miR-17-5p slows progression of hepatocellular carcinoma by downregulating TGFBR2

Objective Downregulation of miR-17-5p has been reported in several cancers, but whether and how miR-17-5p is downregulated in hepatocellular carcinoma (HCC) is unknown. Here, we examined whether miR-17-5p is downregulated in HCC and whether that affects expression of its target gene encoding transforming growth factor β receptor 2 (TGFβR). Methods We screened for potential microRNAs (miRNAs) involved in HCC by analyzing published transcriptomes from HCC patients. Expression of miR-17-5p was measured in HCC cell lines and in tissues from HCC patients using quantitative real-time PCR. The in vitro effects of miR-17-5p on HCC cells were assessed by EdU proliferation assay, CCK-8 cell proliferation assay, colony-formation assay, transwell migration/invasion assay, wound healing assay, and flow cytometry. Effects of miR-17-5p were evaluated in vivo using mice with subcutaneous tumors. Effects of the miRNA on the epithelial–mesenchymal transition (EMT) were assessed, while its effects on TGFβR2 expression were analyzed using bioinformatics and a dual luciferase reporter assay. Results Patients with low miR-17-5p expression showed lower rates of overall and recurrence-free survival than patients with high miR-17-5p expression, and multivariate Cox regression identified low miR-17-5p expression as an independent predictor of poor overall survival in HCC patients. In vitro, miR-17-5p significantly inhibited HCC cell proliferation, migration, invasion, and the EMT, while promoting apoptosis. In vivo, it slowed the development of tumors. These protective effects of miR-17-5p were associated with downregulation of TGFβR2. Conclusion The miRNA miR-17-5p can negatively regulate the expression of TGFβR2 and inhibit the EMT, thereby slowing tumor growth in HCC, suggesting a potential therapeutic approach against HCC (AU)

miR-17-5p slows progression of hepatocellular carcinoma by downregulating TGFßR2.

OBJECTIVE: Downregulation of miR-17-5p has been reported in several cancers, but whether and how miR-17-5p is downregulated in hepatocellular carcinoma (HCC) is unknown. Here, we examined whether miR-17-5p is downregulated in HCC and whether that affects expression of its target gene encoding transforming growth factor ß receptor 2 (TGFßR). METHODS: We screened for potential microRNAs (miRNAs) involved in HCC by analyzing published transcriptomes from HCC patients. Expression of miR-17-5p was measured in HCC cell lines and in tissues from HCC patients using quantitative real-time PCR. The in vitro effects of miR-17-5p on HCC cells were assessed by EdU proliferation assay, CCK-8 cell proliferation assay, colony-formation assay, transwell migration/invasion assay, wound healing assay, and flow cytometry. Effects of miR-17-5p were evaluated in vivo using mice with subcutaneous tumors. Effects of the miRNA on the epithelial-mesenchymal transition (EMT) were assessed, while its effects on TGFßR2 expression were analyzed using bioinformatics and a dual luciferase reporter assay. RESULTS: Patients with low miR-17-5p expression showed lower rates of overall and recurrence-free survival than patients with high miR-17-5p expression, and multivariate Cox regression identified low miR-17-5p expression as an independent predictor of poor overall survival in HCC patients. In vitro, miR-17-5p significantly inhibited HCC cell proliferation, migration, invasion, and the EMT, while promoting apoptosis. In vivo, it slowed the development of tumors. These protective effects of miR-17-5p were associated with downregulation of TGFßR2. CONCLUSION: The miRNA miR-17-5p can negatively regulate the expression of TGFßR2 and inhibit the EMT, thereby slowing tumor growth in HCC, suggesting a potential therapeutic approach against HCC.

Comparison of survival rates as predicted by total tumor volume or tumor burden score in patients with hepatocellular carcinoma concurrent with fatty liver disease and hepatitis B virus.

OBJECTIVES: To analyze prognostic value of total tumor volume (TTV) and tumor burden score (TBS) in surgically treated patients with hepatocellular carcinoma and concurrent fatty liver disease and hepatitis B virus (FLD-HCC). METHODS: FLD-HCC patients who treated with hepatectomy from 2010 to 2018 were analyzed. Prognostic performance of TTV and TBS was determined by ROC analysis. Patients were stratified into low and high tumor burden by optimal cutoff value of 113.4 cm3 for TTV or 6.3 points for TBS. Survival rates were compared between subgroups and independent risk factors were identified by Cox regression. Correlation between TTV and TBS was evaluated. RESULTS: This study enrolled 342 FLD-HCC patients. Survival was significantly higher among patients with low tumor burden than among those with high tumor burden (p < 0.001). High TTV and TBS were independent risk factors for poor survival of FLD-HCC (HR: 3.27 (2.17-4.93) and 3.48 (2.31-5.26), respectively, all p < 0.001). ROC analyses revealed that TTV and TBS had comparable discriminative ability in stratifying overall and recurrence-free survival of FLD-HCC. Correlation analysis revealed a strong correlation between TTV and TBS. CONCLUSIONS: Both TTV and TBS have comparable prognostic value and high TTV/TBS predicts poor survival of patients with FLD-HCC.

Prognosis after hepatic resection of patients with hepatocellular carcinoma related to non-alcoholic fatty liver disease: meta-analysis.

BACKGROUND: Whether the safety and efficacy of hepatic resection differ between patients whose hepatocellular carcinoma (HCC) is related to non-alcoholic fatty liver disease (NAFLD) or has other aetiologies is unknown. A systematic review was performed to explore potential differences between such conditions. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for relevant studies that reported hazard ratios (HRs) for overall and recurrence-free survival between patients with NAFLD-related HCC or HCC of other aetiologies. RESULTS: The meta-analysis involved 17 retrospective studies involving 2470 patients (21.5 per cent) with NAFLD-related HCC and 9007 (78.5 per cent) with HCC of other aetiologies. Patients with NAFLD-related HCC were older and had higher body mass index (BMI), but were less likely to have cirrhosis (50.4 per cent versus 64.0 per cent, P < 0.001). The two groups suffered similar rates of perioperative complications and mortality. Patients with NAFLD-related HCC had slightly higher overall survival (HR 0.87, 95 per cent c.i. 0.75 to 1.02) and recurrence-free survival (HR 0.93, 95 per cent c.i. 0.84 to 1.02) than those with HCC of other aetiologies. In the various subgroup analyses, the only significant finding was that Asian patients with NAFLD-related HCC had significantly better overall survival (HR 0.82, 95 per cent c.i. 0.71 to 0.95) and recurrence-free survival (HR 0.88, 95 per cent c.i. 0.79 to 0.98) than Asian patients with HCC of other aetiologies. CONCLUSION: The available evidence suggests that patients with NAFLD-related HCC have similar perioperative complications and mortality, but potentially longer overall and recurrence-free survival, compared with those with HCC of other aetiologies. Tailored surveillance strategies should be developed for patients with NAFLD without cirrhosis.

Second-line treatment options for hepatocellular carcinoma: current state and challenges for the future.

INTRODUCTION: Since the approval of sorafenib for systemic treatment of advanced hepatocellular carcinoma (HCC), many tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown efficacy and tolerability as first-line treatments. On the other hand, these first-line therapies are associated with low objective response and drug resistance. Many drugs have been successfully tested for second-line treatment of advanced HCC. While the rapid proliferation of second-line treatments for advanced HCC brings hope to patients, it also complicates clinical decision-making. AREAS COVERED: This review aims to facilitate decisions by summarizing the latest guidelines for second-line treatment of HCC in various countries or regions. We then review existing second-line treatment options and discuss challenges that should be addressed in the future. A literature search was conducted in April 2022 of PubMed/Medline, Cochrane library, and abstracts of international cancer meetings. EXPERT OPINION: There is no standard second-line treatment, especially for the case of sequential treatment after atezolizumab plus bevacizumab (atezo+bev) and further studies focused on sequential treatment are warranted in this setting. The design of clinical trials, different etiologies, and complications or quality of life (QoL) are interesting issues in the second-line setting.

Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges.

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

Treatments of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: Current Status and Controversy.

The proportions of patients with hepatocellular carcinoma (HCC) involving portal vein tumor thrombus (PVTT) varies greatly in different countries or regions, ranging from 13% to 45%. The treatment regimens for PVTT recommended by HCC guidelines in different countries or regions also vary greatly. In recent years, with the progress and development of surgical concepts, radiotherapy techniques, systematic therapies (for example, VEGF inhibitors, tyrosine kinase inhibitors and immune checkpoint inhibitors), patients with HCC involving PVTT have more treatment options and their prognoses have been significantly improved. To achieve the maximum benefit, both clinicians and patients need to think rationally about the indications of treatment modalities, the occurrence of severe adverse events, and the optimal fit for the population. In this review, we provide an update on the treatment modalities available for patients with HCC involving PVTT. Trials with large sample size for patients with advanced or unresectable HCC are also reviewed.

Outcomes of Liver Resection for Metabolic Dysfunction-Associated Fatty Liver Disease or Chronic Hepatitis B-Related HCC.

AIMS: This study aims to determine differences in severity of background liver disease at hepatocellular carcinoma (HCC) diagnosis and long-term survival outcomes among patients undergoing liver resection for HCC in the background of metabolic dysfunction-associated fatty liver disease (MAFLD) compared to chronic hepatitis B (CHB) alone or concurrent CHB (CHB/MAFLD). METHODS: Patient demographics and comorbidities, clinicopathologic data, perioperative and long-term outcomes among patients who underwent liver resection for HCC were reviewed. Overall and recurrence-free survival were calculated with the Kaplan-Meier method, with the values compared using the log-rank test. RESULTS: From January 2014 to December 2018, 1325 patients underwent potential curative liver resection of HCC; 67 (5.0%), 176 (13.3%), and 1082 (81.7%) patients had MAFLD alone, CHB concurrent with MAFLD, and CHB alone, respectively. At HCC diagnosis, fewer MAFLD patients had cirrhosis, alpha fetoprotein concentration ≥ 400 ng/mL, tumor size ≥ 5 cm, mulinodular, microvascular invasion, receiving major hepatectomy, and receiving adjuvant transarterial chemoembolization. After a median follow-up of 47 months after liver resection, MAFLD (or MAFLD plus CHB/MAFLD) patients had significantly higher overall and recurrence-free survival than CHB patients before or after propensity score analysis (all P<0.05). CONCLUSION: Patients with HCC in the setting of MAFLD have less-severe background liver disease at HCC diagnosis and better long-term survival after curative liver resection compared to counterparts with CHB/MAFLD or CHB.