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Jt Dis Relat Surg. 2023;34(1):3-8. doi: 10.52312/jdrs.2023.903. Epub 2023 Jan 14.
ABSTRACT
OBJECTIVES: This study aims to increase the awareness of the association between lateralized overgrowth (LO) and abdominal tumor among the pediatric orthopedic community and to evaluate its incidence in our center.
PATIENTS AND METHODS: Between January 1997 and December 2021, a total of 166 patients with Wilms tumors and hepatoblastomas were retrospectively analyzed. Data including age, sex, initial clinical signs (hematuria, abdominal mass with or without general discomfort), type of asymmetric regional body overgrowth (isolated or in relation with any syndrome), and tumor stage at diagnosis were recorded. In addition, age at which asymmetric regional body overgrowth was described and age at the time of tumor diagnosis were noted.
RESULTS: Of a total of 166 patients, 133 were diagnosed with Wilms tumors (nephroblastomas) and 33 were diagnosed with hepatoblastomas. In 94% of the cases, the initial clinical signs were an abdominal mass and/or hematuria. Overall, five (3%) patients presented with LO. Four patients with Wilms tumor presented it at the initial clinical examinations. In three of these cases (2.3%), we found it isolated and, in the remaining patient (0.75%), it was associated with Beckwith-Wiedemann spectrum. Only one patient affected from hepatoblastoma (3%) presented with an isolated LO at the time of tumor diagnosis.
CONCLUSION: Our study results show an incidence of LO in relation to intra-abdominal tumors of 3%. The latest updates recommend genetic testing to identify subgroups with a higher risk for tumor development that are more likely to benefit from tumor protocol surveillance.
PMID:36700257 | DOI:10.52312/jdrs.2023.903
2023 Jan 19. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002–.
ABSTRACT
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Front Immunol. 2023 Jan 5;13:1053216. doi: 10.3389/fimmu.2022.1053216. eCollection 2022.
ABSTRACT
INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis.
METHODS AND PATIENTS: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results.
RESULTS: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA - ) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/DR07/DR13 was present in only some patients.
CONCLUSION: HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro.
PMID:36685568 | PMC:PMC9849683 | DOI:10.3389/fimmu.2022.1053216
Biomedicines. 2022 Dec 23;11(1):36. doi: 10.3390/biomedicines11010036.
ABSTRACT
Circular RNAs (circRNAs) are a class of single-stranded closed noncoding RNA molecules which are formed as a result of reverse splicing of mRNAs. Despite their relative abundance, only recently there appeared an increased interest in the understanding of their regulatory importance. Among their most relevant characteristics are high stability, abundance and evolutionary conservation among species. CircRNAs are implicated in several cellular functions, ranging from miRNA and protein sponges to transcriptional modulation and splicing. Additionally, circRNAs' aberrant expression in pathological conditions is bringing to light their possible use as diagnostic and prognostic biomarkers. Their use as indicator molecules of pathological changes is also supported by their peculiar covalent closed cyclic structure which bestows resistance to RNases. Their regulatory role in cancer pathogenesis and metastasis is supported by studies involving human tumors that have investigated different expression profiles of these molecules. As endogenous competitive RNA, circRNAs can regulate tumor proliferation and invasion and they arouse great consideration as potential therapeutic biomarkers and targets for cancer. In this review, we describe the most recent findings on circRNAs in the most common pediatric solid cancers (such as brain tumors, neuroblastomas, and sarcomas) and in more rare ones (such as Wilms tumors, hepatoblastomas, and retinoblastomas).
PMID:36672544 | PMC:PMC9856195 | DOI:10.3390/biomedicines11010036
Cancers (Basel). 2023 Jan 11;15(2):467. doi: 10.3390/cancers15020467.
ABSTRACT
Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB.
PMID:36672416 | PMC:PMC9857147 | DOI:10.3390/cancers15020467
Cureus. 2023 Jan 15;15(1):e33799. doi: 10.7759/cureus.33799. eCollection 2023 Jan.
ABSTRACT
Lipoblastoma is a rare benign soft tissue neoplasm rising from embryonic white adipose tissue known as lipoblast that keeps proliferating during the postnatal period. Although lipoblastomas are benign, they often grow rapidly. Most lipoblastomas are asymptomatic at presentation; they can present as a growing painless palpable mass and progressive symptoms of various organ compression depending on localization. A giant mesenteric lipoblastoma is a rare case with only a few cases reported. An infant with large intraabdominal masses may present preoperative diagnostic difficulties. Differential diagnoses are broad and may include sarcomas, germ-cell tumors, lipomas, lymphomas, hepatoblastomas, Wilm's tumors, and neuroblastomas. Thorough clinical, radiological, and pathological investigations are ultimately required to obtain a definitive diagnosis. Regardless of location, the treatment of choice for lipoblastoma is complete surgical resection. All patients should be followed up for a minimum of five years We report a rare case of a giant compressive mesenteric lipoblastoma that was initially suspected as abdominal malignancy in a nine-month-old infant. As physicians, we must always consider the underlying cause as well as the malignant or benign nature of a growing mass to treat the patient appropriately.
PMID:36660240 | PMC:PMC9845517 | DOI:10.7759/cureus.33799
Thorac Cancer. 2023 Jan 15. doi: 10.1111/1759-7714.14797. Online ahead of print.
ABSTRACT
Pulmonary metastases from hepatoblastoma (HB) have traditionally been identified by preoperative computed tomography scan image evaluation, and intraoperative visual and palpatory examinations through thoracotomy have been generally recommended. However, the safety and accuracy of surgery can be problematic in patients with small multiple lung metastases due to postoperative respiratory dysfunction risk secondary to decreased residual lung capacity in wedge resections. We present an 8-month-old patient with metastatic HB with multiple metachronous pulmonary lesions in whom thoracoscopic lung resections were performed guided by indocyanine green (ICG) administered intravenously 24 h earlier (0.5 mg/kg). ICG fluorescence allowed identification and limited resection of lung parenchyma, avoiding postoperative respiratory dysfunction. A total of 16 lung lesions were resected during four operations (two bilateral and two right thoracoscopies), with no postoperative complications. ICG-guided thoracoscopic surgery allowed identification and resection of metastatic nodules in both lungs during the same procedure, achieving a hospital stay of less than 3 days for each intervention. The patient is currently 24 months old and remains asymptomatic, with no distant disease at the last imaging control. ICG-guided resection via a thoracoscopic approach is particularly useful in patients with multiple and/or metachronous metastases requiring multiple surgical interventions.
PMID:36642863 | DOI:10.1111/1759-7714.14797
Tissue Cell. 2022 Nov 25;81:101989. doi: 10.1016/j.tice.2022.101989. Online ahead of print.
ABSTRACT
This study is to explore the mechanism of KDM1A-regulated hepatoblastoma (HB) development. Cancerous and paracancer tissues of 30 HB patients were collected for detection of KDM1A and DKK3 expression. HuH-6 and HepG2 cells were subjected to assays of cellular activities after treatment with sh-KDM1A, sh-DKK3, and/or XAV-939 (an inhibitor of the Wnt/β-catenin pathway). Chromatin immunoprecipitation was used to determine the interaction of KDM1A with DKK3. Nude mice were injected with HuH-6 cells in which KDM1A was knocked down. KDM1A was highly expressed and DKK3 was lowly expressed in HB patients. Knockdown of KDM1A reduced the proliferative and invasive capabilities of HepG2 and HuH-6 cells and accelerated the cell apoptosis; these influences were nullified by knockdown of DKK3. KDM1A inhibited DKK3 transcription by reducing H3 methylation. XAV-939 treatment inhibited the development of HepG2 and HuH-6 cells in which KDM1A and DKK3 were both knocked down. Knockdown of KDM1A reduced the tumor mass, inactivated the Wnt/β-catenin signaling, and increased the expression of DKK3 in nude mice. KDM1A stimulates HB development by activating the Wnt/β-catenin pathway through inhibition of DKK3 transcription.
PMID:36642006 | DOI:10.1016/j.tice.2022.101989
J Pathol. 2023 Jan 15. doi: 10.1002/path.6054. Online ahead of print.
ABSTRACT
CRISPR/Cas9-driven cancer modeling studies are based on disruption of tumor suppressor genes (TSGs) by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of β-catenin induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon skipping events in patients with hepatocellular carcinoma (HCC). Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer. This article is protected by copyright. All rights reserved.
PMID:36641763 | DOI:10.1002/path.6054
Pediatr Surg Int. 2023 Jan 12;39(1):81. doi: 10.1007/s00383-022-05356-z.
ABSTRACT
Hepatoblastoma is the most common primary malignant paediatric liver tumour and surgery remains the cornerstone of its management. The aim of this article is to present the principles of surgical treatment of hepatoblastoma. All aspects of surgery in hepatoblastoma are discussed, from biopsy, through conventional and laparoscopic liver resections, to extreme resection with adjacent structures, staged hepatectomy and transplantation.
PMID:36631526 | PMC:PMC9834363 | DOI:10.1007/s00383-022-05356-z
Pediatr Surg Int. 2023 Jan 9;39(1):76. doi: 10.1007/s00383-022-05362-1.
ABSTRACT
OBJECTIVE: Hepatoblastoma (HB) tumor rupture is a high-risk criterion in the International Childhood Liver Tumors Strategy Group (SIOPEL) 3/4 protocol. However, the causes and risk factors for HB rupture are still unknown, and whether tumor rupture is an independent risk factor for HB prognosis is still controversial. The purpose of this study was to retrospectively analyze the clinical characteristics of children with HB tumor rupture and to search for clinical risk factors to conduct early prediction and intervention.
METHODS: We conducted a retrospective study of 27 patients with HB rupture between July 2009 and July 2019. To further identify the risk factors for HB rupture, we included 97 nonruptured HB patients from January 2013 to January 2019. We searched for potentially useful characteristics for HB rupture by univariate and multivariate logistic regression analyses.
RESULTS: There were 27 patients with HB rupture, with the median age of 31 (12, 69) months. Nineteen cases (70.37%) were spontaneous tumor rupture, 1 case (3.70%) was posttraumatic rupture, 2 cases (7.41%) were tumor rupture after the biopsy, and 5 cases (18.52%) were tumor rupture after chemotherapy. After the tumor rupture, 4 patients died of hemorrhagic shock and multiple organ dysfunction syndrome (MODS), 4 patients refused further therapy and were discharged against medical advice, and the remaining 19 patients were stable after emergency treatment. After the treatment, 14 patients survived without disease, 2 patients died, and 3 patients were lost to follow-up. The median follow-up was 48 (33, 60) months, the 3-year overall survival (OS) was 54.7%. Compared with the non-tumor rupture group by multivariate logistic regression analysis, it was found that the maximum diameter of the primary tumor > 13.4 cm, and vascular invasion were independent risk factors for tumor rupture.
CONCLUSION: HB rupture is rare, but it seriously threatens the life and health of children. In the acute phase of tumor rupture, surgery, rescue chemotherapy, transcatheter arterial embolization (TAE) and other supportive care can be adopted. Large tumors and vascular invasion are risk factors for HB rupture.
LEVEL OF EVIDENCE: Level IV.
PMID:36622431 | DOI:10.1007/s00383-022-05362-1
Nutrients. 2022 Dec 21;15(1):40. doi: 10.3390/nu15010040.
ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) begins with lipid accumulation within hepatocytes, but the relative contributions of different macronutrients is still unclear. We investigated the impact of fatty acids, glucose and fructose on lipid accumulation in primary human hepatocytes (PHH) and three different cell lines: HepG2 (human hepatoblastoma-derived cell line), Huh7 (human hepatocellular carcinoma cell line) and McA-RH7777 (McA, rat hepatocellular carcinoma cell line). Cells were treated for 48 h with fatty acids (0 or 200 μM), glucose (5 mM or 11 mM) and fructose (0 mM, 2 mM or 8 mM). Lipid accumulation was measured via Nile Red staining. All cell types accumulated lipid in response to fatty acids (p < 0.001). PHH and McA, but not HepG2 or Huh7 cells, accumulated more lipid with 11 mM glucose plus fatty acids (p = 0.004, fatty acid × glucose interaction, for both), but only PHH increased lipid accumulation in response to fructose (p < 0.001). Considerable variation was observed between PHH cells from different individuals. Lipid accumulation in PHH was increased by insulin (p = 0.003) with inter-individual variability. Similarly, insulin increased lipid accumulation in both HepG2 and McA cells, with a bigger response in McA in the presence of fatty acids (p < 0.001 for fatty acid × insulin). McA were more insulin sensitive than either HepG2 or Huh7 cells in terms of AKT phosphorylation (p < 0.001 insulin × cell type interaction). Hence, glucose and fructose can contribute to the accumulation of lipid in PHH with considerable inter-individual variation, but hepatoma cell lines are not good models of PHH.
PMID:36615698 | PMC:PMC9824391 | DOI:10.3390/nu15010040
Cancers (Basel). 2022 Dec 20;15(1):3. doi: 10.3390/cancers15010003.
ABSTRACT
Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications.
PMID:36612001 | PMC:PMC9817797 | DOI:10.3390/cancers15010003
Cells. 2022 Dec 23;12(1):69. doi: 10.3390/cells12010069.
ABSTRACT
Human-hepatoblastoma-derived cell line, HepG2, has been widely used in liver and liver cancer studies. HepG2 spheroids produced in a three-dimensional (3D) culture system provide a better biological model than cells cultured in a two-dimensional (2D) culture system. Since cells at the center of spheroids exhibit specific behaviors attributed to hypoxic conditions, a 3D cell culture system that allows the observation of such cells using conventional optical or fluorescence microscopes would be useful. In this study, HepG2 cells were cultured in "Cell Dome", a micro-dome in which cells are enclosed in a cavity consisting of a hemispherical hydrogel shell. HepG2 cells formed hemispherical cell aggregates which filled the cavity of Cell Domes on 18 days of culture and the cells could continue to be cultured for 29 days. The cells at the center of hemispherical cell aggregates were observed using a fluorescence microscope. The cells grew in Cell Domes for 18 days exhibited higher Pi-class Glutathione S-Transferase enzymatic activity, hypoxia inducible factor-1α gene expression, and higher tolerance to mitomycin C than those cultured in 2D on tissue culture dishes (* p < 0.05). These results indicate that the center of the glass adhesive surface of hemispherical cell aggregates which is expected to have the similar environment as the center of the spheroids can be directly observed through glass plates. In conclusion, Cell Dome would be useful as an evaluation platform for organized HepG2 cells.
PMID:36611862 | PMC:PMC9818560 | DOI:10.3390/cells12010069
Cells. 2022 Dec 23;12(1):62. doi: 10.3390/cells12010062.
ABSTRACT
Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (p62/Keap1/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers.
PMID:36611859 | PMC:PMC9818499 | DOI:10.3390/cells12010062
Eur J Med Genet. 2023 Feb;66(2):104694. doi: 10.1016/j.ejmg.2022.104694. Epub 2022 Dec 31.
NO ABSTRACT
PMID:36592690 | DOI:10.1016/j.ejmg.2022.104694
Toxicol Rep. 2022 Dec 12;10:32-39. doi: 10.1016/j.toxrep.2022.12.005. eCollection 2023.
ABSTRACT
Diazinon (DZN) is an insecticide extensively used to control pests in crops and animals. However, its indicriminated use may lead to liver damage in animals and humans. This study aimed to evaluate the toxicity of DZN (25-150 µM) on human hepatoblastoma (HepG2) cells after 24 and 48 h of exposure and the role of its biotransformation on the toxicological potential. We also tested the protective effect of tetrahydrocurcumin (THC), an antioxidant agent, in the DZN-induced citotoxicity. DZN caused cytotoxicity in the HepG2 cells, inhibiting cell proliferation and reducing cell viability in a dose- and time-dependent manner. The pre-incubation of HepG2 cells with chemical inducers of cytochrome P450 monooxygenase 3-methylcholanthrene and phenobarbital resulted in a further decrease of cell viability associated with DZN exposure. In addition, the metabolite diazoxon was more toxic than DZN. Our results also revealed that THC alleviated DZN-induced cytotoxicity and reactive oxygen and nitrogen species (RONS) generation in HepG2 cells. In conclusion, our data provide novel insights into the involvement of biotransformation in the mechanisms of DZN-induced cytotoxicity and suggest that amelioration of RONS accumulation might be involved in the protective effect of THC on DZN-induced liver injury.
PMID:36578673 | PMC:PMC9791245 | DOI:10.1016/j.toxrep.2022.12.005
Mol Cell Biochem. 2022 Dec 28. doi: 10.1007/s11010-022-04636-5. Online ahead of print.
ABSTRACT
Hepatoblastoma is the most common type of hepatic tumors occurring in children between 0 and 5 years. And the exact pathophysiology of the disease is still mysterious. Accumulating studies on LncRNA have shown its pivotal role in the development and progression of distinct human cancers. However, the role of LINC01023 in hepatoblastoma is unknown. The relative expression of LINC01023, miR-378a-5p, and Wnt3 on hepatoblastoma tissue and cell lines was determined by quantitative polymerase chain reaction (qRT-PCR). The effect of LINC01023 downregulation and upregulation on cell proliferation, colony formation and apoptosis activities in HUH6 and HepG2 Cells was assessed by CKK8, clonogenic and flow cytometry analysis, respectively. Dual luciferase, RNA immunoprecipitation (RIP), and RNA pull-down were performed to confirm the interaction between LINC01023 and miR-378a-5p. Similarly, Dual luciferase assay was performed to confirmed the interaction between Wnt3 and miR-378a-5p. The xenograft tumorgenicity test was performed to elucidate the tumorgenicity potential of LINC01023. LINC01023 was significantly upregulated in hepatoblastoma tissue and cell lines rather than in adjacent normal hepatic tissue and QSG7701 cell lines. LINC01023 silencing attenuated cell proliferation, colony formation and increased cell apoptosis. Conversely, LINC01023 upregulation results in significant increase in cell proliferation, and colony formation activities however, a significant reduction in apoptosis activity was reported. Interaction between the LINC01023 and WNT3 was confirmed by dual luciferase assay. Xenograft animal tumorgenicity test confirmed the in-vivo tumorigenesis potential of LINC01203. To the best of our knowledge, this study is the first study demonstrating the role of LINC01023 in hepatoblastoma tumorigenesis through the LINC01023/miR-378a-5p/Wnt3 axis. It could be a potential therapeutic target and a prognostic biomarker in hepatoblastoma.
PMID:36576714 | DOI:10.1007/s11010-022-04636-5
Medicina (Kaunas). 2022 Nov 23;58(12):1715. doi: 10.3390/medicina58121715.
ABSTRACT
Agents of platinum-based chemotherapy, such as cisplatin or carboplatin, are used in the treatment of a wide range of malignancies that affect children, such as brain tumors, osteosarcoma, neuroblastoma, hepatoblastoma, and germ cell tumors (GCTs). The Cyclophosphamide Equivalent Dose (CED) calculator for reproductive risk does not take platinum-based chemotherapy into account, despite the fact that it accounts for the majority of chemotherapy medications that are typically administered for pediatric GCTs. As a result, exposure to platinum-based drugs throughout infancy can have predictable long-term effects such as infertility, as well as other rare encounters such as lipoma formation and lipomatosis. Lipomas are the most prevalent benign soft tissue tumor subtype. They may be either solitary entities or engaged in multiple lipomatosis, which may have a familial origin or be an acquired disorder. Chemotherapy is a possible cause of lipomatosis. Chemotherapy based on cisplatin has been linked to a variety of long-term consequences, including kidney damage, neurotoxicity, and pulmonary toxicity, and may even create secondary cancers. However, lipoma development is known to occur in fewer than 1 in 100 individuals, and only a few examples of multiple cutaneous lipomatosis triggered by this therapy have been documented. Here we present a very rare case of lipomatosis in a pediatric patient with GCT under cisplatin therapy, which might be the third report of this kind affecting children.
PMID:36556917 | PMC:PMC9784424 | DOI:10.3390/medicina58121715
Int J Mol Sci. 2022 Dec 8;23(24):15575. doi: 10.3390/ijms232415575.
ABSTRACT
Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA-Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA-Doxo nanotransporters, the conditions for the DNA-Doxo compaction process induced by gold nanoparticles were first explored using fluorescence spectroscopy, circular dichroism and atomic force microscopy techniques. The reverse process, which is fundamental for Doxo liberation at the site of action, was found to occur at higher CAu@16-Ph-16 concentrations using these techniques. Zeta potential, dynamic light scattering and UV-visible spectroscopy reveal that the prepared compacted nanosystems are stable, highly charged and of adequate size for the effective delivery of Doxo to the cell. This fact is verified by in vitro biocompatibility and internalization studies using two prostate cancer-derived cell lines (LNCaP and DU145) and one hepatocellular carcinoma-derived cell line (SNU-387), as well as a non-tumor prostate (PNT2) cell line and a non-hepatocarcinoma hepatoblastoma cell line (Hep-G2) model used as a control in liver cells. However, the most outstanding results of this work are derived from the use of the CI+NI combined treatments which present strong action in cancer-derived cell lines, while a protective effect is observed in non-tumor cell lines. Hence, novel therapeutic targets based on gold nanoparticles denote high selectivity compared to conventional treatment based on free Doxo at the same concentration. The results obtained show the viability of both the proposed methodology for internalization of compacted nanocomplexes inside the cell and the effectiveness of the possible treatment and minimization of side effects in prostate and liver cancer.
PMID:36555216 | PMC:PMC9779246 | DOI:10.3390/ijms232415575
Cells. 2022 Dec 8;11(24):3974. doi: 10.3390/cells11243974.
ABSTRACT
The Myc Network, comprising a small assemblage of bHLH-ZIP transcription factors, regulates many hundreds to thousands of genes involved in proliferation, energy metabolism, translation and other activities. A structurally and functionally related set of factors known as the Mlx Network also supervises some of these same functions via the regulation of a more limited but overlapping transcriptional repertoire. Target gene co-regulation by these two Networks is the result of their sharing of three members that suppress target gene expression as well as by the ability of both Network's members to cross-bind one another's consensus DNA sites. The two Networks also differ in that the Mlx Network's control over transcription is positively regulated by several glycolytic pathway intermediates and other metabolites. These distinctive properties, functions and tissue expression patterns potentially allow for sensitive control of gene regulation in ways that are differentially responsive to environmental and metabolic cues while allowing for them to be both rapid and of limited duration. This review explores how such control might occur. It further discusses how the actual functional dependencies of the Myc and Mlx Networks rely upon cellular context and how they may differ between normal and neoplastic cells. Finally, consideration is given to how future studies may permit a more refined understanding of the functional interrelationships between the two Networks.
PMID:36552737 | PMC:PMC9777120 | DOI:10.3390/cells11243974
Biomedicines. 2022 Dec 1;10(12):3091. doi: 10.3390/biomedicines10123091.
ABSTRACT
Cancer is one of the leading causes of death in children and adolescents worldwide; among the types of liver cancer, hepatoblastoma (HBL) is the most common in childhood. Although it affects only two to three individuals in a million, it is mostly asymptomatic at diagnosis, so by the time it is detected it has already advanced. There are specific recommendations regarding HBL treatment, and ongoing studies to stratify the risks of HBL, understand the pathology, and predict prognostics and survival rates. Although magnetic resonance imaging spectroscopy is frequently used in diagnostics of HBL, high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy of HBL tissues is scarce. Using this technique, we studied the alterations among tissue metabolites of ex vivo samples from (a) HBL and non-cancer liver tissues (NCL), (b) HBL and adjacent non-tumor samples, and (c) two regions of the same HBL samples, one more centralized and the other at the edge of the tumor. It was possible to identify metabolites in HBL, then metabolites from the HBL center and the border samples, and link them to altered metabolisms in tumor tissues, highlighting their potential as biochemical markers. Metabolites closely related to liver metabolisms such as some phospholipids, triacylglycerides, fatty acids, glucose, and amino acids showed differences between the tissues.
PMID:36551847 | PMC:PMC9775661 | DOI:10.3390/biomedicines10123091
Cancers (Basel). 2022 Dec 13;14(24):6135. doi: 10.3390/cancers14246135.
ABSTRACT
Hepatoblastomas (HB) are the most common pediatric liver tumor with several subgroups described, of which teratoid HB is the rarest. The aim of this study is to characterize the histologic and phenotypic spectrum of teratoid HB in order to better understand the biology and behavior of these tumors. A retrospective analysis of all teratoid HB diagnosed at a major pediatric hospital as well as the consultation files of one of the authors (SR) was performed with the available clinical data and surgical pathology material reviewed. A detailed immunohistochemical workup was also performed. A total of 28 cases were included from patients ranging from 5 to 84 months of age and a M:F ratio of 1.07:1. Four patients had syndromic associations. In 14/28 cases, the tumors contained primitive glandular elements with histologic and immunophenotypic overlap with the yolk sac tumor which in two cases became predominant in metastatic sites. One case had extensive primitive neural epithelium mimicking a primitive neuroectodermal tumor (PNET). Other unique elements included melanin, mature neuroglial tissue, rhabdomyoblastic differentiation, and neuroendocrine carcinoma-like areas (n = 2). In conclusion, this study provides the largest series of teratoid HB to date with clinical and outcome data, highlights previously undescribed or under-recognized histologic patterns in these tumors, and describes the immunohistochemical profile of these tumors to aid in diagnosis.
PMID:36551621 | PMC:PMC9776033 | DOI:10.3390/cancers14246135
Cancers (Basel). 2022 Dec 9;14(24):6062. doi: 10.3390/cancers14246062.
ABSTRACT
BACKGROUND AND AIMS: Hepatoblastoma (HBL), a deadly malignancy in children, is the most common type of pediatric liver cancer. We recently demonstrated that β-catenin, phosphorylated at S675 (ph-S675-β-catenin), causes pathological alterations in fibrolamellar hepatocellular carcinoma (FLC), by activating oncogenes and fibrotic genes via human genomic regions, known as cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs). The aim of this study was to determine the role of the ph-S675-β-catenin-TCF4-CEGRs/ALCDs pathway in HBL.
METHODS: The ph-S675-β-catenin-TCF4-CEGRs/ALCDs pathway was examined in a large cohort of HBL specimens, in HBL cell lines HepG2 and Huh6, and in patient-derived xenografts (PDXs).
RESULTS: β-catenin is phosphorylated at S675 in a large portion of tested HBL patients. In these patients, ph-S675-β-catenin forms complexes with TCF4 and opens CEGRs/ALCDs-dependent oncogenes for transcription, leading to a massive overexpression of the oncogenes. The inhibition of the β-catenin-TCF4-CEGRs/ALCDs axis inhibits the proliferation of cancer cells and tumor growth in HBL cell lines and HBL-PDXs. The ph-S675-β-catenin is abundant in mitotic cells. We found that markers of HBL Glypican 3 (GPC3) and Alpha Fetoprotein (AFP) are increased in HBL patients by β-catenin-TCF4-p300 complexes.
CONCLUSIONS: The phosphorylation-mediated activation of the β-catenin-TCF4-p300-CEGRs/ALCDs pathway increases oncogene expression in patients with aggressive liver cancer and promotes the development of hepatoblastoma.
PMID:36551548 | PMC:PMC9775972 | DOI:10.3390/cancers14246062
Cancers (Basel). 2022 Dec 9;14(24):6057. doi: 10.3390/cancers14246057.
ABSTRACT
Background: Hepatoblastoma (HB) is the most common form of liver cancer in children. To date, complete tumor resection is still the gold standard for treating HB. Indocyanine green (ICG) has been identified as a sensitive adjunct that is highly effective in the identification and surgical management of local and metastatic HB. It has thus becomes an increasingly popular choice among surgeons in HB resection surgeries that are fluorescence-guided. However, laparotomy remains the preferred choice in most cases since the applications and limitations of fluorescence-guided laparoscopic surgery in treating HB remain unclear. In this study, the characteristics and outcomes of laparoscopic HB resections that were guided by intraoperative ICG fluorescent imaging were investigated. Methods: Seven HB patients underwent ICG-guided laparoscopic HB resection surgery from August 2019 to December 2021. ICG was intravenously administered to the patients at a dosage of 0.5 mg/kg 48 h prior to the scheduled operation. During operation, tumor localization and resection boundary were guided by fluorescence visualization. The data on surgical and clinical features were collected retrospectively. Results: The resection area and tumor boundary could be clearly viewed in real-time under the ICG fluorescence imaging navigation system during operation, except for one patient who had received interventional chemoembolization before surgery. The image produced by laparoscopic fluorescence navigation was clear since it was not affected by ambient light. All tumors were completely resected as confirmed by negative margins for HB during postoperative pathological examination. No residual or recurrence were also found through computed tomography during follow-up visits from 9 to 37 months. Conclusions: ICG fluorescence-guided laparoscopic surgery is safe and effective in treating HB due to its ability to provide clear information on tumor localization and delineate tumor margins in real-time.
PMID:36551543 | PMC:PMC9775977 | DOI:10.3390/cancers14246057
Pediatr Dev Pathol. 2022 Dec 22:10935266221122934. doi: 10.1177/10935266221122934. Online ahead of print.
ABSTRACT
PURPOSE AND CONTEXT: Glypican-3 is often used to discriminate between neoplastic and nonneoplastic liver. In focal lesions, positivity may be considered suggestive of a malignancy such as hepatoblastoma. However, glypican-3 is also normally expressed in the immature liver. We present a series of 5 cases of focal nodular hyperplasia (FNH)-like lesions arising in very young patients with glypican-3 expression and highlight the challenges these lesions present in the differential diagnosis of hepatoblastoma.
METHODS: Cases were obtained from the files of 3 tertiary pediatric hospitals. Clinical data were obtained from the electronic medical record and histopathologic material including immunohistochemical stains were reviewed.
KEY RESULTS: Patients were aged 2 weeks to 6 months with peak AFP levels ranging from 88.6 to 204,696 ng/mL. Microscopically, all were variably demarcated hepatocellular lesions with cords of hepatocytes, marked sinusoidal dilatation, and occasional fibrous bands and areas reminiscent of central scar with bile ducts. No significant cytologic atypia or increased mitotic activity were present. All showed glypican-3 expression and were negative for nuclear beta-catenin with intact reticulin framework.
CONCLUSIONS: Our study highlights the pitfalls of evaluating focal liver lesions in infants when high AFP levels and glypican-3 expression may reflect immaturity rather than neoplasia.
PMID:36546616 | DOI:10.1177/10935266221122934
Front Pediatr. 2022 Dec 1;10:878095. doi: 10.3389/fped.2022.878095. eCollection 2022.
ABSTRACT
OBJECTIVE: This study analyzed the feasibility of upfront surgical resection for pediatric PRETEXT III and IV hepatoblastoma (HB).
SUMMARY BACKGROUND DATA: Neoadjuvant chemotherapy is recommended for patients with PRETEXT III and IV HB to obtain a chance of curative surgery. However, chemotherapy can cause toxic side effects and adverse outcomes, and the PRETEXT staging system may overstage the patients. Therefore, whether preoperative chemotherapy is necessary for HB patients remains unclear.
METHODS: The clinical data of 37 children who underwent surgical resection for PRETEXT III and IV HB at our hospital were obtained retrospectively. Patients were divided into the neoadjuvant chemotherapy group (NCG; n = 19) and the routine surgery group (RSG; n = 18). Clinicopathologic characteristics, treatment regimens, and outcomes were compared between the groups.
RESULTS: The RSG had a lower incidence of portal vein involvement than the NCG (p < 0.002). The estimated 3-year event-free survival rates were similar (RSG: 89 ± 0.7% and NCG: 79 ± 0.9%, p = 0.3923). The RSG underwent fewer courses of chemotherapy than the NCG (five vs. six; p < 0.001). Furthermore, the RSG had lower incidences of febrile neutropenia, myelosuppression, and gastrointestinal reactions (all p < 0.05). The severity of surgery-related complications did not differ significantly.
CONCLUSION: Upfront surgical resection in children with PRETEXT III and IV HB is safe and feasible, and reduces the total number of courses and side effects of chemotherapy. The degree of vascular involvement is the most important consideration when evaluating resectability during diagnosis.
PMID:36533225 | PMC:PMC9751315 | DOI:10.3389/fped.2022.878095
Front Genet. 2022 Nov 30;13:1070971. doi: 10.3389/fgene.2022.1070971. eCollection 2022.
ABSTRACT
Hepatoblastoma is a malignant embryonal tumor with multiple differentiation modes and is the clearest liver malignancy in children. However, little is known about genetic and epigenetic events in Hepatoblastoma. Increased research has recently demonstrated, unique genetic and epigenetic events in Hepatoblastoma, providing insights into its origin and precise treatment. Some genetic disorders and congenital factors are associated with the risk of Hepatoblastoma development, such as the Beckwith-Wiedemann syndrome, Familial Adenomatous polyposis, and Hemihypertrophy. Epigenetic modifications such as DNA modifications, histone modifications, and non-coding RNA regulation are also essential in the development of Hepatoblastoma. Herein, we reviewed genetic and epigenetic events in Hepatoblastoma, focusing on the relationship between these events and cancer susceptibility, tumor growth, and prognosis. By deciphering the genetic and epigenetic associations in Hepatoblastoma, tumor pathogenesis can be clarified, and guide the development of new anti-cancer drugs and prevention strategies.
PMID:36531231 | PMC:PMC9748487 | DOI:10.3389/fgene.2022.1070971
Biochem Pharmacol. 2023 Jan;207:115373. doi: 10.1016/j.bcp.2022.115373. Epub 2022 Dec 10.
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.
PMID:36513143 | DOI:10.1016/j.bcp.2022.115373