bhajan SK, Gupta RD, Jalouli M, Parvez MAK, Shaikh MH, Hoque Apu E, Harrath AH, Moon S, Kim B. Advancements in Utilizing Natural Compounds for Modulating Autophagy in Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Cells 2024; 13:1186. [PMID: 39056768 PMCID: PMC11274515 DOI: 10.3390/cells13141186] [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: 04/16/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Autophagy, an intrinsic catabolic mechanism that eliminates misfolded proteins, dysfunctional organelles, and lipid droplets, plays a vital function in energy balance and cytoplasmic quality control, in addition to maintaining cellular homeostasis. Liver cancer such as hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths globally and shows resistance to several anticancer drugs. Despite the rising incidence and poor prognosis of malignant HCC, the underlying molecular mechanisms driving this aggressive cancer remain unclear. Several natural compounds, such as phytochemicals of dietary and non-dietary origin, affect hepatocarcinogenesis signaling pathways in vitro and in vivo, which may help prevent and treat HCC cells. Current HCC cells treatments include chemotherapy, radiation, and surgery. However, these standard therapies have substantial side effects, and combination therapy enhances side effects for an acceptable therapeutic benefit. Therefore, there is a need to develop treatment strategies for HCC cells that are more efficacious and have fewer adverse effects. Multiple genetic and epigenetic factors are responsible for the HCC cells to become resistant to standard treatment. Autophagy contributes to maintain cellular homeostasis, which activates autophagy for biosynthesis and mitochondrial regulation and recycling. Therefore, modifying autophagic signaling would present a promising opportunity to identify novel therapies to treat HCC cells resistant to current standard treatments. This comprehensive review illustrates how natural compounds demonstrate their anti-hepatocellular carcinoma function through autophagy.
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Affiliation(s)
- Md Ataur Rahman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - S M Rakib-Uz-Zaman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
- Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Dhaka 1212, Bangladesh
| | - Somdeepa Chakraborti
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
| | - Sujay Kumar Bhajan
- Department of Biotechnology & Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj 8100, Bangladesh;
| | - Rajat Das Gupta
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA;
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia;
| | | | - Mushfiq H. Shaikh
- Department of Otolaryngology-Head & Neck Surgery, Western University, London, ON N6A 4V2, Canada;
| | - Ehsanul Hoque Apu
- Department of Biomedical Sciences, College of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37923, USA;
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN 37752, USA
- Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1–5 Hoegidong Dongdaemun-gu, Seoul 02447, Republic of Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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Zhao Z, Cui T, Wei F, Zhou Z, Sun Y, Gao C, Xu X, Zhang H. Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: pathogenic role and therapeutic target. Front Oncol 2024; 14:1367364. [PMID: 38634048 PMCID: PMC11022604 DOI: 10.3389/fonc.2024.1367364] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and one of the leading causes of cancer-related deaths worldwide. The Wnt/β-Catenin signaling pathway is a highly conserved pathway involved in several biological processes, including the improper regulation that leads to the tumorigenesis and progression of cancer. New studies have found that abnormal activation of the Wnt/β-Catenin signaling pathway is a major cause of HCC tumorigenesis, progression, and resistance to therapy. New perspectives and approaches to treating HCC will arise from understanding this pathway. This article offers a thorough analysis of the Wnt/β-Catenin signaling pathway's function and its therapeutic implications in HCC.
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Affiliation(s)
- Zekun Zhao
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Tenglu Cui
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Radiotherapy Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhiming Zhou
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yuan Sun
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Chaofeng Gao
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaodong Xu
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Huihan Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Second General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, China
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8
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Wang W, Zhang N, Chen L, Zhao X, Shan Y, Yang F, Wang B, Gao H, Xu M, Tang P, Qin S, Gu S. Whole-genome sequencing and RNA sequencing analysis reveals novel risk genes and differential expression patterns in hepatoblastoma. Gene 2024; 897:147991. [PMID: 37972697 DOI: 10.1016/j.gene.2023.147991] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Hepatoblastoma (HB) is an uncommon malignant liver cancer primarily affecting infants and children, characterized by the presence of tissue that resembling fetal hepatocytes, mature liver cells or bile duct cells. The primary symptom in affected children is abdominal lumps. HB constitutes approximately 28% of all liver tumors and two-thirds of liver malignancies in the pediatric and adolescent population. Despite its high prevalence, the underlying mechanism of HB pathogenesis remain largely unknown. To reveal the genetic alternations associated with HB, we conducted a comprehensive genomic study using whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) techniques on five HB patients. We aimed to use WGS to identify somatic variant loci associated with HB, including single nucleotide polymorphisms (SNPs), insertions and deletions (Indels), and copy number variations (CNVs). Notably, we found deleterious mutation in CTNNB1, AXIN2 and PARP1, previously implicated in HB. In addition, we discovered multiple novel genes potentially associated with HB, including BRCA2 and GPC3 which require further functional validation to reveal their contributions to HB development. Furthermore, the American College of Medical Genetics and Genomics (ACMG) analysis identified the ABCC2 gene was the pathogenic gene as a potential risk gene linked with HB. To study the gene expression patterns in HB, we performed RNA-seq analysis and qPCR validation to reveal differential expression of four candidate genes (IGF1R, METTL1, AXIN2 and TP53) in tumors compared to nonneoplastic liver tissue in HB patients (P-Val < 0.01). These findings shed lights on the molecular mechanisms underlying HB development and facilitate to advance future personalized diagnosis and therapeutic interventions of HB.
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Affiliation(s)
- Wuqian Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Jiaxing Maternity and Children Health Care Hospital, Affiliated Women and Children Hospital Jiaxing University, Jiaxing, Zhejiang, China
| | - Na Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Luan Chen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xianglong Zhao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yuhua Shan
- Department of General Surgery, Shanghai Children's Medical Center, (National Children's Medical Center), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fan Yang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Research Center for Lin He Academician New Medicine, Institutes for Shanghai Pudong Decoding Life, Shanghai, China
| | - Bo Wang
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 511436, China
| | - Hongxiang Gao
- Department of General Surgery, Shanghai Children's Medical Center, (National Children's Medical Center), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Min Xu
- Department of General Surgery, Shanghai Children's Medical Center, (National Children's Medical Center), School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ping Tang
- Jiaxing Maternity and Children Health Care Hospital, Affiliated Women and Children Hospital Jiaxing University, Jiaxing, Zhejiang, China.
| | - Shengying Qin
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Song Gu
- Department of General Surgery, Shanghai Children's Medical Center, (National Children's Medical Center), School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Song H, Qiu J, Hua K. USP14 promotes the proliferation of cervical cancer via upregulating β-catenin. ENVIRONMENTAL TOXICOLOGY 2024; 39:1031-1043. [PMID: 38069565 DOI: 10.1002/tox.23990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/24/2023] [Accepted: 09/21/2023] [Indexed: 01/09/2024]
Abstract
In recent years, the ubiquitin-proteasome system (UPS) has become a hot spot in medical research in cervical cancer (CC) and has received extensive attention. Among them, ubiquitin-specific protease 14 (USP14) is involved in a wide variety of typical cell signaling pathways and is recognized to be involved in the progression of most known tumors. However, the expression and significance of USP14 in CC have not been directly studied. Through database analysis, we found that USP14 was overexpressed in CC, which influenced the FIGO stage and prognosis of CC patients, and it was positively correlated with the expression level of β-catenin. In this study, USP14 promoted the G1-S phase transition of Hela and Siha cells and inhibited cell apoptosis, thereby promoting the proliferation, migration, and invasion of CC cells. In addition, USP14 also significantly promoted the growth of subcutaneous tumor in nude mice. We also found that overexpression of USP14 significantly upregulated β-catenin expression and increased the activity of Wnt/β-catenin signaling pathway. While knockdown of USP14 resulted in the opposite. These results suggest that USP14 may promote the proliferation of CC by up-regulating the expression of β-catenin, contributing to a deeper understanding of the mechanisms of CC and providing a potential therapeutic target.
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Affiliation(s)
- Han Song
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Junjun Qiu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Keqin Hua
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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10
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Qiu L, Sun Y, Ning H, Chen G, Zhao W, Gao Y. The scaffold protein AXIN1: gene ontology, signal network, and physiological function. Cell Commun Signal 2024; 22:77. [PMID: 38291457 PMCID: PMC10826278 DOI: 10.1186/s12964-024-01482-4] [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: 10/23/2023] [Accepted: 01/06/2024] [Indexed: 02/01/2024] Open
Abstract
AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.
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Affiliation(s)
- Lu Qiu
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yixuan Sun
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Haoming Ning
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Guanyu Chen
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Wenshan Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
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Aghababaei F, Nejati M, Karami H, Darvish M, Mirzaei H. The Combination of 5-FU and Resveratrol Can Suppress the Growth of Glioblastoma Cells Through Downregulation of TRPM2 and β-Catenin. J Mol Neurosci 2024; 74:7. [PMID: 38193979 DOI: 10.1007/s12031-023-02174-3] [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: 08/30/2023] [Accepted: 12/05/2023] [Indexed: 01/10/2024]
Abstract
Glioblastoma multiforme (GBM) is the most common as well as the most fatal primary malignant tumor of the central nervous system (CNS), which still lacks a definitive cure. 5-FU is an anti-metabolite anti-cancer agent which has shown promising results for GBM treatment. Resveratrol (Res) is a phytochemical anti-oxidant that has also been effective in suppressing the progression of GBM. The combination of 5-FU and Res has been studied in a variety of cancers, but no study has assessed this combination in GBM. In this study, we investigated how 5-FU and Res, in combination and alone, may affect the growth and apoptosis of GBM cells and also the potential of TRPM2 and β-catenin as the mediator of their effects. U87 cells were cultured as the in vitro model. MTT assay was used for measuring cellular growth, and RT-qPCR was used to measure the level of caspase-3, TRPM2, and β-catenin; caspase-3 level served as the indicator of apoptotic rate. 5-FU and Res, in combination and alone, suppressed the growth while promoting the apoptosis of U87 cells; these effects were significantly greater when they were used in combination. RT-qPCR showed downregulation of TRPM-2 and β-catenin in response to this combination, which suggested that these two molecules may mediate the cited anti-oncogenic effects. In conclusion, our study confirmed the synergism between 5-FU and Res in suppressing the progression of GBM and suggested the putative axis of TRPM2/ β-catenin as the downstream mediator of this therapeutic regime. Future studies may be able to approve the eligibility of this therapeutic regime for GBM treatment and also the underlying mechanism.
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Affiliation(s)
- Farzaneh Aghababaei
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hadi Karami
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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12
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Idrissi YA, Rajabi MR, Beumer JH, Monga SP, Saeed A. Exploring the Impact of the β-Catenin Mutations in Hepatocellular Carcinoma: An In-Depth Review. Cancer Control 2024; 31:10732748241293680. [PMID: 39428608 PMCID: PMC11528747 DOI: 10.1177/10732748241293680] [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: 07/05/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/22/2024] Open
Abstract
Liver cancer, primarily hepatocellular carcinoma, represents a major global health issue with significant clinical, economic, and psychological impacts. Its incidence continues to rise, driven by risk factors such as hepatitis B and C infections, nonalcoholic steatohepatitis, and various environmental influences. The Wnt/β-Catenin signaling pathway, frequently dysregulated in HCC, emerges as a promising therapeutic target. Critical genetic alterations, particularly in the CTNNB1 gene, involve mutations at key phosphorylation sites on β-catenin's N-terminal domain (S33, S37, T41, and S45) and in armadillo repeat domains (K335I and N387 K). These mutations impede β-catenin degradation, enhancing its oncogenic potential. In addition to genetic alterations, molecular and epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNAs, further influence β-catenin signaling and tumor progression. However, β-catenin activation alone is insufficient for hepatocarcinogenesis; additional genetic "hits" are required for tumor initiation. Mutations or alterations in genes such as Ras, c-Met, NRF2, and LKB1, when combined with β-catenin activation, significantly contribute to HCC development and progression. Understanding these cooperative mutations provides crucial insights into the disease and reveals potential therapeutic strategies. The complex interplay between genetic variations and the tumor microenvironment, coupled with novel therapeutic approaches targeting the Wnt/β-Catenin pathway, offers promise for improved treatment of HCC. Despite advances, translating preclinical findings into clinical practice remains a challenge. Future research should focus on elucidating how specific β-catenin mutations and additional genetic alterations contribute to HCC pathogenesis, leveraging genetically clengineered mouse models to explore distinct signaling impacts, and identifying downstream targets. Relevant clinical trials will be essential for advancing personalized therapies and enhancing patient outcomes. This review provides a comprehensive analysis of β-Catenin signaling in HCC, highlighting its role in pathogenesis, diagnosis, and therapeutic targeting, and identifies key research directions to improve understanding and clinical outcomes.
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Affiliation(s)
- Yassine Alami Idrissi
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Mohammad Reza Rajabi
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Jan H. Beumer
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA, USA
| | - Satdarshan P. Monga
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA
| | - Anwaar Saeed
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lee DH, Jeong IH, Jang B. Elevated expression of Axin2 in intestinal metaplasia and gastric cancers. J Pathol Transl Med 2023; 57:315-322. [PMID: 37926983 PMCID: PMC10660364 DOI: 10.4132/jptm.2023.10.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND The Wnt signaling pathway regulates crucial cellular processes, including stem cell development and tissue repair. Dysregulation of this pathway, particularly β-catenin stabilization, is linked to colorectal carcinoma and other tumors. Axin2, a critical component in the pathway, plays a role in β-catenin regulation. This study examines Axin2 expression in normal gastric mucosa and various gastric pathologies. METHODS Formalin-fixed and paraffin-embedded tissue samples from normal stomach, gastritis, intestinal metaplasia (IM), and gastric carcinoma were collected. Axin2 and β-catenin expression were evaluated using RNA in situ hybridization and immunohistochemistry, respectively. Histo-scores (H-scores) were calculated to quantify expression levels of Axin2. Associations between Axin2 expression and clinicopathological variables were examined. RESULTS Axin2 expression was examined in normal stomach, gastritis, and IM tissues. Axin2 expression was mainly observed in the surface and isthmus areas in the normal stomach and gastritis, whereas Axin2 expression was markedly higher at the bases of IM. Axin2 H-scores were significantly elevated in IM (mean ± standard deviation [SD], 87.0 ± 38.9) compared to normal (mean ± SD, 18.0 ± 4.5) and gastritis tissues (mean ± SD, 33.0 ± 18.6). In total, 30% of gastric carcinomas showed higher Axin2 expression. Axin2 expression did not have significant associations with age, sex, Lauren classification, histological differentiation, invasion depth, and lymph node metastasis. However, a strong positive correlation was observed between Axin2 and nuclear β-catenin in gastric carcinomas (p < .001). CONCLUSIONS Axin2 expression was significantly increased in IM compared to normal and gastritis cases. In addition, Axin2 showed a strong positive association with nuclear β-catenin expression in gastric carcinomas, demonstrating a close relationship with abnormal Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Dong Hui Lee
- Department of Pathology, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea
| | - In Ho Jeong
- Department of Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea
| | - Bogun Jang
- Department of Pathology, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea
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15
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Liu F, Liao Z, Zhang Z. MYC in liver cancer: mechanisms and targeted therapy opportunities. Oncogene 2023; 42:3303-3318. [PMID: 37833558 DOI: 10.1038/s41388-023-02861-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/28/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023]
Abstract
MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.
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Affiliation(s)
- Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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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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17
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Li C, Furth EE, Rustgi AK, Klein PS. When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex. Cells 2023; 12:2256. [PMID: 37759479 PMCID: PMC10528086 DOI: 10.3390/cells12182256] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.
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Affiliation(s)
- Chenchen Li
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA
| | - Peter S. Klein
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Catalano T, Selvaggi F, Esposito DL, Cotellese R, Aceto GM. Infectious Agents Induce Wnt/β-Catenin Pathway Deregulation in Primary Liver Cancers. Microorganisms 2023; 11:1632. [PMID: 37512809 PMCID: PMC10386003 DOI: 10.3390/microorganisms11071632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/18/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Interaction between infectious agents and liver tissue, as well as repeated and extreme biological events beyond adaptive capacities, may result in pathological conditions predisposing people to development of primary liver cancers (PLCs). In adults, PLCs mainly comprise hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Various infectious agents in the hepatic microenvironment can destabilize normal liver cell functions by modulating the Wnt/β-catenin pathway components. Among them, hepatotropic viruses B, C, and D are involved in Wnt/β-catenin signaling dysregulation. Other microbial agents, including oncogenic viruses such as Epstein-Barr virus (EBV) and human papilloma virus (HPV), bacteria, e.g., Mycoplasma hyorhinis and Salmonella Typhi, the protozoan parasite Toxoplasma gondii, the fungus Aspergillus flavus, and liver flukes such as Clonorchissinensis or Opisthorchis viverrini, may induce malignant transformation in hepatocytes or in target cells of the biliary tract through aberrant Wnt signaling activation. This review focuses on new insights into infectious agents implicated in the deregulation of Wnt signaling and PLC development. Since the Wnt/β-catenin pathway is a driver of cancer following viral and bacterial infections, molecules inhibiting the complex axis of Wnt signaling could represent novel therapeutic approaches in PLC treatment.
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Affiliation(s)
- Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
| | - Federico Selvaggi
- Unit of General Surgery, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata, 66100 Chieti, Italy;
| | - Diana Liberata Esposito
- Center for Advanced Studies and Technology (CAST), 66100 Chieti, Italy;
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
- Villa Serena Foundation for Research, 65013 Città Sant’Angelo, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
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Li M, Mei YX, Wen JH, Jiao YR, Pan QR, Kong XX, Li J. Hepatoid adenocarcinoma-Clinicopathological features and molecular characteristics. Cancer Lett 2023; 559:216104. [PMID: 36863507 DOI: 10.1016/j.canlet.2023.216104] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/17/2023] [Accepted: 02/20/2023] [Indexed: 03/04/2023]
Abstract
Hepatoid adenocarcinoma (HAC) is a rare, malignant, extrahepatic tumor with histologic features similar to those of hepatocellular carcinoma. HAC is most often associated with elevated alpha-fetoprotein (AFP). HAC can occur in multiple organs, including the stomach, esophagus, colon, pancreas, lungs, and ovaries. HAC differs greatly from typical adenocarcinoma in terms of its biological aggression, poor prognosis, and clinicopathological characteristics. However, the mechanisms underlying its development and invasive metastasis remain unclear. The purpose of this review was to summarize the clinicopathological features, molecular traits, and molecular mechanisms driving the malignant phenotype of HAC, in order to support the clinical diagnosis and treatment of HAC.
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Affiliation(s)
- Ming Li
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China
| | - Yan-Xia Mei
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China
| | - Ji-Hang Wen
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China
| | - Yu-Rong Jiao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China
| | - Qiang-Rong Pan
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China
| | - Xiang-Xing Kong
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China.
| | - Jun Li
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China.
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Park WJ, Kim MJ. A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities. Cells 2023; 12:cells12081110. [PMID: 37190019 DOI: 10.3390/cells12081110] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/03/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody-drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target 'undruggable' Wnt signaling.
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Affiliation(s)
- Woo-Jung Park
- Department of Life Science, Gachon University, Seongnam 13120, Republic of Korea
| | - Moon Jong Kim
- Department of Life Science, Gachon University, Seongnam 13120, Republic of Korea
- Department of Health Sciences and Technology, GAIHST, Lee Gil Ya Cancer and Diabetes Institute, Incheon 21999, Republic of Korea
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21
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State of the art and perspectives in pediatric hepatocellular carcinoma. Biochem Pharmacol 2023; 207:115373. [PMID: 36513143 DOI: 10.1016/j.bcp.2022.115373] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022]
Abstract
Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are rare primary malignant liver cancers in children and young adults. HB is the most common and accounts for about 70 % cases; it is usually diagnosed during the first 3 years of life. Instead, pediatric HCC is uncommon, and it is associated with a poor prognosis. Overall, the prognosis of pediatric HCC is dismal with 5-year event-free survival of <30 % as compared to >80 % for HB. Surgery approaches, either resection or transplant, remain the best chance for the cure of pediatric HCC. However, chemotherapy can be helpful as an adjuvant or neoadjuvant treatment. International groups have done trials in pediatric HCC with a chemotherapy regimen, based on cisplatin and doxorubicin (PLADO) as for HB, but the efficacy is limited. Sorafenib, a multi-kinase inhibitor, following positive results in adults and in a pilot study in children, is now tested in conjunction with chemotherapy in the PHITT phase III clinical trial. Some studies have been exploring the genetic profiles of patients to find biological hallmarks that determine the aggressiveness of pediatric HCC. Pathways involved in growth and differentiation are dysregulated and as demonstrated in HB and adult HCC, an important role of the Wnt/CTNNB1 pathway in the pathogenesis of pediatric HCC is also emerging. An extended molecular analysis of tumor samples could give information about pathways as possible targets of biological and immunotherapeutic agents bringing new pharmacological options for the treatment of pediatric HCC.
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22
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CARNEIRO VF, MACHADO RA, BARBOSA MC, DIAS VO, MARTELLI DRB, MARTELLI-JÚNIOR H. Dental anomalies in syndromes displaying hypertrichosis in the clinical spectrum. Braz Oral Res 2023; 37:e030. [PMID: 37018811 DOI: 10.1590/1807-3107bor-2023.vol37.0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 09/19/2022] [Indexed: 04/05/2023] Open
Abstract
Hypertrichosis and dental anomalies may occur alone or in combination in the spectrum of many syndromes. To identify genetic entities characterized by hypertrichosis and dental anomalies, a search was performed in the Mendelian Inheritance in Man database with the terms "hypertrichosis" or "hirsutism" and "tooth" or "dental abnormalities." Nondependent androgen metabolism disturbances were classified as hypertrichosis. Genetic entities with hypertrichosis and dental anomalies were included in the study. Additional searches were performed in the PubMed and Orphanet databases, when necessary, in order to include data from scientific articles. An integrative analysis of the genes associated with the identified syndromes was conducted using STRING to characterize biological processes, pathways, and interactive networks. The p-values were subjected to the false discovery rate for the correction of multiple tests. Thirty-nine syndromes were identified, and dental agenesis was the most frequent dental anomaly present in 41.02% (n = 16) of the syndromes. Causative genes were identified in 33 out of 39 genetic syndromes. Among them, 39 genes were identified, and 38 were analyzed by STRING, which showed 148 biological processes and three pathways that were statistically significant. The most significant biological processes were the disassembly of the nucleosome (GO:0006337, p = 1.09e-06), chromosomal organization (GO:0051276, p = 1.09e-06) and remodeling of the chromatin (GO: 0006338, p = 7.86e-06), and the pathways were hepatocellular carcinoma (hsa05225, p = 5.77e-05), thermogenesis (hsa04714, p = 0.00019), and cell cycle (hsa04110, p = 0.0433). Our results showed that the identification of hypertrichosis and dental anomalies may raise the suspicion of one of the thirty-nine syndromes with both phenotypes.
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23
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Kumar AR, L A, Nair B, Mathew B, Sugunan S, Nath LR. Decoding the Mechanism of Drugs of Heterocyclic Nature against Hepatocellular Carcinoma. Anticancer Agents Med Chem 2023; 23:882-893. [PMID: 35440316 DOI: 10.2174/1871520622666220418115310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/19/2022] [Accepted: 02/18/2022] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and accounts for ~90% of cases, with an approximated incidence of >1 million cases by 2025. Currently, the backbone of HCC therapy is the oral multi-kinase inhibitor, Sorafenib, which consists of a Pyridine heterocycle ring system. This review highlights the introspective characteristics of seven anticancer drugs of heterocyclic nature against HCC along with their structural activity relationships and molecular targets. METHODS Literature collection was performed using PubMed, Google Scholar, SCOPUS, and Cross ref. Additional information was taken from the official website of the FDA and GLOBOCAN. Key findings/ Results: Based on the available literature, approved heterocyclic compounds show promising results against HCC, including Sorafenib (Pyridine), Regorafenib (Pyridine), Lenvatinib (Quinoline), Cabozantinib (Quinoline), Gemcitabine (Pyrimidine), 5-Fluorouracil (Pyrimidine)and Capecitabine (Pyrimidine), their mechanism of action and key aspects regarding its structural activity were included in the review. CONCLUSION Heterocyclic compounds represent almost two-thirds of the novel drugs approved by FDA between 2010 and 2020 against Cancer. This review summarizes the clinical relevance, mechanism of action, structural activity relationship, and challenges of the seven available anticancer drugs with heterocyclic ring systems against HCC.
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Affiliation(s)
- Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Anitha L
- Department of Pharmaceutical Chemistry, GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad Campus, Rudraram, Sangareddy, Telangana 502329, India
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Sinoy Sugunan
- Department of Pharmaceutical Chemistry, GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad Campus, Rudraram, Sangareddy, Telangana 502329, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
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24
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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25
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Mohapatra P, Chandrasekaran N. Wnt/β-catenin targeting in liver carcinoma through nanotechnology-based drug repurposing: A review. Biomed Pharmacother 2022; 155:113713. [PMID: 36126453 DOI: 10.1016/j.biopha.2022.113713] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/08/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Liver cancer is the fifth most widespread in the world, with a high fatality rate and poor prognosis.However,surgicalresction,thermal/radiofrequencyablation,chemo/radioembolization and pathway targeting to the cancer cells are all possible options for treating Liver Carcinoma. Unfortunately, once the tumour has developed and spread, diagnosis often occurs too late. The targeted therapy has demonstrated notable, albeit modest, efficacy in some patients with advanced HCC. This demonstrates the necessity of creating additional focused treatments and, in pursuit of this end, the need to find ever-more pathways as prospective targets. Despite the critical need, there are currently no Wnt signalling directed therapy on the research field, only a few methods have progressed beyond the early stage of clinical studies. In the present study, we report that repurposing of drug previously licensed for other diseases is one possible strategy inhibit malignant cell proliferation and renewal by removing individuals protein expression in the Wnt/β-catenin pathway. Particularly β-catenin complex is present in Liver cancer, where tumour necrosis factor is indispensable for the complex formation and β-catenin interactions are disrupted upon drug in nano-carrier through nanotechnology. This study findings not only highlight that repurposing drug could improve liver cancer treatment outcomes but also focused to character traits and functions of the Wnt signalling cascade's molecular targets and how they could be used to get anti-tumour results method to targeting Wnt/β-catenin in liver carcinoma.
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26
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Flanagan DJ, Woodcock SA, Phillips C, Eagle C, Sansom OJ. Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition. Pharmacol Ther 2022; 238:108179. [PMID: 35358569 PMCID: PMC9531712 DOI: 10.1016/j.pharmthera.2022.108179] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/20/2022]
Abstract
Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.
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Affiliation(s)
- Dustin J Flanagan
- Cancer Research UK Beatson Institute, Glasgow, UK; Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | | | | | | | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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27
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Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers (Basel) 2022; 14:cancers14143421. [PMID: 35884482 PMCID: PMC9322180 DOI: 10.3390/cancers14143421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
- Correspondence:
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
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28
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Lazar I, Fabre B, Feng Y, Khateb A, Frit P, Kashina A, Zhang T, Avitan-Hersh E, Kim H, Brown K, Topisirovic I, Ronai ZA. Arginyl-tRNA-protein transferase 1 (ATE1) promotes melanoma cell growth and migration. FEBS Lett 2022; 596:1468-1480. [PMID: 35561126 PMCID: PMC10118390 DOI: 10.1002/1873-3468.14376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 11/10/2022]
Abstract
Arginyl-tRNA-protein transferase 1 (ATE1) catalyses N-terminal protein arginylation, a post-translational modification implicated in cell migration, invasion and the cellular stress response. Herein, we report that ATE1 is overexpressed in NRAS-mutant melanomas, while it is downregulated in BRAF-mutant melanomas. ATE1 expression was higher in metastatic tumours, compared with primary tumours. Consistent with these findings, ATE1 depletion reduced melanoma cell viability, migration and colony formation. Reduced ATE1 expression also affected cell responses to mTOR and MEK inhibitors and to serum deprivation. Among putative ATE1 substrates is the tumour suppressor AXIN1, pointing to the possibility that ATE1 may fine-tune AXIN1 function in melanoma. Our findings highlight an unexpected role for ATE1 in melanoma cell aggressiveness and suggest that ATE1 constitutes a potential new therapeutic target.
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Affiliation(s)
- Ikrame Lazar
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.,Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.,MCD, Centre de Biologie Intégrative (CBI), CNRS, UT3, Université de Toulouse, France
| | - Bertrand Fabre
- Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.,Laboratoire de Recherche en Sciences Végétales, UMR5546, UT3, INP, CNRS, Université de Toulouse, Auzeville-Tolosane, France
| | - Yongmei Feng
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Ali Khateb
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.,Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Philippe Frit
- Institut de Pharmacologie et de Biologie Structurale (IPBS), UMR 5089, CNRS, UT3, Université de Toulouse, France
| | - Anna Kashina
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Emily Avitan-Hersh
- Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Hyungsoo Kim
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Kevin Brown
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Ivan Topisirovic
- Gerald Bronfman Department of Oncology, Departments of Experimental Medicine and Biochemistry, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Ze'ev A Ronai
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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29
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Lau JF, Vokuhl C. [Epithelial childhood liver tumors : An overview of the new WHO classification for pediatric tumors]. DER PATHOLOGE 2022; 43:202-209. [PMID: 35384506 DOI: 10.1007/s00292-022-01067-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/24/2022] [Indexed: 06/14/2023]
Abstract
Pediatric liver tumors are very rare tumors and account for less than 1% of all childhood malignancies. By far the most common tumors are hepatoblastomas. This review discusses epithelial malignant childhood liver tumors, with particular attention to the morphology of the different hepatoblastoma subtypes. In addition, other malignant liver tumors such as the so-called hepatocellular tumor NOS and the second-most common childhood liver tumor, the hepatocellular carcinoma, are discussed. In addition to the typical morphological characteristics, the immunohistochemical and molecular aspects are also be presented, which can help to distinguish these entities with often overlapping morphology.
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Affiliation(s)
- J F Lau
- Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland
| | - C Vokuhl
- Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland.
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30
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Selvaggi F, Catalano T, Cotellese R, Aceto GM. Targeting Wnt/β-Catenin Pathways in Primary Liver Tumours: From Microenvironment Signaling to Therapeutic Agents. Cancers (Basel) 2022; 14:1912. [PMID: 35454818 PMCID: PMC9024538 DOI: 10.3390/cancers14081912] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 12/17/2022] Open
Abstract
Primary liver cancers (PLCs) are steadily increasing in incidence and mortality in the world. They have a poor prognosis due to their silent nature, late discovery and resistance to common chemotherapy. At present, there are limited treatment alternatives, and the understanding of PLC molecular aspects is essential to develop more efficient drugs and therapeutic surgical and loco-regional strategies. A clear causal link with liver damage, inflammation, and regeneration has been found in the occurrence of PLC over the last few decades. Physiologically, Wingless/It (Wnt)-β-catenin signaling plays a key role in liver development, metabolic zonation and regeneration. Loss of functional homeostasis of this pathway appears to be a major driver of carcinogenesis in the liver parenchyma. In the hepatic microenvironment, molecular deregulations that exceed the Wnt signaling biological capacity can induce tumor initiation and progression. Indeed, somatic mutations are identified in key components of canonical and non-canonical Wnt signaling and in PLCs and precancerous lesions. In this review, the altered functions of Wnt/β-catenin signaling are considered in human PLCs, with emphasis on hepatocellular carcinomas (HCC), cholangiocarcinomas (CCA) and hepatoblastomas (HB). Based on recent literature, we also focused on liver cancerogenesis through Wnt deregulation. An overview of preclinical and clinical studies on approved and experimental drugs, targeting the Wnt/β-catenin cascade in PLCs, is proposed. In addition, the clinical implication of molecule inhibitors that have been shown to possess activity against the Wnt pathway in association with conventional surgical and loco-regional therapies are reviewed.
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Affiliation(s)
- Federico Selvaggi
- Unit of General Surgery, Ospedale Floraspe Renzetti, 66034 Lanciano, Chieti, Italy;
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
- Villa Serena Foundation for Research, 65013 Città Sant’Angelo, Pescara, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;
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31
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Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 2022; 7:3. [PMID: 34980884 PMCID: PMC8724284 DOI: 10.1038/s41392-021-00762-6] [Citation(s) in RCA: 1105] [Impact Index Per Article: 368.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.
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32
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Zhu J, Wu Y, Lao S, Shen J, Yu Y, Fang C, Zhang N, Li Y, Zhang R. Targeting TRIM54/Axin1/β-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma. Front Oncol 2021; 11:759842. [PMID: 34956880 PMCID: PMC8695909 DOI: 10.3389/fonc.2021.759842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/15/2021] [Indexed: 11/15/2022] Open
Abstract
Accumulating evidence demonstrates that dysregulation of ubiquitin-mediated degradation of oncogene or suppressors plays an important role in several diseases. However, the function and molecular mechanisms of ubiquitin ligases underlying hepatocellular carcinoma (HCC) remain elusive. In the current study, we show that overexpression of TRIM54 was associated with HCC progression. TRIM54 overexpression facilitates proliferation and lung metastasis; however, inhibition of TRIM54 significantly suppressed HCC progression both in vitro and in vivo. Mechanically, we demonstrated that TRIM54 directly interacts with Axis inhibition proteins 1 (Axin1) and induces E3 ligase-dependent proteasomal turnover of Axin1 and substantially induces sustained activation of wnt/β-catenin in HCC cell lines. Furthermore, we showed that inhibition of the wnt/β-catenin signaling pathway via small molecule inhibitors significantly suppressed TRIM54-induced proliferation. Our data suggest that TRIM54 might function as an oncogenic gene and targeting the TRIM54/Axin1/β-catenin axis signaling may be a promising prognostic factor and a valuable therapeutic target for HCC.
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Affiliation(s)
- Jinrong Zhu
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yongqi Wu
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shaoxi Lao
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jianfei Shen
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yijian Yu
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Chunqiang Fang
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Na Zhang
- Department of General Practice, Heyuan People's Hospital, Heyuan, Guangdong, China
| | - Yan Li
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Rongxin Zhang
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
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33
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Genomic and transcriptomic profiling of hepatoid adenocarcinoma of the stomach. Oncogene 2021; 40:5705-5717. [PMID: 34326469 DOI: 10.1038/s41388-021-01976-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 12/24/2022]
Abstract
Hepatoid adenocarcinoma of the stomach (HAS), a rare subtype of gastric cancer (GC), has a low incidence but a high mortality rate. Little is known about the molecular features of HAS. Here we applied whole-exome sequencing (WES) on 58 tumours and the matched normal controls from 54 HAS patients, transcriptome sequencing on 30 HAS tumours, and single-cell RNA sequencing (scRNA-seq) on one HAS tumour. Our results reveal that the adenocarcinomatous component and hepatocellular-like component of the same HAS tumour originate monoclonally, and HAS is likely to initiate from pluripotent precursor cells. HAS has high stemness and high methionine cycle activity compared to classical GC. Two genes in the methionine cycle, MAT2A, and AHCY are potential targets for HAS treatments. We provide the first integrative genomic profiles of HAS, which may facilitate its diagnosis, prognosis, and treatment.
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Wu C, Guo X, Li M, Shen J, Fu X, Xie Q, Hou Z, Zhai M, Qiu X, Cui Z, Xie H, Qin P, Weng X, Hu Z, Liang J. DeepHBV: a deep learning model to predict hepatitis B virus (HBV) integration sites. BMC Ecol Evol 2021; 21:138. [PMID: 34233610 PMCID: PMC8261932 DOI: 10.1186/s12862-021-01869-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/29/2021] [Indexed: 01/05/2023] Open
Abstract
Background The hepatitis B virus (HBV) is one of the main causes of viral hepatitis and liver cancer. HBV integration is one of the key steps in the virus-promoted malignant transformation. Results An attention-based deep learning model, DeepHBV, was developed to predict HBV integration sites. By learning local genomic features automatically, DeepHBV was trained and tested using HBV integration site data from the dsVIS database. Initially, DeepHBV showed an AUROC of 0.6363 and an AUPR of 0.5471 for the dataset. The integration of genomic features of repeat peaks and TCGA Pan-Cancer peaks significantly improved model performance, with AUROCs of 0.8378 and 0.9430 and AUPRs of 0.7535 and 0.9310, respectively. The transcription factor binding sites (TFBS) were significantly enriched near the genomic positions that were considered. The binding sites of the AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra, and Foxo3 were highlighted by DeepHBV in both the dsVIS and VISDB datasets, revealing a novel integration preference for HBV. Conclusions DeepHBV is a useful tool for predicting HBV integration sites, revealing novel insights into HBV integration-related carcinogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12862-021-01869-8.
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Affiliation(s)
- Canbiao Wu
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Xiaofang Guo
- Department of Medical Oncology of the Eastern Hospital, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510700, Guangzhou, China
| | - Mengyuan Li
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Jingxian Shen
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Xiayu Fu
- Department of Thoracic Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Qingyu Xie
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,School of Computer Science, South China Normal University, Guangzhou, 510631, China
| | - Zeliang Hou
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Manman Zhai
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,School of Psychology, South China Normal University, Guangzhou, 510080, Guangdong, China
| | - Xiaofan Qiu
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China
| | - Zifeng Cui
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China
| | - Hongxian Xie
- Generulor Company Bio-X Lab, Guangzhou, 510006, Guangdong, China
| | - Pengmin Qin
- School of Psychology, South China Normal University, Guangzhou, 510080, Guangdong, China
| | - Xuchu Weng
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China.,Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Guangzhou, 510080, Guangdong, China
| | - Zheng Hu
- Department of Gynecological Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, 510080, Guangzhou, China. .,Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
| | - Jiuxing Liang
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, Guangdong, China. .,Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Guangzhou, 510080, Guangdong, China.
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Gai Z, Wang Y, Tian L, Gong G, Zhao J. Whole Genome Level Analysis of the Wnt and DIX Gene Families in Mice and Their Coordination Relationship in Regulating Cardiac Hypertrophy. Front Genet 2021; 12:608936. [PMID: 34168671 PMCID: PMC8217762 DOI: 10.3389/fgene.2021.608936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 05/17/2021] [Indexed: 12/27/2022] Open
Abstract
The Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays essential roles in embryonic development, organogenesis, and many other biological activities. Both Wnt proteins and DIX proteins are important components of Wnt signaling. Systematic studies of Wnt and DIX families at the genome-wide level may provide a comprehensive landscape to elucidate their functions and demonstrate their relationships, but they are currently lacking. In this report, we describe the correlations between mouse Wnt and DIX genes in family expansion, molecular evolution, and expression levels in cardiac hypertrophy at the genome-wide scale. We observed that both the Wnt and DIX families underwent more expansion than the overall average in the evolutionarily early stage. In addition, mirrortree analyses suggested that Wnt and DIX were co-evolved protein families. Collectively, these results would help to elucidate the evolutionary characters of Wnt and DIX families and demonstrate their correlations in mediating cardiac hypertrophy.
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Affiliation(s)
- Zhongchao Gai
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, China
| | - Yujiao Wang
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, China
| | - Lu Tian
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, China
| | - Guoli Gong
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, China
| | - Jieqiong Zhao
- Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
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36
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Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res 2021; 167:105532. [DOI: 10.1016/j.phrs.2021.105532] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/14/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
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Prochownik EV. Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity. Cancers (Basel) 2021; 13:cancers13091996. [PMID: 33919162 PMCID: PMC8122429 DOI: 10.3390/cancers13091996] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/06/2021] [Accepted: 04/16/2021] [Indexed: 01/20/2023] Open
Abstract
Simple Summary Hepatoblastoma (HB), the most common form of childhood liver cancer, is associated with dual mutation and/or dysregulation of the Wnt/β-catenin and Hippo pathways in ~50% of cases. However, this mutational simplicity cannot explain HB’s biological and histologic diversity. This discussion focuses upon recent work showing that specific β-catenin mutants are key determinants of this HB variability as well as their metabolic and transcriptional signatures. Dysregulation of the anti-oxidant NFE2L2 pathway also contributes to tumorigenesis by being directly transforming in association with either of the other two factors. The transcriptional overlap of tumors generated by pairs of factors identifies crucial targets that likely mediate HB tumorigenesis, behavior and appearance. Abstract Hepatoblastoma (HB), the most common childhood liver cancer, is associated with seven distinct histologic subtypes and variable degrees of clinical aggressiveness and presentation. Yet it is among the least genomically altered tumors known, with about half of HBs showing mutation and/or dysregulation of the Wnt/β-catenin and Hippo pathways. This raises the question of how this mutational simplicity can generate such biological and histologic complexity. Recent work shows that the identity of the underlying β-catenin mutation is a major contributor. Mutation or over-expression of the NFE2L2/NRF2 transcription factor, previously thought only to promote anti-oxidant responses, has also recently been shown to accelerate the growth of HBs generated by mutations in the Wnt/β-catenin and Hippo pathways while imparting novel features such as the tumor-associated cysts and necrosis. Moreover, patient-associated NFE2L2 mutations are overtly transforming when co-expressed with either mutant β-catenin or a Hippo pathway effector. The finding that tumorigenesis can be driven by any two arms of the β-catenin/Hippo/NFE2L2 axis has permitted the identification of a small subset of coordinately regulated tumor-specific transcripts, some of whose levels correlate with inferior long-term outcomes in HB and other cancers. Collectively, these findings begin to provide for more refined and molecularly based classification, survival algorithms and design of chemotherapeutic regimens.
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Affiliation(s)
- Edward V. Prochownik
- Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
- The Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
- The University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA 15232, USA
- The University of Pittsburgh Liver Research Center, Pittsburgh, PA 15213, USA
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38
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Liu J, Gao C, Wang L, Jian X, Ma M, Li T, Hao X, Zhang Q, Chen Y, Zhao J, Niu H, Zhu C, Zhao J, Xia N, Li Z, Dong Q. Trans-Ancestry Mutation Landscape of Hepatoblastoma Genomes in Children. Front Oncol 2021; 11:669560. [PMID: 33968779 PMCID: PMC8096978 DOI: 10.3389/fonc.2021.669560] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/29/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatoblastoma (HB) is the most common malignant tumor in the liver of infants and young children. The incidence rate varies among different populations. However, genetic differences in HB patients with different epidemiological and ancestral backgrounds have not been found. In this study, we aim to analyze data from 16 patients treated at our center and collected published data from whole-exome sequencing studies on HB, and to explore the genetic differences between races. Data from a total of 75 HB patients of three races (24 Asian, 37 Caucasian and 14 Hispanic) were analyzed. We identified 16 genes with recurrent somatic mutations and 7 core pathway modules. Among them, the Wnt/β-catenin pathway had the highest mutation rate, and the mutation frequency in Caucasians and Hispanics was approximately twice as high as that in Asians. In addition, this study compared the characteristics of gene mutations between patients who underwent preoperative chemotherapy and those who did not and found that there was no significant difference in gene mutations between the two groups. We also preliminarily verified the function of cancer-associated candidate genes (CTNNB1 and KMT2D). In conclusion, we found ethnic differences in HB biology at the genomic level, which expands our understanding of the genetics of HB in children.
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Affiliation(s)
- Jie Liu
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- Department of Pediatric Surgery, Yijishan Hospital of Wannan Medical College, Wannan Medical College, Wuhu, China
| | - Chengwen Gao
- Laboratory of Medical Biology, Medical Research Center, The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Liping Wang
- Key Laboratory, Department of Urology and Andrology, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xuemin Jian
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
| | - Mingdi Ma
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Tong Li
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - XiWei Hao
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Qian Zhang
- Laboratory of Medical Biology, Medical Research Center, The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Yuanbin Chen
- Key Laboratory, Department of Urology and Andrology, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jing Zhao
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Haitao Niu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
- Institute of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
| | - Jie Zhao
- Institute of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
- Shandong College Collaborative Innovation Center of Digital Medicine Clinical Treatment and Nutrition Health, Qingdao University, Qingdao, China
| | - Nan Xia
- Institute of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
- Shandong Provincial Key Laboratory of Digital Medicine and Computer-assisted Surgery, Qingdao University, Qingdao, China
- Shandong College Collaborative Innovation Center of Digital Medicine Clinical Treatment and Nutrition Health, Qingdao University, Qingdao, China
| | - Zhiqiang Li
- Laboratory of Medical Biology, Medical Research Center, The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Qian Dong
- Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Akbari S, Kunter I, Azbazdar Y, Ozhan G, Atabey N, Firtina Karagonlar Z, Erdal E. LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines. Cell Signal 2021; 82:109972. [PMID: 33684507 DOI: 10.1016/j.cellsig.2021.109972] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/03/2021] [Indexed: 11/16/2022]
Abstract
Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a newly defined stem cell marker in endoderm-derived organs such as the small intestine, colon and pancreas. Recently, LGR5 was demonstrated to be an important factor in liver regeneration and stem cell maintenance. Moreover, LGR5 expression is highly up-regulated in various cancers including hepatocellular carcinoma. Herein, we demonstrate that LGR5 expression is specifically observed in certain subset of HCC cell lines with "hepatoblast-like" appearance, characterized by the expression of liver fetal/progenitor markers. Notably, the activation of the canonical Wnt pathway significantly increases the expression of LGR5 in this subset of cell lines, whereas it does not cause any induction of LGR5 expression in mesenchymal like cell lines SNU-475 and SNU-449. Furthermore, we showed that treatment of the hepatoblast-like HCC cell lines HuH-7 and Hep3B with LGR5 ligand R-Spo1 significantly amplifies the induction of LGR5 expression, the phosphorylation of LRP6 and β-catenin resulting in enhanced TCF/LEF activity either alone or in combination with Wnt3a. Consistently, the silencing of the LGR5 gene attenuates the co-stimulatory effect of R-Spo1/Wnt3a on TCF/LEF activity while overexpression of LGR5 enhances it. On the contrary, overexpression of LGR5 does not change TCF/LEF activity induced by R-Spo1/Wnt3a in mesenchymal-like HCC line, SNU-449. Importantly, LGR5-overexpressing cells have increased expression of several Wnt target genes and stemness-related genes including EpCAM and CK19 upon R-Spo1/Wnt3a treatment. LGR5-overexpressing cells also have increased spheroid forming, migration and invasion abilities and stimulation with R-Spo1/Wnt3a augments these abilities of LGR5-overexpressing cells. In addition, ectopic overexpression of LGR5 significantly increases cell proliferation rate independent of R-Spo1/Wnt3a stimulation. Moreover, in vitro tubulogenesis assay demonstrates that treatment with R-Spo1/Wnt3a enhances the sprouting of capillary tubules in only LGR5-overexpressing cells. Finally, R-Spo1/Wnt3a significantly promotes dissemination of LGR5-overexpressing cells in vivo in a zebrafish xenograft model. Our study unravels a tumor-promoting role for LGR5 through activation of canonical Wnt/β-catenin signaling in the hepatoblast-like HCCs. In conclusion, our results suggest that LGR5/R-Spo1/Wnt3a generates an axis that mediates the acquisition of aggressive phenotype specifically in hepatoblast-like subset of HCCs and might represent a valuable target for treatment of HCC tumors with aberrant activation of Wnt/β-catenin pathway.
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Affiliation(s)
- Soheil Akbari
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Imge Kunter
- Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey
| | - Yagmur Azbazdar
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, 35340 Izmir, Turkey
| | - Gunes Ozhan
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, 35340 Izmir, Turkey
| | - Nese Atabey
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey
| | | | - Esra Erdal
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, 35340 Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir 35340, Turkey.
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40
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Jackson SS, Van De Wyngard V, Pfeiffer RM, Cook P, Hildesheim A, Pinto LA, Jackson SH, Choi K, Verdugo RA, Cuevas M, Yáñez C, Tobar-Calfucoy E, Retamales-Ortega R, Araya JC, Ferreccio C, Koshiol J. Inflammatory profiles in Chilean Mapuche and non-Mapuche women with gallstones at risk of developing gallbladder cancer. Sci Rep 2021; 11:3686. [PMID: 33574564 PMCID: PMC7878792 DOI: 10.1038/s41598-021-83300-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 02/01/2021] [Indexed: 01/11/2023] Open
Abstract
Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P = 0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P = 0.03 and P < 0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
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Affiliation(s)
- Sarah S Jackson
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, USA.
| | - Vanessa Van De Wyngard
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile
| | - Ruth M Pfeiffer
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, USA
| | - Paz Cook
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile
| | - Allan Hildesheim
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, USA
| | - Ligia A Pinto
- Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Sharon H Jackson
- Division of Intramural Research, National Institute on Minority Health and Health Disparities, Bethesda, MD, USA
| | - Kelvin Choi
- Division of Intramural Research, National Institute on Minority Health and Health Disparities, Bethesda, MD, USA
| | - Ricardo A Verdugo
- Programa de Genética Human, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mara Cuevas
- Programa de Genética Human, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Cristian Yáñez
- Programa de Genética Human, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Eduardo Tobar-Calfucoy
- Programa de Genética Human, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Rocío Retamales-Ortega
- Programa de Genética Human, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Juan Carlos Araya
- Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile.,Hospital Dr. Hernan Henríquez Aravena, Temuco, Chile.,Department of Pathology, Faculty of Medicine, Universidad de la Frontera, Temuco, Chile
| | - Catterina Ferreccio
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile
| | - Jill Koshiol
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, USA
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Caspi M, Wittenstein A, Kazelnik M, Shor-Nareznoy Y, Rosin-Arbesfeld R. Therapeutic targeting of the oncogenic Wnt signaling pathway for treating colorectal cancer and other colonic disorders. Adv Drug Deliv Rev 2021; 169:118-136. [PMID: 33346022 DOI: 10.1016/j.addr.2020.12.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 02/08/2023]
Abstract
The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator β-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/β-catenin pathway has been implicated in carcinogenesis. Aberrant Wnt signaling has been reported in a variety of malignancies, and its role in both hereditary and sporadic colorectal cancer (CRC), has been the subject of intensive study. Interestingly, the vast majority of colorectal tumors harbor mutations in the tumor suppressor gene adenomatous polyposis coli (APC). The Wnt pathway is complex, and despite decades of research, the mechanisms that underlie its functions are not completely known. Thus, although the Wnt cascade is an attractive target for therapeutic intervention against CRC, one of the malignancies with the highest morbidity and mortality rates, achieving efficacy and safety is yet extremely challenging. Here, we review the current knowledge of the Wnt different epistatic signaling components and the mechanism/s by which the signal is transduced in both health and disease, focusing on CRC. We address some of the important questions in the field and describe various therapeutic strategies designed to combat unregulated Wnt signaling, the development of targeted therapy approaches and the emerging challenges that are associated with these advanced methods.
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42
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Kwee SA, Tiirikainen M. Beta-catenin activation and immunotherapy resistance in hepatocellular carcinoma: mechanisms and biomarkers. ACTA ACUST UNITED AC 2021; 7. [PMID: 33553649 PMCID: PMC7861492 DOI: 10.20517/2394-5079.2020.124] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.
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Affiliation(s)
- Sandi A Kwee
- Cancer Biology Program (SAK) and Population Sciences in the Pacific Program (MT), University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813, USA.,Hamamatsu/Queen's PET Imaging Center, The Queen's Medical Center, Honolulu, Hawaii 96813, USA
| | - Maarit Tiirikainen
- Cancer Biology Program (SAK) and Population Sciences in the Pacific Program (MT), University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813, USA
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Rossetti LZ, Bekheirnia MR, Lewis AM, Mefford HC, Golden‐Grant K, Tarczy‐Hornoch K, Briere LC, Sweetser DA, Walker MA, Kravets E, Stevenson DA, Bruenner G, Sebastian J, Knapo J, Rosenfeld JA, Marcogliese PC, Undiagnosed Diseases Network, Wangler MF. Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. Mol Genet Genomic Med 2021; 9:e1542. [PMID: 33350591 PMCID: PMC7963417 DOI: 10.1002/mgg3.1542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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Affiliation(s)
- Linda Z. Rossetti
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Mir Reza Bekheirnia
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Andrea M. Lewis
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Heather C. Mefford
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | - Katie Golden‐Grant
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | | | - Lauren C. Briere
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - David A. Sweetser
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Melissa A. Walker
- Department of NeurologyDivision of NeurogeneticsChild NeurologyMassachusetts General HospitalBostonMAUSA
| | - Elijah Kravets
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - David A. Stevenson
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - Georgette Bruenner
- Division of Medical GeneticsDepartment of PediatricsCohen Children’s Medical CenterQueensNYUSA
| | - Jessica Sebastian
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Julia Knapo
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Jill A. Rosenfeld
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Paul C. Marcogliese
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
| | | | - Michael F. Wangler
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
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Hu H, Zhang W, Zhi T, Li J, Wen Y, Li F, Mei Y, Huang D. Genotypic Characteristics of Hepatoblastoma as Detected by Next Generation Sequencing and Their Correlation With Clinical Efficacy. Front Oncol 2021; 11:628531. [PMID: 34426785 PMCID: PMC8379014 DOI: 10.3389/fonc.2021.628531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 07/20/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Hepatoblastoma (HB) is the most common malignant embryonic liver tumor type in children under 3 years of age. In the present study, the next generation sequencing (NGS) method was used to detect the genotype characteristics of HB and summarize the correlation between the common mutation genotypes noted in this disease and the clinical treatment and prognosis. The results may aid clinical prognosis and the successful application of targeted drugs. METHODS Initially, DNA was extracted from tumor tissue specimens and peripheral blood derived from 19 pediatric patients with HB. Subsequently, DNA panel and NGS methods were used to detect tumor diagnosis and the expression levels of treatment-associated genes, followed by the summary of genotype characteristics. In addition, in order to further assess the application of immunotherapy in HB, immunohistochemical detection of programmed cell death 1 ligand 1 (PDL1) was performed in combination with tumor mutation burden (TMB) and DNA mismatch repair status analysis. Furthermore, the clinical treatment effect and prognosis of the pediatric patients were statistically analyzed according to the characteristics of the genotype. Overall prognosis and prognostic analyses in different groups were performed by Kaplan-Meier and log-rank tests, respectively. Finally, expression validation and diagnostic analysis of commonly reported genes were performed in the GSE75271 dataset, which was obtained from the Gene Expression Omnibus (GEO) database. RESULTS In the present study, certain mutated genes, including nuclear factor erythroid 2-related factor 2 (NFE2L2), catenin β1 (CTNNB1), MYCN, tumor protein p53, axis inhibition protein 1 (AXIN1) and adenomatous polyposis coli (APC) were associated with the pathogenesis of HB. During TMB and DNA mismatch repair status analyses, pediatric patients had a low TMB. All of them did not present with microsatellite instability. The immunohistochemical results indicated lower expression levels of PDL1 in HB. The complete remission (CR) rate of pediatric patients in the gene abnormality group was lower than that of the non-reported disease-associated gene abnormality group. The 2-year overall survival rate and disease-free survival rate of 19 pediatric patients with HB were 72.1% and 42.4%, respectively. Receiver operating characteristic (ROC) analysis demonstrated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and insulin growth factor 2 (IGF2) may be potential biomarkers that could be used for the diagnosis of HB. CONCLUSION The genotype changes in HB were more common and the CR rate of the pediatric patients with an altered genotype was lower than that of pediatric patients without an altered genotype. In addition, pediatric patients with HB exhibited lower TMB compared with adult patients. Moreover, the data indicated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and IGF2 may be potential biomarkers that can be used for the diagnosis of HB.
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Liu Y, Wu D, Cheng H, Chen L, Zhang W, Zou L, Gao Q, Zhao Z, Chen Q, Zeng W, Zhang Z, Jiang W, Huang C, Liu G. Wnt8B, transcriptionally regulated by ZNF191, promotes cell proliferation of hepatocellular carcinoma via Wnt signaling. Cancer Sci 2020; 112:629-640. [PMID: 33197287 PMCID: PMC7894019 DOI: 10.1111/cas.14738] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 10/28/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Dysregulation of wingless‐type (Wnt) signaling is implicated in hepatocellular carcinoma (HCC). Wnt family member 8B (Wnt8B), one of the canonical Wnt ligands, is implicated in oncogenesis. However, the role of Wnt8B in human HCCs and its transcriptional regulation mechanism are presently unknown . Here, we report that Wnt8B expression was frequently increased in HCCs and was significantly associated with poorer patient prognosis. Wnt8B knockdown suppresses HCC cell growth both in vitro and in vivo via inhibiting the canonical Wnt signaling. Zinc finger transcription factor 191 (ZNF191) can positively regulate Wnt8B mRNA and protein expression, and promoter luciferase assay indicated that ZNF191 can increase the transcription activity of the 2‐Kbps WNT8B promoter. Chromatin immunoprecipitation‐qPCR and electrophoretic mobility shift assay showed that ZNF191 protein directly binds to the WNT8B promoter, and the binding sites are at nt‐1491(ATTAATT) and nt‐1178(ATTCATT). Moreover, Wnt8B contributes to the effect of ZNF191 on cell proliferation, and Wnt8B expression correlates positively with ZNF191 in human HCCs. Our findings suggested that Wnt8B, directly transcriptionally regulated by ZNF191, plays a pivotal role in HCC proliferation via the canonical Wnt pathway and may serve as a new prognostic biomarker and a potential therapeutic target for HCC patients.
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Affiliation(s)
- Yufeng Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Di Wu
- The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Hanghang Cheng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lei Chen
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Weidi Zhang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Liping Zou
- Departmant of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiongmei Gao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhonghua Zhao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qi Chen
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenjiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhigang Zhang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wei Jiang
- Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, The Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Cheng Huang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoyuan Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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Kim E, Viatour P. Hepatocellular carcinoma: old friends and new tricks. Exp Mol Med 2020; 52:1898-1907. [PMID: 33268834 PMCID: PMC8080814 DOI: 10.1038/s12276-020-00527-1] [Citation(s) in RCA: 191] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and a leading cause of cancer-related deaths worldwide. Ninety percent of HCC cases arise from cirrhosis, during which liver cells undergo chronic cycles of necrosis and regeneration. The complex genomic landscape of HCC has been extensively investigated to draw correlations between recurrently mutated pathways and patient prognosis. However, our limited success with targeted therapy shows that knowing the presence of somatic mutations alone is insufficient for us to gauge the full spectrum of their functional consequences in the context of tumor evolution. In addition, the current molecular classification of HCC offers little information on the relationship between the molecular features and immunological properties of HCC tumors and their immune microenvironment. This review introduces current challenges and advancements made in HCC surveillance, diagnosis, and treatment. We also discuss the suite of HCC-associated genetic changes and describe recent studies that provide evidence for an evolving functional model and its implications for understanding and targeting HCC progression.
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Affiliation(s)
- Eunsun Kim
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
| | - Patrick Viatour
- Children's Hospital of Philadelphia, Center for Childhood Cancer Research, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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Chen Y, Chen Z, Tang Y, Xiao Q. The involvement of noncanonical Wnt signaling in cancers. Biomed Pharmacother 2020; 133:110946. [PMID: 33212376 DOI: 10.1016/j.biopha.2020.110946] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/12/2020] [Accepted: 10/25/2020] [Indexed: 12/18/2022] Open
Abstract
Wnt signaling is one of the key cascades regulating normal tissue development and has been tightly associated with cancer. The Wnt signaling can be subdivided into two categories: canonical & noncanonical. Noncanonical Wnt signaling pathways mainly include Wnt/PCP (planar cell polarity) signaling and Wnt-cGMP (cyclic guanosine monophosphate) /Ca2+ signaling. It has been well studied by previous researches that noncanonical Wnt signaling regulates multiple cell functions including proliferation, differentiation, adhesion, polarity, motility, and migration. The aberrant activation or inhibition of noncanonical Wnt signaling is crucial in cancer progression, exerting both oncogenic and tumor-suppressive effects. Recent studies show the involvement of noncanonical Wnt in regulating cancer cell invasion, metastasis, metabolism, and inflammation. Here, we review current insights into novel components of non-canonical signalings and describe their involvement in various cancer types. We also summarize recent biological and clinical discoveries that outline non-canonical Wnt signaling in tumorigenesis. Finally, we provide an overview of current strategies to target non-canonical Wnt signaling in cancer and challenges that are associated with such approaches.
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Affiliation(s)
- Yongfeng Chen
- Department of General Surgery, Zhejiang Yuhuan People's Hospital, Taizhou, Zhejiang, China
| | - Zhengxi Chen
- Department of Orthodontics, Shanghai Ninth People׳s Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China; Department of Cell Biology, Yale School of Medicine, New Haven, CT, United States
| | - Yin Tang
- Omni Family Health, Bakersfield, CA, United States
| | - Qian Xiao
- Department of Cell Biology, Yale School of Medicine, New Haven, CT, United States.
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Tchorz JS. The Conundrum of the Pericentral Hepatic Niche: WNT/-Catenin Signaling, Metabolic Zonation, and Many Open Questions. Gene Expr 2020; 20:119-124. [PMID: 32962796 PMCID: PMC7650010 DOI: 10.3727/105221620x16007982788168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
WNT/-catenin signaling promotes stemness, proliferation, and cell fate decisions in various tissue stem cell compartments, which maintain organs with a high turnover of cells (e.g., skin, stomach, and gut). Thus, the -catenin target genes AXIN2 and LGR5 are widely considered as tissue stem cell markers. In contrast, AXIN2 and LGR5 are expressed in pericentral hepatocytes, which do not show overt proliferation during liver homeostasis. Given the low hepatocyte turnover, the liver does not require constant high rates of proliferation, whereas WNT/-catenin signaling is critical for metabolic zonation. Yet, WNT/-catenin pathway upregulation, including AXIN2 and LGR5 induction in hepatocytes throughout the liver, enables hepatocyte regeneration in response to various injuries. In this brief review, I discuss the role of WNT/-catenin signaling in controlling metabolic zonation and the conundrum around pericentral hepatocytes that have been proposed as liver stem cells.
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Affiliation(s)
- Jan S. Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
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50
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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