Effectiveness of edoxaban in portal vein thrombosis associated with liver cirrhosis.

Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child-Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Management of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis patients.

BACKGROUND: Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established. AIM: To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies. METHODS: We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment. RESULTS: In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events. CONCLUSION: HCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable. TRIAL REGISTRATION: This trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 - 238, registered on 4 Feb 2020.

A Case of Idiopathic Portal Hypertension Diagnosed by Noninvasive Fibrosis Evaluation Using Elastography.

Idiopathic portal hypertension (IPH) is often misdiagnosed as liver cirrhosis. Because it is difficult to distinguish between the two using diagnostic imaging, invasive tests, such as pathology and hepatic vein pressure gradient measurement, are necessary to make a diagnosis. Several studies have shown that the measurement of liver and spleen stiffnesses using elastography is useful in the diagnosis of IPH; however, there are few concrete reports on this subject. Herein, we report the case of a 58-year-old woman with IPH in which elastography was helpful for the diagnosis.

Efficacy and outcome of molecular targeted therapies in elderly patients with hepatocellular carcinoma: Relative dose intensity associated with overall survival.

AIM: Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting. METHODS: In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old). RESULTS: Overall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI. CONCLUSIONS: MTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.

Predictors of therapeutic response to peginterferon α­2a and nucleos(t)ide analog combination therapy for HBeAg­negative chronic hepatitis B: 1­year follow­up after treatment.

Chronic hepatitis B (CHB) is a major global health concern. Guidelines for the management of hepatitis B virus (HBV) indicate that the loss of hepatitis B surface antigen (HBsAg) is a key endpoint of interest. The present study aimed to examine long-term changes in HBsAg levels in HBV-DNA-negative, hepatitis B e-antigen (HBeAg)-negative patients treated with peginterferon (Peg-IFN) α-2a and nucleos(t)ide analog (NA), and to examine the conditions that make them susceptible to HBsAg decline. A total of 17 patients with CHB treated with NA and Peg-IFN were observed for 96 weeks (48 weeks of Peg-IFN therapy and 48 weeks of post-treatment follow-up). In this study, responders were defined as those with a 50% or greater decrease in HBsAg levels from baseline at week 96. Beginning at week 16 of Peg-IFN therapy, there was a significant difference in the decrease in HBsAg levels from baseline between the responders and non-responders. In responders, HBsAg levels tended to be >60% lower 16 weeks after Peg-IFN initiation than before initiation. Age at the start of NA use and the duration of NA use before Peg-IFN treatment initiation were significant pretreatment factors associated with HBsAg response. In conclusion, Peg-IFN was revealed to be more effective in HBeAg-negative patients with CHB who started NA at a young age and have been on long-term treatment, particularly if the HBsAg levels decreased to less than 60% of the starting level at week 16 after starting Peg-IFN treatment.

MicroRNAs and Nonalcoholic Steatohepatitis: A Review.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.

Relationship between Accurate Diagnosis of Sarcopenia and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab Combination Therapy.

Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4-26.4) and 10.6 (1.1-24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4-27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (p < 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia.

Usefulness of the Measurement of Psoas Muscle Volume for Sarcopenia Diagnosis in Patients with Liver Disease.

Computed tomography (CT) is often used in the diagnosis of sarcopenia. In this study, we validated the assessment of sarcopenia by the psoas muscle volume using versatile software. The study involved a retrospective analysis of data from 190 patients with liver disease who underwent grip-strength testing and abdominal pelvic computed tomography. To assess sarcopenia, SYNAPSE 3D was used to obtain the skeletal muscle index, the psoas muscle index (PMI), and the simple method. We also used the recently proposed PMI cutoff values, for which the usefulness has been evaluated (O-PMI). The cutoff value of the psoas muscle volume index (PMVI) was determined using one of the diagnostic methods as the gold standard. All diagnostic methods showed that patients with sarcopenia had shorter survival, with O-PMI having the highest hazard ratio (HR) (HR, 6.12; 95% confidence interval [CI], 2.6-14.41; p < 0.001). Even when sarcopenia could not be diagnosed by O-PMI, low PMVI was associated with shorter survival (HR, 3.53; 95% CI, 1.34-9.32; p = 0.01). PMVI may be useful in the evaluation of sarcopenia, including the identification of poor overall survival in cases that cannot be diagnosed by O-PMI, which is considered more useful than PMI.

Galectin-9 in Gastroenterological Cancer.

Immunochemotherapy has become popular in recent years. The detailed mechanisms of cancer immunity are being elucidated, and new developments are expected in the future. Apoptosis allows tissues to maintain their form, quantity, and function by eliminating excess or abnormal cells. When apoptosis is inhibited, the balance between cell division and death is disrupted and tissue homeostasis is impaired. This leads to dysfunction and the accumulation of genetically abnormal cells, which can contribute to carcinogenesis. Lectins are neither enzymes nor antibodies but proteins that bind sugar chains. Among soluble endogenous lectins, galectins interact with cell surface sugar chains outside the cell to regulate signal transduction and cell growth. On the other hand, intracellular lectins are present at the plasma membrane and regulate signal transduction by regulating receptor-ligand interactions. Galectin-9 expressed on the surface of thymocytes induces apoptosis of T lymphocytes and plays an essential role in immune self-tolerance by negative selection in the thymus. Furthermore, the administration of extracellular galectin-9 induces apoptosis of human cancer and immunodeficient cells. However, the detailed pharmacokinetics of galectin-9 in vivo have not been elucidated. In addition, the cell surface receptors involved in galectin-9-induced apoptosis of cancer cells have not been identified, and the intracellular pathways involved in apoptosis have not been fully investigated. We have previously reported that galectin-9 induces apoptosis in various gastrointestinal cancers and suppresses tumor growth. However, the mechanism of galectin-9 and apoptosis induction in gastrointestinal cancers and the detailed mechanisms involved in tumor growth inhibition remain unknown. In this article, we review the effects of galectin-9 on gastrointestinal cancers and its mechanisms.

Nutritional Support for Alcoholic Liver Disease.

Malnutrition is a common finding in alcohol use disorders and is associated with the prognosis of patients with alcoholic liver disease (ALD). These patients also frequently show deficiencies in vitamins and trace elements, increasing the likelihood of anemia and altered cognitive status. The etiology of malnutrition in ALD patients is multifactorial and complex and includes inadequate dietary intake, abnormal absorption and digestion, increased skeletal and visceral protein catabolism, and abnormal interactions between ethanol and lipid metabolism. Most nutritional measures derive from general chronic liver disease recommendations. Recently, many patients with ALD have been diagnosed with metabolic syndrome, which requires individualized treatment via nutritional therapy to avoid overnutrition. As ALD progresses to cirrhosis, it is frequently complicated by protein-energy malnutrition and sarcopenia. Nutritional therapy is also important in the management of ascites and hepatic encephalopathy as liver failure progresses. The purpose of the review is to summarize important nutritional therapies for the treatment of ALD.

Prognostic Value of Skeletal Muscle Loss in Patients with Hepatocellular Carcinoma Treated with Hepatic Arterial Infusion Chemotherapy.

Sarcopenia-related factors, including the skeletal muscle index (SMI), are reportedly associated with prognosis in patients with hepatocellular carcinoma (HCC) receiving various treatments. However, there is no evidence relating to hepatic arterial infusion chemotherapy (HAIC). In this study, we investigated whether a low SMI was associated with worse clinical outcomes of HAIC. Seventy patients with advanced HCC were included. Clinical outcomes were compared between the decreased SMI (n = 27) and non-decreased SMI (n = 43) groups, which were classified according to changes in the SMI after 3 weeks of treatment. In the prognostic analysis, patients in the decreased SMI group had significantly shorter progression-free and overall survival (OS) than those in the non-decreased SMI group. In addition, poor nutritional status and liver function were associated with an immediate decrease in the SMI after HAIC. The therapeutic effect was worse in the decreased SMI group than in the non-decreased SMI group, although the incidence of adverse events did not significantly differ. In multivariate analysis, a decreased SMI at 3 weeks after HAIC was identified as a significant independent factor associated with OS. A decreased SMI in patients with advanced HCC undergoing HAIC was associated with poor prognosis. It is effective to monitor the SMI to evaluate general conditions and predict clinical outcomes.

Pegylated interferon therapy-related microRNA-6126 downregulates sodium taurocholate cotransporting polypeptide expression in hepatocytes.

Hepatitis B virus (HBV) infection is one of the most serious global health problems. Our previous data using an in vitro assay revealed that miR-6126 suppressed the extracellular HBs antigen level, suggesting that miR-6126 had potential to suppress viral activity of HBV. In the current study, we aimed to clarify whether miR-6126 downregulated the expression level of sodium taurocholate cotransporting polypeptide (NTCP), a host cell receptor required for HBV entry. In brief, HepG2-NTCP cells were utilized to evaluate the expression level of NTCP and the PreS1 attachment to NTCP after transfection with miR-6126. The protein expression level of NTCP was evaluated using Western blot analysis and immunostaining. In addition to HepG2-NTCP cells, PXB cells were also utilized to validate inhibitory effect of miR-6126 on PreS1 attachment. The HBs antigen level in the culture supernatant was measured to evaluate reduction of HBV entry into hepatocytes. The stability of NTCP mRNA was evaluated to ascertain the cause of the downregulation of NTCP mRNA. The expression profile of messenger RNAs was evaluated using next-generation sequencing to search for direct targets of miR-6126. Consequently, transfection of miR-6126 decreased the NTCP expression level in HepG2-NTCP cells. Attachment of the PreS1 probe on the cell surface decreased in HepG2-NTCP cells and PXB cells, primary human hepatocytes. HBs antigen level in the culture supernatant also declined in PXB cells. Stability of NTCP mRNA was reduced by miR-6126 transfection in HepG2 cells. In conclusion, miR-6126 downregulated the expression of NTCP mRNA, which contributed to the inhibition of HBV entry into hepatocytes exerted by miR-6126.

Pemafibrate improves liver dysfunction and non-invasive surrogates for liver fibrosis in patients with non-alcoholic fatty liver disease with hypertriglyceridemia: a multicenter study.

BACKGROUND: This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia. METHODS: A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used. RESULTS: Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (p = 0.003). The levels of AST (p = 0.038), alanine aminotransferase (ALT) (p = 0.003), and gamma-glutamyl transferase (GGT) (p = 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (p < 0.05). However, serum HDL-cholesterol (p = 0.193), LDL-cholesterol (p = 0.967), and eGFR (p = 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers' Type IV collagen (p = 0.753) and FIB-4 index (p = 0.333) did not significantly differ, while Autotaxin (p = 0.006) and the AST-to-platelet ratio index (APRI) (p = 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (p = 0.959) and CAP (p = 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (p = 0.0475). CONCLUSION: Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.

Ledipasvir/Sofosbuvir Is Effective for Relapsed Genotype 1b Hepatitis C Virus Patients after Achieving a Sustained Virological Response at Post-treatment Week 12 with Glecaprevir/Pibrentasvir.

A patient with genotype 1b chronic hepatitis C virus who had been treated with pegylated interferon and ribavirin (RBV) was treated with glecaprevir/pibrentasvir (GLE/PIB) for 12 weeks. A sustained virological response at post-treatment week 12 (SVR12) was achieved, but relapse occurred approximately 31 weeks after the end of treatment. The patient had a history of allergy to RBV and was treated with ledipasvir/sofosbuvir (LDV/SOF), achieving SVR12 and remaining hepatitis C virus-negative until 24 weeks after the completion of treatment. LDV/SOF can thus be a secondary treatment for GLE/PIB.

MicroRNA profiles following telmisartan treatment in pancreatic ductal adenocarcinoma cells.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most devastating of all cancers with an extremely poor prognosis. It has few effective and reliable therapeutic strategies. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). Telmisartan inhibits cancer cell proliferation, but the underlying mechanisms in PDAC, remain unknown. Material and Methods: In the present study, we evaluated the effects of telmisartan on human PDAC cell proliferation in vitro. We assessed the effects of telmisartan on human PDAC cells using the cell lines PK-1 and PANC-1. Results: Telmisartan inhibited the proliferation of these cells via blockade of the G0 to G1 cell cycle transition. This was accompanied by a strong decrease in cyclin D1. Telmisartan was also shown by receptor tyrosine kinase and angiogenesis arrays to reduce the phosphorylation of epidermal growth factor receptor (EGFR), and miRNA expression was markedly altered by telmisartan in PK-1 cells. Conclusion: In conclusion, telmisartan inhibits human PDAC cell proliferation by inducing cell cycle arrest. Furthermore, telmisartan significantly altered miRNA expression in vitro. Taken together, our study demonstrated the therapeutic potential of telmisartan and provides molecular mechanistic insights into its anti-tumor effect on PDAC cells.

Effect of Lenvatinib treatment on the cell cycle and microRNA profile in hepatocellular carcinoma cells.

Lenvatinib is a tyrosine kinase receptor inhibitor used to treat unresectable hepatocellular carcinoma (HCC). In this study, we investigated the antitumor effects of Lenvatinib treatment on HCC cell lines. Proliferation was examined in four HCC cell lines (HuH-7, Hep3B, Li-7, and PLC/PRF/5) using Cell Counting Kit-8 assays. Xenograft mouse models were used to assess the effects of Lenvatinib in vivo. Cell cycle, western blotting, and microRNA (miRNA) expression analyses were performed to identify the antitumor inhibitory potential of Lenvatinib on HCC cells. Lenvatinib treatment suppressed proliferation of HuH-7 and Hep3B, but not Li-7 and PLC/PRF/5 cells and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in Lenvatinib-sensitive cells. Lenvatinib treatment also reduced tumor growth in HuH-7 xenograft mouse models. miRNA microarrays revealed that Lenvatinib treatment altered the expression of miRNAs in HuH7 cells and exosomes. Our results demonstrated the therapeutic potential of Lenvatinib and provide molecular mechanistic insights into its antitumor effects for treating HCC.

Giant cutaneous metastasis from hepatocellular carcinoma.

Cutaneous metastases from hepatocellular carcinoma (HCC) are rare and mostly occur on the face, scalp, chest, and shoulders, often with rapid growth. We report the case of an 86-year-old man who presented to our hospital with a mass, 5 cm in diameter, on the left side of his nose. His past history included a partial hepatectomy for HCC, 3 years previously, and a subsequent diagnosis of lung metastases. Skin and gingival biopsies confirmed the diagnosis of metastatic HCC and he was treated with immunotherapy followed by transarterial embolization (TAE). The latter resulted in a significant reduction in the cutaneous tumour mass.

Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 µg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.

Characterization of Cisplatin Effects in Lenvatinib-resistant Hepatocellular Carcinoma Cells.

BACKGROUND/AIM: Drug resistance to molecular targeted agents, such as lenvatinib, is an important issue. The aim of this study was to explore the mechanism of lenvatinib resistance and to investigate potential drugs that may improve the treatment of lenvatinib-resistant (LR) hepatocellular carcinoma (HCC). MATERIALS AND METHODS: LR cells were developed by long-term culture under lenvatinib exposure. We analyzed the biological characteristics of LR cells in vitro, and investigated the antitumor effects and endogenous mechanisms of cisplatin in LR cells. RESULTS: The proliferative potential of LR cells was enhanced by activation of ERK signaling and changes in several miRNAs. Cisplatin inhibited cell proliferation of LR cells and induced G2/M cell cycle arrest. Furthermore, cisplatin triggered the DNA damage response, via the ATM/ATR-Chk1/Chk2 signaling pathway. CONCLUSION: Proliferation of LR cells was induced upon ERK signaling activation. Cisplatin exerted antitumor effects in LR cells and was involved in the regulation of miRNAs associated with drug resistance.

Antitumor Effect of Regorafenib on MicroRNA Expression in Hepatocellular Carcinoma Cell Lines.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.