Background/purpose: The prognosis of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is generally poor and hepatectomy is optional for these patients. This study aims to explore the survival benefits of neoadjuvant hepatic arterial infusion chemotherapy (HAIC) for resectable HCC with PVTT. Methods: This retrospective study included 120 resectable HCC patients with PVTT who underwent hepatectomy, from January 2017 to January 2021 at Sun Yat-sen University Cancer Center. Of these patients, the overall survival (OS) and recurrence-free survival (RFS) of 55 patients who received hepatectomy alone (Surgery group) and 65 patients who received neoadjuvant HAIC followed by hepatectomy (HAIC-Surgery group) were compared. Logistic regression analysis was conducted to develop a model predicting the response to neoadjuvant HAIC. Results: The OS rates for the HAIC-Surgery group at 1, 3, and 5 years were 94.9%, 78%, and 66.4%, respectively, compared with 84.6%, 47.6%, and 37.2% in the Surgery group (p < 0.001). The RFS rates were 88.7%, 56.2%, and 38.6% versus 84.9%, 38.3%, and 22.6% (p = 0.002). The subgroup analysis revealed that the survival benefit of neoadjuvant HAIC was limited to patients who responded to it. The logistic model, consisting of AFP and CRP, that predicted the response to neoadjuvant HAIC performed well, with an area under the ROC curve (AUC) of 0.756. Conclusion: Neoadjuvant HAIC followed by hepatectomy is associated with a longer survival outcome than hepatectomy alone for HCC patients with PVTT and the survival benefit is limited to patients who respond to neoadjuvant FOLFOX-HAIC.

UNASSIGNED: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial.
UNASSIGNED: First, cBioPortal was used to visualize genetic alterations and DNA copy number alterations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta-analysis was performed to evaluate the effect of ARID1A mutation or expression on the prognosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments.
UNASSIGNED: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/FOXO3 pathway.
UNASSIGNED: ARID1A can be considered a potential prognostic biomarker and candidate therapeutic target for HCC.

Metastasis is a major obstacle in the treatment of hepatocellular carcinoma (HCC). Microtubule-associated protein 4 (MAP4) plays an important role as a coordinator between microtubules and microfilaments. However, the role of MAP4 in HCC migration and epithelial mesenchymal transition (EMT) is unclear. We compared the protein and mRNA levels of MAP4 in human HCC and adjacent normal tissues using western blotting, immunohistochemistry and RT-qPCR. The migration and invasion abilities and the levels of EMT markers (E-Cadherin, N-Cadherin, Vimentin, and Snail) were compared between MAP4-knockdown and MAP4-overexpressed HCC cells. Finally, we examined whether β-catenin and glycogen synthase kinase 3β (GSK3β) are involved in the stimulatory effects of MAP4 on HCC migration, invasion and EMT. The results revealed that MAP4 levels were higher in the HCC tissues than in the normal hepatic tissues. More importantly, MAP4 knockdown suppressed migration and invasion abilities and EMT processes in HCC cells, which were confirmed by the stimulatory effects of MAP4 overexpression on EMT processes in HCC cells. Further evidence demonstrated that the up-regulation of β-catenin activity induced by the interaction between MAP4 and GSK3β possibly accounted for the pro-migration and pro-EMT effects of MAP4 on HCC cells. Taken together, these results suggest that MAP4 promotes migration, invasion, and EMT in HCC cells by regulating the GSK3β/β-catenin pathway.

UNASSIGNED: Primary hepatic sarcomatoid carcinoma (PHSC) is a rare type of malignant tumor in the liver. Nevertheless, few studies have focused on the imaging diagnosis of PHSC. In this study, we collected clinical and computed tomography (CT) imaging data of PHSC from two institutions, aiming to investigate the clinical and radiological characteristics of PHSC.
UNASSIGNED: We retrospectively investigated the clinical characteristics and CT features of 22 PHSC patients (19 males and 3 females; mean age, 63.4 years; range, 49 to 76 years), 95 hepatocellular carcinoma (HCC) patients and 50 intrahepatic cholangiocarcinoma (ICC) patients. Two radiologists independently evaluated the CT features of the three groups. Subsequently, we analyzed the differences in the clinical characteristics and CT features between the PHSC and control groups.
UNASSIGNED: Most PHSCs were larger than 5 cm (72.7%). PHSC mainly showed irregular (81.8%), heterogeneous (100%) masses with ill-defined (72.7%) borders with necrosis (86.4%) on CT, which are more common CT features versus HCC (p < 0.001). In the arterial phase, PHSC always showed noticeable heterogeneous enhancement (100.0%), mainly manifesting as partial arterial phase hyperenhancement (APHE) (86.4%). The enhancement patterns of PHSC mainly included delayed progressive enhancement (72.7%), nonperipheral washout (22.7%), and unclassified enhancement (4.5%), which were significantly different from the HCC enhancement pattern but similar to the enhancement pattern of ICC. In addition, vein tumor thrombus (18.2%), intrahepatic metastasis (27.3%), and lymphadenopathy (27.3%) were relatively common in PHSC. Furthermore, most PHSC tumors classified as LR-M (66.7%) were similar to ICC.
UNASSIGNED: PHSC generally presents as irregularly large masses with necrosis, intrahepatic metastasis, and lymphadenopathy. The CT enhancement of PHSC is mainly part of APHE and delayed progressive enhancement.

Hepatitis B virus (HBV) infection is still one kind of the infectious diseases that seriously threaten human health. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. HBV infection complicated with NAFLD is increasingly common. This review mainly describes the interaction between HBV infection and NAFLD, the interaction between steatosis and antiviral drugs, and the prognosis of HBV infection complicated with NAFLD. Most studies suggest that HBV infection may reduce the incidence of NAFLD. NAFLD can promote the spontaneous clearance of hepatitis B surface antigen (HBsAg), but whether it affects antiviral efficacy has been reported inconsistently. HBV infection combined with NAFLD can promote the progression of liver fibrosis, especially in patients with severe steatosis. The outcome of HBV infection combined with NAFLD predisposing to the progression of HCC remains controversial.

UNASSIGNED: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.
UNASSIGNED: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.
UNASSIGNED: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001).
UNASSIGNED: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.
UNASSIGNED: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Post-transcriptional modifications in RNAs regulate their biological behaviors and functions. N1-methyladenosine (m1A), which is dynamically regulated by writers, erasers and readers, has been found as a reversible modification in tRNA, mRNA, rRNA and long non-coding RNA (lncRNA). m1A modification has impacts on the RNA processing, structure and functions of targets. Increasing studies reveal the critical roles of m1A modification and its regulators in tumorigenesis. Due to the positive relevance between m1A and cancer development, targeting m1A modification and m1A-related regulators has been of attention. In this review, we summarized the current understanding of m1A in RNAs, covering the modulation of m1A modification in cancer biology, as well as the possibility of targeting m1A modification as a potential target for cancer diagnosis and therapy.

UNASSIGNED: SCY1-like pseudokinase 3 (SCYL3) was identified as a binding partner of ezrin, implicating it in metastasis. However, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. In this study, we aimed to elucidate the role of SCYL3 in the progression of hepatocellular carcinoma (HCC).
UNASSIGNED: The clinical significance of SCYL3 in HCC was evaluated in publicly available datasets and by qPCR analysis of an in-house HCC cohort. The functional significance and mechanistic consequences of SCYL3 were examined in SCYL3-knockdown/overexpressing HCC cells. In vivo tumor progression was evaluated in Tp53 KO/c-Myc OE mice using the sleeping beauty transposon system. Potential downstream pathways were investigated by co-immunoprecipitation, western blotting analysis and immunofluorescence staining.
UNASSIGNED: SCYL3 is often overexpressed in HCC; it is preferentially expressed in metastatic human HCC tumors and is associated with worse patient survival. Suppression of SCYL3 in HCC cells attenuated cell proliferation and migration as well as in vivo metastasis. Intriguingly, endogenous SCYL3 overexpression increased tumor development and metastasis in Tp53 KO/c-Myc OE mice. Mechanistic investigations revealed that SCYL3 physically binds and regulates the stability and transactivating activity of ROCK2 (Rho kinase 2) via its C-terminal domain, leading to the increased formation of actin stress fibers and focal adhesions.
UNASSIGNED: These findings reveal that SCYL3 plays a critical role in promoting the progression of HCC and have implications for developing new therapeutic strategies to tackle metastatic HCC.
UNASSIGNED: SCYL3 was first reported to be a binding partner of a metastasis-related gene, ezrin. To date, the clinical relevance and functional role of SCYL3 in cancer remain uncharacterized. Herein, we uncover its crucial role in liver cancer progression. We show that it physically binds and regulates the stability and transactivating activity of ROCK2 leading to HCC tumor progression. Our data provide mechanistic insight that SCYL3-mediated ROCK2 protein stability plays a pivotal role in growth and metastasis of HCC cells. Targeting SCYL3/ROCK2 signaling cascade may be a novel therapeutic strategy for treatment of HCC patients.

Effective systemic treatment for hepatocellular carcinoma (HCC) remains urgently needed. Sorafenib is the first FDA-approved systemic treatment for HCC. However, individual HCC patents\' response to sorafenib varies greatly. How to enhance the anti-HCC effect of sorafenib is still a significant challenge. T cell immunoglobulin mucin-3 (Tim-3) is a newly identified immune checkpoint molecule and a promising target for HCC treatment. Herein, we developed a novel pH-triggered drug-eluting nanoparticle (CC@SR&SF@PP) for simultaneously delivery of Tim-3 siRNA and sorafenib to HCC in situ. By a single emulsification method, a representative HCC targeted-therapeutic drug sorafenib (SF) was encapsulated into the pH-triggered positive-charged mPEG5K-PAE10K (PP) nanoparticles, followed by condensing of negative-charged Tim-3 siRNA. Then, carboxymethyl chitosan (CMCS), an amphoteric polysaccharide with negative charge in the physiological pH and positive charge in the acidic environment of the tumor, was eventually adsorbed onto the surface of nanoparticles. This co-delivery nanoparticle rapidly and specifically accumulated in the tumor site of the liver and enhanced the targeted, specific and multiple release of siRNA and sorafenib. Enhanced Tim-3 siRNA transfected into tumor cells can not only directly inhibit the growth of tumor cells by knock down the expression Tim-3, but also induce the immune response and enhance the recruitment of cytotoxic T cells to kill tumor cells. The following pH-triggered sorafenib release from SF@PP NPs greatly inhibited the tumor proliferation and angiogenesis, resulting in remarkable tumor growth inhibition in a mouse hepatoma 22 (H22) orthotopic tumor model. Thus, co-delivery of Tim-3 siRNA and sorafenib via this novel pH triggered drug-eluting nanoparticle enhances their anti-tumor efficacy. We expect that such combination treatment strategy will have great potential in future clinical applications.

Transient receptor potential (TRP) channels are one primary type of calcium (Ca2+) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors\' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.