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Gastroenterology Clinics of North... Mar 2024This review discusses the diagnostic challenges of diagnosing and treating precursor lesions of hepatocellular carcinoma (HCC) in both cirrhotic and non-cirrhotic... (Review)
Review
This review discusses the diagnostic challenges of diagnosing and treating precursor lesions of hepatocellular carcinoma (HCC) in both cirrhotic and non-cirrhotic livers. The distinction of high-grade dysplastic nodule (the primary precursor lesion in cirrhotic liver) from early HCC is emphasized based on morphologic, immunohistochemical, and genomic features. The risk factors associated with HCC in hepatocellular adenomas (precursor lesion in non-cirrhotic liver) are delineated, and the risk in different subtypes is discussed with emphasis on terminology, diagnosis, and genomic features.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Cirrhosis; Precancerous Conditions
PubMed: 38280744
DOI: 10.1016/j.gtc.2023.11.005 -
FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation.Oncogene Sep 2023FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its...
FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Cell Line, Tumor; F-Box Proteins; Epithelial-Mesenchymal Transition; Ubiquitins; Gene Expression Regulation, Neoplastic; Cell Movement; Neoplasm Metastasis; SKP Cullin F-Box Protein Ligases; Snail Family Transcription Factors
PubMed: 37596321
DOI: 10.1038/s41388-023-02809-0 -
Carcinogenesis Oct 2023Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total... (Review)
Review
Globally, primary liver cancer is the third leading cause of cancer-related deaths, with approximately 830 000 deaths worldwide in 2020, accounting for 8.3% of total deaths from all cancer types (1). This disease disproportionately affects those in countries with low or medium Human Development Index scores in Eastern Asia, South-Eastern Asia, and Northern and Western Africa (2). Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often develops in the background of chronic liver disease, caused by hepatitis B or C virus, non-alcoholic steatohepatitis (NASH), or other diseases that cause cirrhosis. Prognosis can vary dramatically based on number, size, and location of tumors. Hepatic synthetic dysfunction and performance status (PS) also impact survival. The Barcelona Clinic Liver Cancer (BCLC) staging system best accounts for these variations, providing a reliable prognostic stratification. Therapeutic considerations of this complex disease necessitate a multidisciplinary approach and can range from curative-intent surgical resection, liver transplantation or image-guided ablation to more complex liver-directed therapies like transarterial chemoembolization (TACE) and systemic therapy. Recent advances in the understanding of the tumor biology and microenvironment have brought new advances and approvals for systemic therapeutic agents, often utilizing immunotherapy or VEGF-targeted agents to modulate the immune response. This review will discuss the current landscape in the treatments available for early, intermediate, and advanced stage HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Antineoplastic Agents; Treatment Outcome; Neoplasm Staging; Tumor Microenvironment
PubMed: 37428789
DOI: 10.1093/carcin/bgad052 -
Free Radical Biology & Medicine Nov 2023Cisplatin (CPT) is one of the standard treatments for hepatocellular carcinoma (HCC). However, its use is limits as a monotherapy due to drug resistance, and the...
Cisplatin (CPT) is one of the standard treatments for hepatocellular carcinoma (HCC). However, its use is limits as a monotherapy due to drug resistance, and the underlying mechanism remains unclear. To solve this problem, we tried using canagliflozin (CANA), a clinical drug for diabetes, to reduce chemoresistance to CPT, and the result showed that CANA could vigorously inhibit cell proliferation and migration independent of the original target SGLT2. Mechanistically, CANA reduced aerobic glycolysis in HCC by targeting PKM2. The downregulated PKM2 directly bound to the transcription factor c-Myc in the cytoplasm to form a complex, which upregulated the level of phosphorylated c-Myc Thr58 and promoted the ubiquitination and degradation of c-Myc. Decreased c-Myc reduced the expression of GLS1, a key enzyme in glutamine metabolism, leading to impaired glutamine utilization. Finally, intracellular glutamine starvation induced ferroptosis and sensitized HCC to CPT. In conclusion, our study showed that CANA re-sensitized HCC to CPT by inducing ferroptosis through dual effects on glycolysis and glutamine metabolism. This is a novel mechanism to increase chemosensitivity, which may provide compatible chemotherapy drugs for HCC.
Topics: Humans; Canagliflozin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Glutamine; Glycolysis; Liver Neoplasms; Proto-Oncogene Proteins c-myc; Thyroid Hormone-Binding Proteins
PubMed: 37696420
DOI: 10.1016/j.freeradbiomed.2023.09.006 -
Frontiers in Immunology 2024
Topics: Humans; Liver Neoplasms; Immunotherapy; Animals; Tumor Microenvironment; Drug Resistance, Neoplasm
PubMed: 38751429
DOI: 10.3389/fimmu.2024.1420381 -
Bioscience Trends Jan 2024Hepatoblastoma (HB) remains the most common paediatric liver tumour and survival in children with hepatoblastoma has improved considerably since the advent of sequential...
Hepatoblastoma (HB) remains the most common paediatric liver tumour and survival in children with hepatoblastoma has improved considerably since the advent of sequential surgical regimens of chemotherapy based on platinum-based chemotherapeutic agents in the 1980s. With the advent of modern diagnostic imaging and pathology techniques, new preoperative chemotherapy regimens and the maturation of surgical techniques, new diagnostic and treatment options for patients with hepatoblastoma have emerged and international collaborations are investigating the latest diagnostic approaches, chemotherapy drug combinations and surgical strategies. Diagnosis of hepatoblastoma relies on imaging studies (such as ultrasound, computed tomography, and magnetic resonance imaging), alpha-fetoprotein (AFP) levels, and histological confirmation through biopsy. The standard treatment approach involves a multimodal strategy with neoadjuvant chemotherapy followed by surgical resection. In cases where complete resection is not feasible or tumors exhibit invasive characteristics, liver transplantation is considered. The management of metastatic and recurrent hepatoblastoma poses significant challenges, and ongoing research focuses on developing targeted therapies and exploring the potential of immunotherapy. Further studies are necessary to gain a better understanding of the etiology of hepatoblastoma, develop prevention strategies, and personalize treatment approaches. We aim to review the current status of diagnosis and treatment of hepatoblastoma.
Topics: Child; Humans; Infant; Hepatoblastoma; Neoplasm Recurrence, Local; Liver Neoplasms; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Hepatectomy; Treatment Outcome
PubMed: 38143081
DOI: 10.5582/bst.2023.01311 -
The Surgical Clinics of North America Feb 2024A quarter century has passed since the milestone study by Mazzaferro and colleagues on liver transplantation (LT) for hepatocellular carcinoma (HCC). The increasing... (Review)
Review
A quarter century has passed since the milestone study by Mazzaferro and colleagues on liver transplantation (LT) for hepatocellular carcinoma (HCC). The increasing demand for LT for HCC has led to the continued efforts to expand LT indications. Downstaging to within Milan criteria has been incorporated into the organ allocation policy for HCC in the United States in 2017 and provides acceptable long-term survival. The present review focuses on the rationale of neoadjuvant immune checkpoint inhibitor (ICI) in HCC, the experience of ICI in the pre- and posttransplant setting.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Transplantation; Treatment Outcome; Immunotherapy; Neoplasm Recurrence, Local
PubMed: 37953034
DOI: 10.1016/j.suc.2023.07.009 -
JCI Insight Sep 2023Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear....
Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear. Applying a genome-scale CRISPR knockout screen, we identified that the H3K4 methyltransferase SETD1A and other members of Trithorax group proteins drive cancer stemness in HCC. SET domain containing 1A (SETD1A) was positively correlated with poor clinical outcome in patients with HCC. Combination of SETD1A and serum alpha fetoprotein substantially improved the accuracy of predicting HCC relapse. Mechanistically, SETD1A mediates transcriptional activation of various histone-modifying enzymes, facilitates deposition of trimethylated H3K4 (H3K4me3) and H3K27me3, and activates oncogenic enhancers and super-enhancers, leading to activation of oncogenes and inactivation of tumor suppressor genes simultaneously in liver CSCs. In addition, SETD1A cooperates with polyadenylate-binding protein cytoplasmic 1 to regulate H3K4me3 modification on oncogenes. Our data pinpoint SETD1A as a key epigenetic regulator driving HCC stemness and progression, highlighting the potential of SETD1A as a candidate target for HCC intervention and therapy.
Topics: Humans; Carcinoma, Hepatocellular; Epigenesis, Genetic; Liver Neoplasms; Neoplasm Recurrence, Local; Stem Cells
PubMed: 37581938
DOI: 10.1172/jci.insight.168375 -
International Journal of Surgery... Oct 2023Nucleot(s)ide analog treatment (entecavir (ETV) and tenofovir (TDF)) is reported to be associated with decreased tumor recurrence and death in hepatitis B virus... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nucleot(s)ide analog treatment (entecavir (ETV) and tenofovir (TDF)) is reported to be associated with decreased tumor recurrence and death in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients, yet further work is needed to evaluate the different efficacies of these two agents on the prognosis of early-stage HBV-related HCC patients after curative liver resection.
MATERIAL AND METHODS
From July 2017 to January 2019, 148 patients with HBV-related HCC who underwent curative liver resection were randomized to receive TDF ( n =74) or ETV ( n =74) therapy. The primary end point was tumor recurrence in the intention-to-treat population. Overall survival and tumor recurrence of patients were compared by multivariable-adjusted Cox regression and competing risk analyses.
RESULTS
During the follow-up with continued antiviral therapy, 37 (25.0%) patients developed tumor recurrence, and 16 (10.8%) patients died ( N =15) or received liver transplantation ( N =1). In the intention-to-treat cohort, the recurrence-free survival for the TDF group was significantly better than that for the ETV group ( P =0.026). In the multivariate analysis, the relative risks of recurrence and death/liver transplantation for ETV therapy were 3.056 (95% CI: 1.015-9.196; P =0.047) and 2.566 (95% CI: 1.264-5.228; P =0.009), respectively. Subgroup analysis of the PP population indicated a better overall survival and RFS of patients receiving TDF therapy ( P =0.048; hazard ratio (HR) =0.362; 95% CI: 0.132-0.993 and P =0.014; HR =0.458; 95% CI: 0.245-0.856). Additionally, TDF therapy was an independent protective factor against late tumor recurrence ( P =0.046; (HR)=0.432; 95% CI: 0.189-0.985) but not against early tumor recurrence ( P =0.109; HR =1.964; 95% CI: 0.858-4.494).
CONCLUSION
HBV-related HCC patients treated with consistent TDF therapy had a significantly lower risk of tumor recurrence than those treated with ETV after curative treatment.
Topics: Humans; Tenofovir; Carcinoma, Hepatocellular; Antiviral Agents; Neoplasm Recurrence, Local; Hepatitis B, Chronic; Liver Neoplasms; Treatment Outcome; Prognosis; Hepatitis B
PubMed: 37335984
DOI: 10.1097/JS9.0000000000000554 -
BMC Cancer Dec 2023Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs)...
BACKGROUND
Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemoresistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to sorafenib in HCC.
METHODS
Immunohistochemistry and immunofluorescence showed that the activation of CAFs was enhanced in HCC tissues. CAFs and paracancerous normal fibroblasts (NFs) were isolated from the cancer and paracancerous tissues of HCC, respectively. Cell cloning assays, ELISAs, and flow cytometry were used to detect whether CAFs induced sorafenib resistance in HCC cells via CXCL12. Western blotting and qPCR showed that CXCL12 induces sorafenib resistance in HCC cells by upregulating FOLR1. We investigated whether FOLR1 was the target molecule of CAFs regulating sorafenib resistance in HCC cells by querying gene expression data for human HCC specimens from the GEO database.
RESULTS
High levels of activated CAFs were present in HCC tissues but not in paracancerous tissues. CAFs decreased the sensitivity of HCC cells to sorafenib. We found that CAFs secrete CXCL12, which upregulates FOLR1 in HCC cells to induce sorafenib resistance.
CONCLUSIONS
CAFs induce sorafenib resistance in HCC cells through CXCL12/FOLR1.
Topics: Humans; Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; Cancer-Associated Fibroblasts; Cell Line, Tumor; Fibroblasts; Drug Resistance, Neoplasm; Cell Proliferation; Folate Receptor 1; Chemokine CXCL12
PubMed: 38057830
DOI: 10.1186/s12885-023-11613-8