The coronavirus disease 2019 (COVID-19) pandemic has killed millions of people globally and severely affected quality of life and the global economy. The present randomized survey aimed to collect information based on vaccination, symptoms, treatments, and post-COVID-19 complications from participants who recovered from COVID-19 to find out the disease pattern, trends, and effective treatment protocols.

The information from participants was collected by an online questionnaire that was circulated among the population of India through emails and social media.

A total of 706 responses were recorded from participants who recovered from COVID-19 from 20 Indian states. Males and females from all age groups took part in the online survey. Among them, 77% of the participants were not vaccinated, 17% were vaccinated with a single dose and 6% with a booster dose. An average of 27% of the total vaccinated participants had a comorbidity that included diabetes, hypertension, and pulmonary disease. Most of the patients with moderate to severe symptoms preferred allopathic treatment. The adoption level of allopathic treatment was significantly higher (p = 0.001) than that of other treatment options. The results showed that 12% of the patients adopted the Ayurvedic treatment and 14% preferred a mixed treatment. Approximately one-third of the participants had various post-COVID-19 complications that were related to breathing and anxiety.

The survey concluded that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected almost the whole population irrespective of gender, age, and region. The study further concluded that vaccination is the main protection against SARS-CoV-2 infection.

Acute-on-chronic liver failure (ACLF) tends to progress rapidly with high short-term mortality. We aimed to create a widely applicable, simple prognostic (WASP) score for ACLF patients.

A retrospective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to develop the new score. A prospective longitudinal cohort was recruited for further validation.

A total of 541 cases were included in the training set, and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table. In the validation set of 671 cases, WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognostic scores at baseline, day 3, week 1, and week 2. The predictive efficacy and clinical validity of the model improved over time. Patients were assigned to low-, intermediate-, and high-risk groups by their WASP-ACLF scores. Compared with the other two groups, intermediate-risk patients had a more uncertain prognosis, with a 90-day mortality of 44.4–50.6%. Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was <20% for patients with a ≥2 point decrease in WASP-ACLF and was up to 56% for patients with a ≥2 points increase. Similar results were observed in prospective data.

The new ACLF prognostic score was simple, widely applicable, and had good predictive efficacy. Continuous assessments and trend of change in WASP-ACLF need to be considered, especially for intermediate-risk patients.

Previous meta-analyses have shown that aspirin use may reduce the risk of hepatocellular carcinoma (HCC). However, the optimal dose, frequency, and duration of aspirin use or the safety and efficacy of aspirin in target populations for HCC prevention remain unclear. The study aim was to investigate the efficacy and safety of aspirin for prevention of HCC.

Publications were retrieved by a comprehensive literature research of several databases. Based on a random-effects model, hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship between aspirin use and HCC risk was assessed with a restricted cubic spline model.

Twenty-two studies were included in the meta-analysis. Aspirin use was associated with a reduced risk of HCC (HR=0.64, 95% CI: 0.56–0.75). The effect was robust across sex and age; however, women and the non-elderly had the greatest benefit from aspirin use. The preventive effect was well reproduced in those with comorbidities. Daily use and long-term use of aspirin appeared to offer greater benefits. Aspirin 100 mg/d was associated with maximum reduction of HCC risk. Aspirin use did slightly increase the risk of bleeding (HR=1.14, 95% CI: 1.02–1.27).

Our meta-analysis confirmed that use of aspirin significantly reduced the incident risk of HCC. Regular and long-term aspirin use offers a greater advantage. Aspirin use was associated with an increased risk of bleeding. We recommend 100 mg/d aspirin as a feasible dose for further research on primary prevention of HCC in a broad at-risk population.

The concurrence of nonalcoholic steatohepatitis (NASH) and ulcerative colitis (UC) is increasingly seen in clinical practice, but the underlying mechanisms remain unclear. This study aimed to develop a mouse model of the phenomenon by combining high-fat high-cholesterol diet (HFHCD)-induced NASH and dextran sulfate sodium (DSS)-induced UC, that would support mechanistic studies.

Male C57BL/6 mice were randomly assigned to two groups receiving either a chow diet or HFHCD for 12 weeks of NASH modeling. The mice were the divided into four subgroups for UC modeling: (1) A control group given a chow diet with normal drinking water; (2) A colitis group given chow diet with 2% DSS in drinking water; (3) A steatohepatitis group given HFHCD with normal drinking water; and (4) A steatohepatitis + colitis group given HFHCD with 2% DSS in drinking water.

NASH plus UC had high mortality (58.3%). Neither NASH nor UC alone were fatal. Although DSS-induced colitis did not exacerbate histological liver injury in HFHCD-fed mice, premorbid NASH significantly increased UC-related gut injury compared with UC alone. It was characterized by a significantly shorter colon, more colonic congestion, and a higher histopathological score (p<0.05). Inflammatory (tumor necrosis factor-alpha, interleukin 1 beta, C-C motif chemokine ligand 2, and nuclear factor kappa B) and apoptotic (Bcl2, Bad, Bim, and Bax) signaling pathways were significantly altered in distal colon tissues collected from mice with steatohepatitis + colitis compared with the other experimental groups.

Premorbid steatohepatitis significantly aggravated DSS-induced colitis and brought about a lethal phenotype. Potential links between NASH and UC pathogeneses can be investigated using this model.

Patients with severe fever with thrombocytopenia syndrome (SFTS) commonly show liver function impairment. This study aimed to characterize the liver function indices in SFTS patients and investigate their association with mortality.

Clinical information and laboratory results of 459 laboratory-confirmed SFTS patients, including 78 deceased and 381 surviving patients, were retrospectively analyzed. To explore the infectivity of SFTS caused by novel Bunyavirus (SFTSV) in hepatocytes, Huh7 human hepatoma cells were infected with various concentrations of SFTSV in vitro.

The proportion of SFTS patients developing liver injury during hospitalization was 73.2% (336/459); the hepatocellular injury was the predominant type. The median time to occurrence of liver injury from disease onset was 8 d. Liver injury in the deceased group occurred earlier than that in the surviving group. Alanine aminotransferase (ALT) level between 2–5 times upper limit of normal (ULN) at 4–6 d and between 5–15 ULN at 7–12 d of disease course were independent predictors of mortality. Alkaline phosphatase (ALP) >2 ULN at 7–9 d and elevated ALP at 10–12 days after disease onset were risk factors for death. ALT and aspartate transaminase (AST) levels were correlated with lymphocyte count and platelet-to-lymphocyte ratio (PLR). Total bilirubin (TB), ALT, AST levels showed positive correlation with viral load. In the in vitro experiment, SFTSV infected and replicated inside Huh7 cells.

Liver injury is common in SFTS patients. ALT and ALP were independent predictors of SFTS-related mortality. Frequent monitoring and evaluation of liver function indices are needed for SFTS patients.

Acute-on-chronic liver failure (ACLF) is associated with very high mortality. Accurate prediction of prognosis is critical in navigating optimal treatment decisions to improve patient survival. This study was aimed to develop a new nomogram integrating two-dimensional shear wave elastography (2D-SWE) values with other independent prognostic factors to improve the precision of predicting ACLF patient outcomes.

A total of 449 consecutive patients with ACLF were recruited and randomly allocated to a training cohort (n=315) or a test cohort (n=134). 2D-SWE values, conventional ultrasound features, laboratory tests, and other clinical characteristics were included in univariate and multivariate analysis. Factors with prognostic value were then used to construct a novel prognostic nomogram. Receiver operating curves (ROCs) were generated to evaluate and compare the performance of the novel and published models including the Model for End-Stage Liver Disease (MELD), MELD combined with sodium (MELD-Na), and Jin’s model. The model was validated in a prospective cohort (n=102).

A ACLF prognostic nomogram was developed with independent prognostic factors, including 2D-SWE, age, total bilirubin (TB), neutrophils (Neu), and the international normalized ratio (INR). The area under the ROC curve (AUC) was 0.849 for the new model in the training cohort and 0.861 in the prospective validation cohort, which were significantly greater than those for MELD (0.758), MELD-Na (0.750), and Jin’s model (0.777, all p <0.05). Calibration curve analysis revealed good agreement between the predicted and observed probabilities. The new nomogram had superior overall net benefit and clinical utility.

We established and validated a 2D-SWE-based noninvasive nomogram to predict the prognosis of ACLF patients that was more accurate than other prognostic models.

Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.

Plantar heel pain (PHP) is a common musculoskeletal disorder that is effectively treated with extracorporeal shockwave therapy (ESWT) and exercise. This review aimed to evaluate the effectiveness of combined ESWT and exercise versus other interventions in treating PHP. A systematic review of effectiveness was conducted, adhering to the PRISMA guidelines. Five databases were searched for studies published between January 2000 and September 2021 with 12 studies (n = 861) meeting the inclusion criteria, which compared ESWT and stretching to various other treatments. High-quality evidence indicates that combined ESWT and stretching interventions are more effective than their individual use or botulinum toxin injections, and low-quality evidence of superiority versus ultrasound and stretching. There was moderate quality evidence that combined ESWT and stretching is no more effective than corticosteroid injection, and high-quality evidence that the combination is no more effective than blood-derived injection therapies, custom orthotics, or low-level laser therapy combined with stretching. There is high-quality evidence that topical corticosteroid or laser therapy in combination with ESWT and stretching increases its effectiveness and moderate-quality evidence for the additive effectiveness of dry needling. Overall, combined ESWT and stretching treatments are effective and may be recommended where they are available and practical to implement. Further high-quality studies comparing combined interventions for PHP, including different exercise activities like resistance training, are required. PROSPERO registration number: CRD42020213286

Metabolic-associated fatty liver disease (MAFLD) is a newly proposed terminology from 2020; yet, the applicability of conventional noninvasive fibrosis models is still unknown for it. We aimed to evaluate the performance of conventional noninvasive fibrosis scores in MAFLD.

The NHANES 2017-2018 datasets were used to compare the performances of different noninvasive fibrosis scores in MAFLD, including the aspartate aminotransferase (AST) to platelet ratio index (APRI), body mass index (BMI)-AST/alanine aminotransferase (ALT) ratio and diabetes score (BARD), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS). Moreover, Asian patients with biopsy-proven MAFLD were enrolled to further validate the findings.

A total of 2,622 participants in the National Health and Nutrition Examination Survey (NHANES) cohort and 293 patients with MAFLD in the Asian cohort were included. Patients in the Asian cohort had a lower BMI and higher liver enzymes (p<0.001). The area under the receiver operating characteristic curve (AUROC) of NFS was the largest in the NHANES cohort and Asian cohorts (0.679 and 0.699, respectively). The AUROC of NFS was followed by APRI, FIB-4, and BARD in the NHANES cohort (0.616, 0.601, and 0.589, respectively). In the Asian cohort, the AUROC of APRI, FIB-4, and BARD for predicting advanced fibrosis were 0.625, 0.683, and 0.615, respectively. The performance of FIB-4 was better in the Asian cohort than that in the NHANES cohort.

NFS is better for predicting advanced fibrosis in MAFLD. FIB-4 can be an alternative choice for MAFLD with high liver enzymes when NFS is unavailable. Novel efficient noninvasive fibrosis scoring systems are highly required for patients with MAFLD.

PTEN-induced putative kinase 1 (PINK1) is a mitochondrial kinase that regulates mitophagy. PINK1-deficient mAPP mice display low LC3B levels, and PINK1 overexpression enhances autophagy and increases the expression level of lysosome-associated membrane protein 1 (LAMP1). The present study evaluated whether altered PINK1 expression could modulate β-amyloid (Aβ)-treated mitophagy in PC12 cells, a simple cellular model to simulate pathological changes in neurodegenerative diseases in vitro.

PC12 cells were transfected with PINK1 siRNA for 48 h, and then incubated with 20 µM Aβ25–35 for 24 h. The relevant protein expression was determined by immunofluorescence, immunoelectron microscopy, and Western blot. Mitochondrial membrane potential (MMP) was tested by JC-1-based confocal fluorescent imaging.

Following Aβ25–35 treatment, PINK1 silencing significantly decreased the levels of LC3B, Parkin, and LAMP1 as well as Parkin in mitochondria, p62 degradation, but increased OPTN and Parkin expression in PC12 cells, relative to that of the control PC12 cells. Furthermore, PINK1 silencing decreased MMP in PC12 cells.

PINK1 deficiency deteriorated the blockade of the Aβ25–35-induced mitophagy-lysosome pathway in PC12 cells. Aβ-treated PC12 cells might be a valuable cellular model to evaluate PINK1-mediated mitophagy and bioactive compound screening.

Sphincter of Oddi dysfunction (SOD) encompasses a spectrum of clinical syndromes that are not fully understood, and various diagnostic and therapeutic methods have had varying results depending on the type of dysfunction. This review explored various mechanisms that might play a role in SOD and methods of diagnosis and management. It is important to rule out other causes of abdominal pain with laboratory testing, imaging studies, and endoscopic procedures. Medications that affect sphincter motility should be identified as well. Manometry is the gold standard for diagnosis but it is not always required. For example, patients with type I SOD may have symptomatic improvement with sphincterotomy without need for a diagnostic manometry. Hepatobiliary scintigraphy and fatty meal sonography may also have diagnostic utility. Sphincterotomy is not always effective for symptomatic improvement in type II and III SOD. Alternate therapies with calcium channel blockers and botulinum toxin have been studied and might be considered as options after discussing the risks and benefits with the patients.

Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.

Hepatic arterioportal fistulas (HAPFs) are abnormal shunts or aberrant functional connections between the portal venous and the hepatic arterial systems. Detection of HAPFs has increased with the advances in diagnostic techniques. Presence of HAPFs over a prolonged period can aggravate liver cirrhosis and further deteriorate liver function. However, the underlying causes of HAPFs and the treatment outcomes are now well characterized. This study aimed to summarize the clinical characteristics of patients with HAPFs, and to compare the outcomes of different treatment modalities.

Data of 97 patients with HAPFs who were admitted to the Second Xiangya Hospital between January 2010 and January 2020 were retrospectively reviewed. Demographic information, clinical manifestations, underlying causes, treatment options, and short-term outcomes were analyzed.

The main cause of HAPF in our cohort was hepatocellular carcinoma (78/97, 80.41%), followed by cirrhosis (10/97, 10.31%). The main clinical manifestations were abdominal distention and abdominal pain. Treatment methods included transcatheter arterial embolization (n=63, 64.9%), surgery (n=13, 13.4%), and liver transplantation (n=2, 2.1%); nineteen (19.6%) patients received conservative treatment. Among patients who underwent transcatheter arterial embolization, polyvinyl alcohol, lipiodol combined with gelatin sponge, and spring steel ring showed comparable efficacy.

Hepatocellular carcinoma and cirrhosis are common causes of HAPFs. Transcatheter arterial embolization is a safe and effective method for the treatment of HAPFs, and polyvinyl alcohol, lipiodol combined with gelatin sponge, and spring steel ring showed comparable efficacy in our cohort.

1,5-Anhydroglucitol (1,5AG) activity has been reported in chronic liver disease. Hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) patients have a high mortality. We aimed to discover the relationship between serum 1,5AG and the prognosis of HBV-ACLF.

Serum 1,5AG levels were determined in 333 patients with HBV-ACLF, 300 without diabetes were allocated to derivation (n=206) and validation cohorts (n=94), and 33 were recruited to evaluate 1,5AG in those with diabetes. Forty patients with chronic hepatitis B, 40 with liver cirrhosis, and 40 healthy people were controls in the validation cohort.

In the derivation and validation cohorts, serum 1,5AG levels were significantly lower in nonsurvivors than in survivors. The AUC of 1,5AG for 28-day mortality was 0.811. In patients with diabetes, serum 1,5AG levels were also significantly lower in nonsurvivors than in survivors. In multivariate Cox regression analysis, serum 1,5AG levels were independently associated with 28-day mortality. A novel predictive model (ACTIG) based on 1,5AG, age, TB, cholesterol, and INR was derived to predict mortality. In ACTIG, the AUC for 28-day mortality was 0.914, which was superior to some prognostic score models. ACTIG was also comparable to those prognostic score models in predicting 6-month mortality. In mice with D-galactosamine/lipopolysaccharide-induced liver failure, 1,5AG levels were significantly reduced in serum and significantly increased in urine and liver tissue.

Serum 1,5AG levels are a promising predictor of short-term mortality in HBV-ACLF patients. The 1,5AG distribution changed in mice with D-galactosamine/ lipopolysaccharide-induced liver failure.

TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression profile, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC).

Bioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments.

The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC.

Upregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

Visceral obesity is a risk factor for nonalcoholic fatty liver disease (NAFLD). We investigated sex-specific optimal cutoff values for visceral fat area (VFA) associated with lean and overweight/obese NAFLD in an Asian population.

This retrospective study included 678 potential living liver donors (mean age, 30.8±9.4 years; 434 men and 244 women) who had undergone abdominal computed tomography (CT) imaging and liver biopsy between November 2016 and October 2017. VFA was measured using single-slice abdominal CT. NAFLD was evaluated by liver biopsy (≥5% hepatic steatosis). Receiver operating characteristic curve analysis was used to determine cutoff values for VFA associated with lean (body mass index [BMI] <23 kg/m2) and overweight/obese (BMI ≥23 kg/m2) NAFLD.

Area under the curve (AUC) values with 95% confidence intervals (CI) for VFA were 0.82 (95% CI, 0.75–0.88) for lean and 0.74 (95% CI, 0.69–0.79) for overweight/obese men with NAFLD. The AUC values were 0.67 (95% CI, 0.58–0.75) for lean and 0.71 (95% CI, 0.62–0.80) for overweight/obese women with NAFLD. The cutoff values for VFA associated with lean NAFLD were 50.2 cm2 in men and 40.5 cm2 in women. The optimal cutoff values for VFA associated with overweight/obese NAFLD were 100.6 cm2 in men and 68.0 cm2 in women.

Sex-specific cutoff values for VFA may be useful for identifying subjects at risk of lean and overweight/obese NAFLD.

Omics data address key issues in liver transplantation (LT) as the most effective therapeutic means for end-stage liver disease. The purpose of this study was to review the current application and future direction for omics in LT. We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication. Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics. Significant molecules were identified and summarized based on omics, with a focus on post-transplant liver fibrosis, early allograft dysfunction, tumor recurrence, and graft failure. We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established. We also outlined the ideal workflow for omics in LT. In step with advances in technology, the quality of omics data can be guaranteed using an improved algorithm at a lower price. Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.

Acute liver failure (ALF) is a potentially fatal clinical syndrome with no effective treatment. This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in modulating the phenotype and immune function of endotoxin-tolerant dendritic cells (ETDCs). In addition, we explored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms.

In the in vitro experiment, ETDCs were transfected with adenovirus to induce SOCS1+/+ETDCs and SOCS1−/−ETDCs. Thereafter, costimulatory molecules and mixed lymphocyte reaction were assessed. Experimental mice were randomly divided into normal control, ALF, ALF+mock-ETDCs, ALF+SOCS1+/+ETDCs, ALF+AG490, and ALF+AG490+SOCS1+/+ETDCs groups. We examined the therapeutic effect of adoptive cellular immunotherapy by tail-vein injection of target ETDCs 12 h before ALF modeling. AG490, a JAK2/STAT3 inhibitor, was used in the in vivo experiment to further explore the protective mechanism of SOCS1+/+ETDCs.

Compared with control ETDCs, SOCS1+/+ETDCs had lower expression of costimulatory molecules, weaker allostimulatory ability, lower levels of IL-6 and TNF-α expression and higher IL-10 secretion. SOCS1−/−ETDCs showed the opposite results. In the in vivo experiments, the ALF+SOCS1+/+ETDCs and ALF+AG490+SOCS1+/+ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway. The changes were more pronounced in the ALF+AG490+SOCS1+/+ETDCs group. Infusion of SOCS1+/+ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.

The SOCS1 gene had an important role in induction of endotoxin tolerance. SOCS1+/+ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.

Transarterial chemoembolization (TACE) is widely applied for the treatment of hepatocellular carcinoma. Repeat TACE is often required in clinical practice because a satisfactory tumor response may not be achieved with a single session. However, repeated TACE procedures can impair liver function and increase treatment-related adverse events, all of which prompted the introduction of the concept of “TACE failure/refractoriness”. Mainly based on evidence from two retrospective studies conducted in Japan, sorafenib is recommended as the first choice for subsequent treatment after TACE failure/refractoriness. Several studies have investigated the outcomes of other subsequent treatments, including locoregional, other molecular targeted, anti-programmed death-1/anti-programed death ligand-1 therapies, and combination therapies after TACE failure/refractoriness. In this review, we summarize the up-to-date information about the outcomes of several subsequent treatment modalities after TACE failure/refractoriness.

Hepatocellular carcinoma (HCC) is a common primary liver neoplasm with high mortality. Dermcidin (DCD), an antimicrobial peptide, has been reported to participate in oncogenesis. This study assessed the effects and underlying molecular events of DCD overexpression and knockdown on the regulation of HCC progression in vitro and in vivo.

The serum DCD level was detected using enzyme-linked immunosorbent assay. DCD overexpression, knockdown, and Ras-related C3 botulinum toxin substrate 1 (Rac1) rescue were performed in SK-HEP-1 cells using plasmids. Immunofluorescence staining, quantitative PCR, and Western blotting were used to detect the expression of different genes and proteins. Differences in HCC cell migration and invasion were detected by Transwell migration and invasion assays. A nude mouse HCC cell orthotopic model was employed to verify the in vitro data.

The level of serum DCD was higher in patients with HCC and in SK-HEP-1 cells. DCD overexpression caused upregulation of DCD, fibronectin, Rac1, and cell division control protein 42 homologue (Cdc42) mRNA and proteins as well as actin-related protein 2/3 (Arp2/3) protein (but reduced Arp2/3 mRNA levels) and activated Rac1 and Cdc42. Phenotypically, DCD overexpression induced HCC cell migration and invasion in vitro, whereas knockout of DCD expression had the opposite effects. A Rac1 rescue experiment in DCD-knockdown HCC cells increased HCC cell migration and invasion and increased the levels of active Rac1/total Rac1, Wiskott-Aldrich syndrome family protein (WASP), Arp2/3, and fibronectin. DCD overexpression induced HCC cell metastasis to the abdomen and liver in vivo.

DCD promotes HCC cell migration, invasion, and metastasis through upregulation of noncatalytic region of tyrosine kinase adaptor protein 1 (Nck1), Rac1, Cdc42, WASP, and Arp2/3, which induce actin cytoskeletal remodeling and fibronectin-mediated cell adhesion in HCC cells.