A case of spontaneous acute obstructive suppurative pancreatic ductitis associated with intraductal papillary mucinous neoplasms.

A 77-year-old woman was referred to our hospital due to left upper abdominal pain, appetite loss and body weight loss for 1 month. Her past medical history was diabetes and intraductal papillary mucinous neoplasms (IPMNs). She had no fever and physical examination revealed mild tenderness in the left upper abdomen. Blood tests showed elevated inflammatory response with normal serum pancreatic enzymes. Contrast-enhanced CT showed marked swelling of the pancreatic tail, increased peripancreatic fatty tissue density, multiple IPMNs and obscuration of the enlarged main pancreatic duct at the tail. EUS showed there was no obvious mass in the pancreas and protein plug was suspected in the main pancreatic duct. EUS-FNA was performed and pathology showed no malignancy. ERCP showed discharge of purulent pancreatic fluid from the major duodenal papilla and stenosis of the main pancreatic duct at the tail. The culture of the purulent pancreatic fluid revealed Streptococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa, leading to diagnosis of acute obstructive suppurative pancreatic ductitis (AOSPD). Endoscopic nasopancreatic drainage and antimicrobial treatment were started. The inflammatory response improved rapidly and the patient was discharged 30 days after admission. To our knowledge, this is the second reported case of spontaneous AOSPD associated with IPMNs.

Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency.

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland.

Comprehensive analyses of the clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma.

AIM: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated. METHODS: Whole-exome sequencing analyses were carried out in 13 primary and 2 recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated. RESULTS: TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 nonmutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case. CONCLUSIONS: The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.

A Rare Case of Donor-Origin Intrahepatic Cholangiocarcinoma After Liver Transplantation for Hepatocellular Carcinoma: A Case Report.

BACKGROUND: Tumors may develop in the grafted liver after liver transplantation for hepatocellular carcinoma, most of which are hepatocellular carcinoma recurrences and are rarely of donor origin. We report a rare case of donor-origin intrahepatic cholangiocarcinoma in a liver allograft after liver transplantation for hepatocellular carcinoma. METHODS: A man in his 60s underwent liver transplantation for hepatocellular carcinoma with hepatitis C virus cirrhosis. The donor was a braindead woman in her 60s who had no history of malignancy. RESULTS: Three years and 5 months after liver transplantation, a tumor developed in the allograft. Computed tomography scans showed a 40-mm tumor that was atypical for hepatocellular carcinoma. Tumor biopsy was most suggestive of intrahepatic cholangiocarcinoma. Fluorescence in situ hybridization of the tumor showed an XX signal pattern, suggesting that it originated from the donor liver. Whole exome sequencing analysis strongly suggested that the tumor was an intrahepatic cholangiocarcinoma derived from the donor. CONCLUSIONS: Although donor-origin cancer after liver transplantation is extremely rare, it should be considered for adequate treatment.

Anti-integrin αvß6 autoantibodies in patients with primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown. METHODS: The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin αvß6 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays. RESULTS: Anti-integrin αvß6 antibodies were detected in 49/55 (89.1%) patients with PSC and 5/150 (3.3%) controls (P < 0.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35/36) and that in PSC alone was 73.7% (14/19) (P = 0.008). Integrin αvß6 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15/33 patients with PSC blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif. CONCLUSIONS: Autoantibodies against integrin αvß6 were detected in most patients with PSC; anti-integrin αvß6 antibody may serve as a potential diagnostic biomarker for PSC.

Complete Metabolic Response by 18 F-FDG PET/CT to Atezolizumab Plus Bevacizumab in Patients With Advanced Hepatocellular Carcinoma.

ABSTRACT: Nowadays, atezolizumab plus bevacizumab is recommended for advanced hepatocellular carcinoma (HCC) as the first-line systemic chemotherapy. Nevertheless, the data with regard to the tumor response still remain limited. We report a complete metabolic response assessed by 18 F-FDG PET/CT in a 74-year-old man with advanced HCC who underwent atezolizumab plus bevacizumab followed by radical hepatectomy. Furthermore, pathological examination revealed that the tumor showed complete response for this therapy. This case suggests that 18 F-FDG PET/CT represents clinical relevance as a useful approach for therapeutic assessment of immune-oncology drugs in HCC.

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma.

Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

Natural History of Hepatic Hemangiomas Larger Than 10 cm: Imaging Findings and Clinical Course of 22 Cases.

INTRODUCTION: The natural history of a large hepatic hemangioma is important in determining the treatment strategy. Although several studies have assessed the natural history of hepatic hemangiomas, no study has focused on hepatic hemangiomas measuring >10 cm. The aim of this study was to assess the natural history of hepatic hemangiomas measuring >10 cm by evaluating imaging findings and clinical course. METHODS: Computed tomography (CT) and magnetic resonance imaging (MRI) reports at Kyoto University Hospital, Kyoto, Japan, between January 2001 and March 2023 were retrospectively searched to find adult patients with hepatic hemangiomas >10 cm. Patients who were followed up without treatment for over six months were included. The maximum diameter of the hepatic hemangioma was compared between the baseline and the final CT or MRI. The clinical course of the patients was evaluated. RESULTS: Twenty-two patients (17 women, five men; median age, 51 years) were identified. The median diameter of hepatic hemangiomas in the baseline study was 114 mm. Two patients had abdominal distention at the time of the baseline imaging, whereas the others were asymptomatic. After follow-up without treatment (the median; 95.5 months), enlargement, no change, shrinkage of hepatic hemangioma was observed in six, 11, and five patients, respectively. The median growth rate of hepatic hemangiomas was 2.5 mm/year. Two patients underwent liver resection for hepatic hemangioma, while the others were followed up without treatment. In four patients, symptoms appeared or worsened. Two patients died: one patient died from prostate cancer progression; the cause of death for the other was not confirmed. CONCLUSION: Hepatic hemangiomas show a slow growth rate during follow-up, and shrinkage is occasionally observed. Some patients experience new symptoms or aggravation of symptoms; however, deaths associated with hepatic hemangiomas are uncommon.

Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives.

High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.

Clinical and Molecular Basis of Hepatocellular Carcinoma after Hepatitis C Virus Eradication.

Hepatocellular carcinoma (HCC) arises in the background of chronic liver diseases, including hepatitis and liver cirrhosis caused by hepatitis C virus (HCV) infection. It is well known that HCV eradication using antiviral drugs can efficiently inhibit hepatocarcinogenesis. Recent advances in and development of direct-acting antiviral (DAA) drugs has revolutionized the treatment of HCV infection, and the vast majority of HCV patients can achieve HCV eradication using DAAs. However, mounting evidence clearly indicates that HCC inevitably occurs in a subset of patients after successful viral eradication using DAA therapy. Cancer is a genetic disease, and the accumulation of genetic and epigenetic aberrations may cause hepatocarcinogenesis in chronically damaged liver, even after virus elimination. In this review, we highlight HCC development after HCV eradication and discuss the current understanding of the molecular mechanisms of tumorigenesis after virus elimination, focusing on the genetic and epigenetic background of chronically damaged liver tissues.

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization.

Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization. SIGNIFICANCE: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.

Ultrasound-guided polidocanol foam sclerotherapy for symptomatic giant hepatic cyst: A single-center experience.

AIM: Simple hepatic cysts are typically benign; however, when they are large and symptomatic, therapeutic intervention is required. We previously reported our initial experience with ultrasound (US)-guided polidocanol foam sclerotherapy in three patients with symptomatic giant hepatic cysts. In the present study, we examined the efficacy and safety of polidocanol foam sclerotherapy in a larger number of patients with long-term follow-up. METHODS: Between May 2016 and April 2021, 15 patients with symptomatic giant hepatic cysts were referred to our hospital. All patients were prospectively included in the study and underwent US-guided polidocanol foam sclerotherapy. RESULTS: The mean maximum diameter and estimated cyst volume were 128.4 mm (77-223 mm) and 922.3 ml (123.2-2797 ml), respectively. Polidocanol foam was successfully administered through an 8.5-Fr pigtail catheter in all patients. The percentages of cyst diameter/volume after 1-3 months, 3-6 months, 6 months-1 year, 1-2 years, and 2-4 years of sclerotherapy were 66.8%/36.5%, 48.1%/14.8%, 34.1%/6.9%, 28.2%/3.7%, and 26.2%/3.1%, respectively. During the follow-up period, there were no cases of symptom recurrence or need for additional treatment due to cyst re-growth. Six patients (40%) had fever, one had nausea, and one had right-sided chest pain, but none of these adverse events required prolonged hospitalization or readmission. CONCLUSIONS: US-guided polidocanol foam sclerotherapy may be an effective and safe method for the treatment of symptomatic giant hepatic cysts.

Genetic Landscape of Multistep Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Although several targeted therapy agents are available for advanced HCC, their antitumor efficacy remains limited. As the complex genetic landscape of HCC would compromise the antitumor efficacy of targeted therapy, a deeper understanding of the genetic landscape of hepatocarcinogenesis is necessary. Recent comprehensive genetic analyses have revealed the driver genes of HCC, which accumulate during the multistage process of hepatocarcinogenesis, facilitating HCC genetic heterogeneity. In addition, as early genetic changes may represent key therapeutic targets, the genetic landscapes of early HCC and precancerous liver tissues have been characterized in recent years, in parallel with the advancement of next-generation sequencing analysis. In this review article, we first summarize the landscape of the liver cancer genome and its intratumor heterogeneity. We then introduce recent insight on early genetic alterations in hepatocarcinogenesis, especially those in early HCC and noncancerous liver tissues. Finally, we summarize the multistep accumulation of genetic aberrations throughout cancer progression and discuss the future perspective towards the clinical application of this genetic information.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictive Marker of Response to Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma.

BACKGROUND: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. METHODS: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. RESULTS: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. CONCLUSIONS: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC.

A simplified method to quantitatively predict the effect of lenvatinib on hepatocellular carcinoma using contrast-enhanced ultrasound with perfluorobutane microbubbles.

Contrast-enhanced computed tomography (CECT) is generally used to evaluate the response to treatment of hepatocellular carcinoma (HCC); however, CECT is unsuitable for the early prediction of therapeutic effects and frequent monitoring. We aimed to investigate the usefulness of our simplified method for the quantification of tumor vascularity using contrast-enhanced ultrasound (CEUS) with perfluorobutane microbubbles [Sonazoid® (GE Healthcare, Oslo, Norway)] to predict the therapeutic effect of lenvatinib. Among the 13 patients studied, nine who had more than a 20% reduction in tumor vascularity within 2 weeks of starting treatment experienced complete response or partial response at 8-12 weeks as assessed by CECT. In contrast, three patients without reductions and one patient with only a slight decrease in tumor vascularity had a poor response to lenvatinib. Quantitative assessment of tumor vascularity by our simplified CEUS-based method could be a useful predictor of therapeutic responses to lenvatinib in patients with HCC.

Genetic Pathogenesis of Inflammation-Associated Cancers in Digestive Organs.

Epidemiological, clinical, and biological studies convincingly demonstrate that chronic inflammation predisposes to the development of human cancers. In digestive organs, inflammation-associated cancers include colitis-associated colorectal cancers, Helicobacter pylori-associated gastric cancer, as well as Barrett's esophagus and esophageal adenocarcinoma associated with chronic duodenogastric-esophageal reflux. Cancer is a genomic disease, and stepwise accumulation of genetic and epigenetic alterations of tumor-related genes leads to the development of tumor cells. Recent genome analyses show that genetic alterations, which are evoked by inflammation, are latently accumulated in inflamed epithelial cells of digestive organs. Production of reactive oxygen and aberrant expression of activation-induced cytidine deaminase, a nucleotide-editing enzyme, could be induced in inflamed gastrointestinal epithelial cells and play a role as a genomic modulator of inflammation-associated carcinogenesis. Understanding the molecular linkage between inflammation and genetic alterations will open up a new field of tumor biology and provide a novel strategy for the prevention of inflammation-associated tumorigenesis.

Mac-2 binding protein glycosylation isomer predicts tolerability and clinical outcome of lenvatinib therapy for hepatocellular carcinoma.

BACKGROUND: Many patients with hepatocellular carcinoma present with impaired hepatic function, which often requires interruption or withdrawal of lenvatinib due to associated adverse events. We aimed to identify pre-treatment predictors of tolerability and clinical outcome of lenvatinib therapy. METHODS: Eighty patients who received lenvatinib at our institution between 2018 and 2020 were included in this study. We assessed essential factors associated with prolonged progression-free survival (PFS), using Cox proportional hazards model. We also investigated the correlation between the factor identified as contributing most to PFS and the relative dose intensity (RDI), response rate, and duration of treatment with lenvatinib. RESULTS: Pre-treatment level of Mac-2-binding protein glycosylation isomer (M2BPGi) showed significant association with PFS (hazard ratio = 0.52, P = .0358). Low M2BPGi levels (<1.5) correlated significantly with longer PFS than higher levels (P = .0003). Patients with M2BPGi <1.5 achieved significantly higher RDI, objective response rate, and disease control rate, and maintained lenvatinib treatment for longer than those with baseline values ≥1.5. Patients with M2BPGi ≥1.5 had a higher incidence of adverse events such as fatigue and anorexia. CONCLUSIONS: Baseline M2BPGi levels may predict the tolerability and treatment response to lenvatinib. Patients with high M2BPGi levels may less likely to benefit from lenvatinib therapy.

Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus.

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA sequencing datasets, consisting of non-cancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive non-cancerous liver tissues, whereas some cancer-related pathways were up-regulated in the non-cancerous liver tissues of both post-SVR and HCV-positive cases. The persistent up-regulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals (DAAs), including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving DAA therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, up-regulated CYR61 could be a possible biomarker for post-SVR-HCC.

DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis.

Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.

Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here, we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers, while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in nonneoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC. SIGNIFICANCE: This study contributes to the identification of the cells of origin that initiate ICC and suggests that HES1 may represent a therapeutic target in ICC.