Moiré effect enables versatile design of topological defects in nematic liquid crystals.

Recent advances in surface-patterning techniques of liquid crystals have enabled the precise creation of topological defects, which promise a variety of emergent applications. However, the manipulation and application of these defects remain limited. Here, we harness the moiré effect to engineer topological defects in patterned nematic liquid crystal cells. Specifically, we combine simulation and experiment to examine a nematic cell confined between two substrates of periodic surface anchoring patterns; by rotating one surface against the other, we observe a rich variety of highly tunable, novel topological defects. These defects are shown to guide the three-dimensional self-assembly of colloids, which can conversely impact defects by preventing the self-annihilation of loop-defects through jamming. Finally, we demonstrate that certain nematic moiré cells can engender arbitrary shapes represented by defect regions. As such, the proposed simple twist method enables the design and tuning of mesoscopic structures in liquid crystals, facilitating applications including defect-directed self-assembly, material transport, micro-reactors, photonic devices, and anti-counterfeiting materials.

Glutamine synthetase and hepatocellular carcinoma.

Glutamine synthetase (GS) is an enzyme that converts ammonia and glutamate to glutamine using adenosine triphosphate. GS is expressed in the brain, kidney, and liver tissues under normal physiological conditions. GS is involved in abnormal lipid metabolism of the liver by catalyzing de novo synthesis of glutamine, thereby inducing liver inflammation. Metabolic dysfunction-associated steatotic liver diseases (MASLD), such as Metabolic Associated Fatty Liver Disease and Metabolic Associated Steato Hepatitis, are considered risk factors for HCC. GS may also be involved in the development and progression of hepatocellular carcinoma (HCC) through other signaling pathways, including the rapamycin (mTOR) and Wnt/ß-catenin signaling pathways. Furthermore, the correct combination of HSP70, GPC3, and GS can improve the accuracy and precision of HCC diagnosis. However, the prognostic value of GS in different HCC populations remains controversial. The expression of GS affects the sensitivity of HCC cells to radiotherapy and chemotherapy. In addition, immunotherapy has been approved for the treatment of advanced HCC. This article delves into the development and application of GS in HCC, laying a theoretical foundation for the subsequent exploration of GS as a potential target for treating HCC.

Influence of surgical margin width on survival rate after resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

OBJECTIVES: Hepatectomy is the best treatment for patients with intrahepatic cholangiocarcinoma (ICC) at present, but there has been controversy about the width of surgical margins. In this study, we systematically investigated the effects of different surgical margin widths on the prognosis of patients with ICC undergoing hepatectomy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and Web of Science databases were systematically searched from inception to June 2022. ELIGIBILITY CRITERIA: Cohort studies reported in English with patients who underwent negative marginal (R0) resection were included. The effects of surgical margin width on overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) in patients with ICC were assessed. DATA EXTRACTION AND SYNTHESIS: Two investigators independently conducted literature screening and data extraction. Risk of bias was assessed using funnel plots and quality was assessed by the Newcastle-Ottawa Scale. Forest plots of HRs and their 95% CIs for outcome indicators were plotted. Heterogeneity was assessed and determined quantitatively using I2, and the stability of the study results was evaluated using sensitivity analysis. Analyses were performed using Stata software. RESULTS: Nine studies were included. With the wide margin group (≥10 mm) as the control, pooled HR of OS in the narrow margin group (<10 mm) was 1.54 (95% CI 1.34 to 1.77). HRs of OS in three subgroups where the margin was less than 5 mm ranged from 5 mm to 9 mm, or was less than 10 mm in length were 1.88 (1.45 to 2.42), 1.33 (1.03 to 1.72) and 1.49 (1.20 to 1.84), respectively. Pooled HR of DFS in the narrow margin group (<10 mm) was 1.51 (1.14 to 2.00). Pooled HR of RFS in the narrow margin group (<10 mm) was 1.35 (1.19 to 1.54). HRs of RFS in three subgroups where the margin was less than 5 mm ranged from 5 mm to 9 mm, or was less than 10 mm in length were 1.38 (1.07 to 1.78), 1.39 (1.11 to 1.74) and 1.30 (1.06 to 1.60), respectively. Neither lymph node lesions (HR 1.44, 95% CI 1.22 to 1.70) nor lymph node invasion (2.14, 1.39 to 3.28) was favourable for postoperative OS in patients with ICC. Lymph node metastasis (1.31, 1.09 to 1.57) was unfavourable for RFS in patients with ICC. CONCLUSION: Patients with ICC who underwent curative hepatectomy with a negative margin ≥10 mm may have a long-term survival advantage, but lymph node dissection also needs to be considered. In addition, tumour-related pathological features need to be explored to see if they affect the surgical outcome of R0 margins.

Collective transport and reconfigurable assembly of nematic colloids by light-driven cooperative molecular reorientations.

Nanomotors in nature have inspired scientists to design synthetic molecular motors to drive the motion of microscale objects by cooperative action. Light-driven molecular motors have been synthesized, but using their cooperative reorganization to control the collective transport of colloids and to realize the reconfiguration of colloidal assembly remains a challenge. In this work, topological vortices are imprinted in the monolayers of azobenzene molecules which further interface with nematic liquid crystals (LCs). The light-driven cooperative reorientations of the azobenzene molecules induce the collective motion of LC molecules and thus the spatiotemporal evolutions of the nematic disclination networks which are defined by the controlled patterns of vortices. Continuum simulations provide physical insight into the morphology change of the disclination networks. When microcolloids are dispersed in the LC medium, the colloidal assembly is not only transported and reconfigured by the collective change of the disclination lines but also controlled by the elastic energy landscape defined by the predesigned orientational patterns. The collective transport and reconfiguration of colloidal assemblies can also be programmed by manipulating the irradiated polarization. This work opens opportunities to design programmable colloidal machines and smart composite materials.

TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis.

The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.

Self-compassion buffers the impact of learned helplessness on adverse mental health during COVID-19 lockdown.

BACKGROUND: Learned helplessness may be the underlying cause of poor mental health status among college students during the COVID-19 lockdown, and self-compassion as a positive psychological quality may influence the link between learned helplessness and mental health. METHODS: A sample of 869 Chinese college students (443 male and 426 female), with a mean age of 20.03 (SD = 1.68), completed the Learned Helplessness Scale (LHS), Self-Compassion Scale (SCS), and DASS-21. The moderating effect of self-compassion on the relationship between learned helplessness and anxiety, depression, and stress were calculated. RESULTS: The interaction term between learned helplessness and self-compassion has a significant coefficient on anxiety, depression, and stress, pointing out self-compassion as a moderator of the association between learned helplessness and adverse mental health. LIMITATIONS: In the absence of longitudinal data or experimental manipulations, cross-sectional methods cannot verify causal conclusions among the study variables. The analysing results are based only on self-reported data. DISCUSSION: The present study contributes to a deeper understanding of how learned helplessness and self-compassion during COVID-19 contribute to adverse mental health. The findings suggest that adverse mental health during lockdown is significantly associated with learned helplessness and that self-compassion can buffer this effect, contributing to future psychotherapy and clinical research. Future studies should examine the relationship through a longitudinal design to sort out whether self-compassion is a protective factor against learned helplessness or a moderator of the effects of learned helplessness on mental health.

Shape Morphing by Topological Patterns and Profiles in Laser-Cut Liquid Crystal Elastomer Kirigami.

Programming shape changes in soft materials requires precise control of the directionality and magnitude of their mechanical response. Among ordered soft materials, liquid crystal elastomers (LCEs) exhibit remarkable and programmable shape shifting when their molecular order changes. In this work, we synthesized, remotely programmed, and modeled reversible and complex morphing in monolithic LCE kirigami encoded with predesigned topological patterns in its microstructure. We obtained a rich variety of out-of-plane shape transformations, including auxetic structures and undulating morphologies, by combining different topological microstructures and kirigami geometries. The spatiotemporal shape-shifting behaviors are well recapitulated by elastodynamics simulations, revealing that the complex shape changes arise from integrating the custom-cut geometry with local director profiles defined by topological defects inscribed in the material. Different functionalities, such as a bioinspired fluttering butterfly, a flower bud, dual-rotation light mills, and dual-mode locomotion, are further realized. Our proposed LCE kirigami with topological patterns opens opportunities for the future development of multifunctional devices for soft robotics, flexible electronics, and biomedicine.

AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.

BACKGROUND AND AIMS: Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. APPROACH AND RESULTS: Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. CONCLUSIONS: Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.

Targeted blocking of CCR2 and CXCR2 improves the efficacy of transarterial chemoembolization of hepatocarcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) has been shown to prolong survival in patients with unresectable hepatocellular carcinoma (HCC); however, the long-term survival remains dismal. Targeting macrophage and neutrophil infiltration is a promising strategy. The CCL2/CCR2 and CXCLs/CXCR2 axes are required for recruitment of macrophages and neutrophils, respectively, in HCC. We investigated the feasibility of CCL2/CCR2 and CXCLs/CXCR2 as therapeutic targets in combination with TACE for treating HCC. METHODS: Expression of CCL2/CCR2 and CXCLs/CXCR2 was analyzed in the primary rat HCC model and one HCC cohort. The relationship between expression levels, neutrophil and macrophage infiltration, hepatocarcinogenesis progression in the rat model, and survival of HCC patients was assessed. The anti-tumor effects of blocking the CCL2/CCR2 and CXCLs/CXCR2 axes by CCR2 and CXCR2 antagonists in combination with TACE were evaluated in HCC rats. The numbers of macrophages, neutrophils, and hepatic progenitor cells were further determined to explore the underlying mechanisms. RESULTS: High macrophage and neutrophil infiltration and CXCL8 expression were associated with poor prognosis in the TCGA liver cancer dataset. High expression of CCL2/CCR2 and CXCL8/CXCR2 in clinical HCC specimens was associated with reduced survival. Expression of CCL2/CCR2 and CXCL1/CXCR2 was correlated with hepatocarcinogenesis progression in the primary rat HCC model. Blockade of CCL2/CCR2 and CXCLs/CXCR2 enhanced the anti-tumor effect of TACE treatment in this model. Blocking the CCL2/CCR2 and CXCLs/CXCR2 axes with CCR2 and CXCR2 antagonists in TACE-treated rats reduced macrophage and neutrophil infiltration and hepatic progenitor cell activation and thus overcame TACE resistance in HCC. CONCLUSIONS: The results demonstrate the translational potential of immunotherapy targeting the CCL2/CCR2 and CXCLs/CXCR2 axes in combination with TACE therapy for the treatment of HCC.

miR-671-5p Promotes Cell Proliferation, Invasion, and Migration in Hepatocellular Carcinoma through Targeting ALDH2.

We explored the mechanism of acetaldehyde dehydrogenase 2 (ALDH2) in modulating cell behaviors in hepatocellular carcinoma (HCC), and provided fresh ideas for targeted treatment of HCC. The target messenger RNA (mRNA) was determined by The Cancer Genome Atlas (TCGA) analysis, and the upstream regulatory gene miRNA was obtained by further analysis. The expression of ALDH2 mRNA and miR-671-5p in HCC cell lines was assayed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and protein expression was assessed by Western blot. The impact of ALDH2 on biological functions of HCC cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing, and Transwell assays. Bioinformatics method was utilized to predict binding site of miR-671-5p and ALDH2, and their targeted relationship was detected by dual-luciferase gene assay, qRT-PCR and Western blot. ALDH2 expression was reduced in HCC tissue and cell lines. ALDH2 worked as a tumor inhibitor in HCC. Overexpressing ALDH2 could hinder proliferation, migration and invasion of HCC cells. miR-671-5p was the upstream regulatory gene of ALDH2, and it presented remarkably high expression in HCC. A negative modulatory relationship existed between miR-671-5p and ALDH2. The rescue experiments further illustrated the effects of the two on the malignant behaviors of HCC cells. Forced expression of miR-671-5p fostered the proliferation, migration and invasion of HCC cells by restraining ALDH2.

Ultrasound elastography in the diagnosis of biliary atresia in pediatric surgery: a systematic review and meta-analysis of diagnostic test.

Background: Biliary atresia (BA) is one of the most fatal hepatobiliary diseases in infants and young children, and is easy to cause obstructive jaundice in infants and children, and liver transplantation in children. BA and infantile hepatitis syndrome are the main causes of cholestatic jaundice. The early clinical manifestations are extremely similar, and timely identification is difficult. Therefore, early and differential diagnosis of BA is crucial. At present, there are many imaging diagnosis methods for BA, such as ultrasound examination and nuclear magnetic resonance. Ultrasound elastography (USE) is the most popular method. However, the application of USE in BA is still in the exploratory stage. Methods: PubMed, Web of Science, Embase, Cochrane Library, and other databases were searched for articles on USE diagnosis of pediatric surgical BA. Later, the articles were screened, and the included articles should meet the following requirements: the research objects were children with BA; the intervention measures were USE diagnosis; the control group was diagnosed by other methods than USE. RevMan5.3 was adopted for quality assessment, and forest maps and summary receiver operating characteristic (SROC) curves were constructed. Results: Finally, seven articles covering 490 patients were included. There were 120 patients in the control group. The included articles showed good quality and there was no obvious bias. The area under the SROC curve (AUC) for USE diagnosis of BA was 0.93, the sensitivity was 0.93 (95% CI: 0.72-1.00), and the specificity was 0.95 (95% CI: 0.74-1.00). Discussion: USE showed high diagnostic value for pediatric surgical biliary tract closure.

Active transformations of topological structures in light-driven nematic disclination networks.

SignificanceTopological defects are marvels of nature. Understanding their structures is important for their applications in, for example, directed self-assembly, sensing, and photonic devices. There is recent interest in active motion and transformation of topological defects in active nematics. In these nonequilibrium systems, however, the motion and transformation of disclinations are difficult to control, thereby hindering their applications. Here, we propose a surface-patterned system engendering periodic three-dimensional disclinations, which can be excited by light irradiation and undergo a programmable transformation between different topological states. Continuum simulations recapitulating these topological structures characterize the bending, breaking, and relinking events of the disclinations during the nonequilibrium process. Our work provides an alternative dynamic system in which active transformation of topological defects can be engineered.

Single cell transcriptional diversity and intercellular crosstalk of human liver cancer.

Liver cancer arises from the evolutionary selection of the dynamic tumor microenvironment (TME), in which the tumor cell generally becomes more heterogeneous; however, the mechanisms of TME-mediated transcriptional diversity of liver cancer remain unclear. Here, we assess transcriptional diversity in 15 liver cancer patients by single-cell transcriptome analysis and observe transcriptional diversity of tumor cells is associated with stemness in liver cancer patients. Tumor-associated fibroblast (TAF), as a potential driving force behind the heterogeneity in tumor cells within and between tumors, was predicted to interact with high heterogeneous tumor cells via COL1A1-ITGA2. Moreover, COL1A1-mediated YAP-signaling activation might be the mechanistic link between TAF and tumor cells with increased transcriptional diversity. Strikingly, the levels of COL1A1, ITGA2, and YAP are associated with morphological heterogeneity and poor overall survival of liver cancer patients. Beyond providing a potential mechanistic link between the TME and heterogeneous tumor cells, this study establishes that collagen-stimulated YAP activation is associates with transcriptional diversity in tumor cells by upregulating stemness, providing a theoretical basis for individualized treatment targets.

Nematic Templated Complex Nanofiber Structures by Projection Display.

Oriented arrays of nanofibers are ubiquitous in nature and have been widely used in recreation of the biological functions such as bone and muscle tissue regenerations. However, it remains a challenge to produce nanofiber arrays with a complex organization by using current fabrication techniques such as electrospinning and extrusion. In this work, we propose a method to fabricate the complex organization of nanofiber structures templated by a spatially varying ordered liquid crystal host, which follows the pattern produced by a maskless projection display system. By programming the synchronization of the rotated polarizer and projected segments with different shapes, various configurations of nanofiber organization ranging from a single to two-dimensional lattice of arbitrary topological defects are created in a deterministic manner. The nanofiber arrays can effectively guide and promote neurite outgrowth. The application of nanofibers with arced profiles and topological defects on neural tissue organization is also demonstrated. This finding, combined with the versatility and programmability of nanofiber structures, suggests that they will help solve challenges in nerve repair, neural regeneration, and other related tissue engineering fields.

Clinicopathological characteristics and prognosis of gastrointestinal stromal tumors containing air-fluid levels.

An air-fluid level within a gastrointestinal stromal tumor (GIST) is unusual and indicates the presence of a fistula within the lumen of the GI tract. Until recently, the optimal management of such patients was not clear-cut. This retrospective study investigated the clinicopathological characteristics, surgical procedures, pre-and post-operative management, and prognosis of patients with GIST containing an air-fluid level. Data of GIST patients, spanning 5 years, including 17 GIST patients with air-fluid levels in the experimental group and 34 GIST patients without air-fluid levels in the control group, were retrieved from two hospitals in China. The clinicopathological characteristics, types of surgery, management, and clinical outcomes of GIST patients were compared between the two groups. GISTs containing air-fluid levels were significantly different from GISTs without air-fluid levels regarding tumor morphology, NIH risk category, invasion of adjacent organs, and necrosis or ulceration. Most GIST patients with air-fluid levels (14/17, 82.4%) received open surgery, significantly higher than the 20.6% in the control group. Targeted therapy with Imatinib mesylate (IM) was implemented in all GIST patients in the experimental group (17/17, 100%); markedly higher than those (3/34, 8.8%) in the control group. During follow-up, recurrence and death rates (5.9% and 5.9%) in the experimental group were higher than those (2.9% and 0%) in the control group. Open surgery is commonly performed in GIST patients with air-fluid levels who also require targeted therapy with IM. The Torricelli-Bernoulli sign could be a risk factor, adversely affecting the patient's prognosis.

Light-Actuated Liquid Crystal Elastomer Prepared by Projection Display.

Soft materials with programmability have been widely used in drug delivery, tissue engineering, artificial muscles, biosensors, and related biomedical engineering applications. Liquid crystal elastomers (LCEs) can easily morph into three-dimensional (3D) shapes by external stimuli such as light, heat, and humidity. In order to program two-dimensional (2D) LCE sheets into desired 3D morphologies, it is critical to precisely control the molecular orientations in LCE. In this work, we propose a simple photopatterning method based on a maskless projection display system to create spatially varying molecular orientations in LCE films. By designing different synchronized rotations of the polarizer and projected images, diverse configurations ranging from individual to 2D lattice of topological defects are fabricated. The proposed technique significantly simplified the photopatterning procedure without using fabricated masks or waveplates. Shape transformations such as a cone and a truncated square pyramid, and functionality mimicking the responsive Mimosa Pudica are demonstrated in the fabricated LCE films. The programmable LCE morphing behaviors demonstrated in this work will open opportunities in soft robotics and smart functional devices.

TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy.

To date, immune checkpoint inhibitors have been successively approved and widely used in clinical cancer treatments, however, the overall response rates are very low and almost all cancer patients eventually progressed to drug resistance, this is mainly due to the intricate tumor microenvironment and immune escape mechanisms of cancer cells. One of the main key mechanisms leading to the evasion of immune attack is the presence of the immunosuppressive microenvironment within tumors. Recently, several studies illustrated that triggering receptor expressed on myeloid cells-2 (TREM2), a transmembrane receptor of the immunoglobulin superfamily, was a crucial pathology-induced immune signaling hub, and it played a vital negative role in antitumor immunity, such as inhibiting the proliferation of T cells. Here, we reviewed the recent advances in the study of TREM2, especially focused on its regulation of tumor-related immune signaling pathways and its role as a novel target in cancer immunotherapy.

The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation.

BACKGROUND: The liver possesses a powerful regeneration ability, which is correlated with the stemness of hepatocytes in the portal vein (PV). However, the mechanism underlying the maintenance of hepatocyte stemness has not been elucidated. Here, we hypothesized that high levels of lipopolysaccharide from the portal vein might maintain the stemness of hepatocytes in the PV area. METHODS: First, we examined the location of hepatic stem cells and the concentration of lipopolysaccharide (LPS) in the portal vein and inferior vena cava. Then, we assessed the effect of LPS on stemness maintenance in mice by using antibiotics to eliminate LPS and knocking out the LPS receptor, TLR4. In vitro, the effect of LPS on the stemness of hepatocytes was investigated by colony and sphere formation assays and assessment of pluripotent and stem cell marker expression. Furthermore, we studied the mechanism by which LPS regulates the stemness of hepatocytes. Finally, we ligated the portal vein branch to further verify the effect of LPS. RESULTS: We found that a high level of LPS from the portal vein was correlated with the location of hepatic stem cells in the PV area, and elimination of LPS by antibiotics inhibited the expression of the stemness marker. LPS promoted colony and sphere formation and induced the upregulation of pluripotent and stem cell markers in AML12 cells. Furthermore, in the reprogramming medium, LPS facilitated the dedifferentiation of mature hepatocytes into hepatic progenitor-like cells, which exhibited a bipotent differentiation capacity in vivo and in vitro. Mechanistically, LPS bound TLR4 to regulate stemness of hepatocytes via the activation of YAP1 signaling, and blockade of YAP1 abolished the LPS-induced cell stemness and upregulation of pluripotent markers. CONCLUSIONS: Our study implies a correlation between LPS/TLR4/YAP1 signaling and cell stemness, and LPS was shown to be involved in stemness maintenance of hepatocytes in the PV area. LPS might be used to induce the dedifferentiation of mature hepatocytes into progenitor-like cells for repair of liver injury.

Oncostatin M promotes hepatic progenitor cell activation and hepatocarcinogenesis via macrophage-derived tumor necrosis factor-α.

Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68+ macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis.