The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma.

ABSTRACT: In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

Pooled and global burdens and trends of five common cancers attributable to diet in 204 countries and territories from 1990 to 2019: an analysis of the Global Burden of Disease Study.

OBJECTIVE: Increasing evidence has shown that dietary behaviors are closely correlated with the carcinogenesis and progression of many types of cancer. However, few studies have assessed the global diet-related burden of cancer. This study aimed to estimate the pooled burdens and trends of five types of cancers attributable to dietary behaviors. METHODS: Data regarding cancer attributable to dietary behaviors were extracted from the Global Burden of Disease study 2019, including the death cases and age-standardized death rates, and disability-adjusted life years (DALYs) estimated according to diseases, age, sex, the socio-demographic index (SDI) and location. RESULTS: According to the Global Burden of Disease study 2019, five types of cancer were affected by dietary behaviors: colon and rectum cancer; tracheal, bronchus and lung cancer; stomach cancer; esophageal cancer and breast cancer. Unhealthy dietary behaviors for cancer caused a total of 605.4 thousand deaths and 13951.3 thousand DALYs globally. The burden of cancer attributable to dietary risks was higher for men than for women. The highest age-standardized death rates in 2019 were observed in southern Latin America, and the lowest rates were observed in North Africa and the Middle East. The greatest increases in the age-standardized death rates, from 1990 to 2019, were found in Western Sub-Saharan Africa, with the greatest decreases in Central Asia. The highest attributable proportions of death or DALYs were colon and rectum cancer. The greatest diet-related cancer burden was observed in regions with a high-middle SDI. CONCLUSION: Global age-standardized deaths and DALYs rates attributable to diet-related cancer are considerable and cause a substantial burden. Successful population-wide initiatives targeting unhealthy dietary behaviors would reduce this burden.

Various interventions for cancer-related fatigue in patients with breast cancer: a systematic review and network meta-analysis.

Purpose: To investigate the effects of various intervention approaches on cancer-related fatigue (CRF) in patients with breast cancer. Method: Computer searches were conducted on PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases from their establishment to June 2023. Selection was made using inclusion and exclusion criteria, and 77 articles were included to compare the effects of 12 interventions on patients with breast cancer. Results: Seventy-seven studies with 12 various interventions were examined. The network findings indicated that cognitive behavioral therapy (CBT) (SMD, -1.56; 95%CI, -3.08~-0.04), Chinese traditional exercises (CTE) (SMD, -0.85; 95%CI, -1.34~-0.36), aerobic exercise (AE) (SMD, -0.77; 95%CI, -1.09~-0.45), multimodal exercise (ME) (SMD, -0.75; 95%CI, -1.26~-0.25), music interventions (MI) (SMD, -0.74; 95%CI, -1.45~-0.03), and yoga (YG) (SMD, -0.44; 95%CI, -0.83 to -0.06) can reduce CRF more than the control group (CG). For relaxation exercises (RE) (MD, -6.69; 95%CI, -9.81~-3.57), MI (MD, -5.45; 95%CI, -7.98~-2.92), AE (MD, -4.34; 95%CI, -5.90~-2.78), ME (MD, -3.47; 95%CI, -4.95~-1.99), YG (MD, -2.07; 95%CI, -3.56~-0.57), and mindfulness training (MD, -1.68; 95%CI, -2.91~-0.46), PSQI improvement was superior to CG. In addition, for CTE (MD, 11.39; 95%CI, 4.11-18.66), YG (MD, 11.28; 95%CI, 1.63-20.93), and AE (MD, 9.34; 95%CI, 0.26~18.42), Functional Assessment of Cancer Therapy-Breast improvement was superior to CG. Conclusion: Cognitive behavioral therapy (CBT) is the most effective measure for alleviating CRF in patients with breast cancer and Relaxation exercises (RE) is the most effective measure for improving sleep quality. In addition, Chinese traditional exercises (CTE) is the best measure for enhancing quality of life. Additional randomized controlled trials (RCTs) are expected to further investigate the efficacy and mechanisms of these interventions. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023471574.

SOX on tumors, a comfort or a constraint?

The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes the physiological function of the SOX family and their multiple roles in tumors, with a focus on the relationship between the SOX family and TIME, aiming to propose their potential role in cancer and promising methods for treatment.

Transcription factor BACH1 in cancer: roles, mechanisms, and prospects for targeted therapy.

Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic.

Effect of yoga on cancer-related fatigue in patients with breast cancer: A systematic review and meta-analysis.

BACKGROUND: Breast cancer is a common malignant tumor in women and most patients with breast cancer experience fatigue. Numerous studies have investigated the relationship between yoga and cancer-related fatigue (CRF) in patients with breast cancer. However, these studies drew their conclusions from small sample sizes and lacked sufficient evidence to demonstrate that yoga can effectively alleviate CRF. Therefore, this meta-analysis aims to systematically examine the effects of yoga on cancer fatigue in patients with breast cancer and establish a scientific basis for enhancing their quality of life. OBJECTIVE: To assess the effect of yoga on CRF in patients with breast cancer. METHODS: Computer searches were conducted on PubMed, Embase, Web of Science, CKNI, and Wanfang databases to retrieve articles related to yoga and CRF in patients with breast cancer from the hospital establishment date to July 2023. The literature was independently screened, and the information was extracted by the researchers. A meta-analysis was conducted using Review Manager Software (version 5.3). RESULTS: The findings from the meta-analysis of 18 studies indicate that yoga can effectively enhance CFR (standardized mean difference (SMD) = -0.51, 95% confidence interval [CI] = -0.92 to -0.10), improve sleep quality (MD = -3.86, 95%CI = -4.03 to -3.70) in patients with breast cancer, alleviate anxiety and depression (SMD = -0.93, 95%CI = -1.68, -0.18, SMD = -1.23, 95%CI = -2.02 to -0.44), and enhance quality of life (MD = -11.20, 95%CI = -14.16 to -8.24). CONCLUSION: Our study offers evidence for the subsequent reduction of CFR in patients with breast cancer. Yoga can alleviate fatigue, improve sleep quality and negative emotions, and improve the quality of life of patients with breast cancer.

Multilocus Distance-Regulated Sensor Array for Recognition of Polyphenols via Machine Learning and Indicator Displacement Assay.

Developing new strategies to construct sensor arrays that can effectively distinguish multiple natural components with similar structures in mixtures is an exceptionally challenging task. Here, we propose a new multilocus distance-modulated indicator displacement assay (IDA) strategy for constructing a sensor array, incorporating machine learning optimization to identify polyphenols. An 8-element array, comprising two fluorophores and their six dynamic covalent complexes (C1-C6) formed by pairing two fluorophores with three distinct distance-regulated quenchers, has been constructed. Polyphenols with diverse spatial arrangements and combinatorial forms compete with the fluorophores by forming pseudocycles with quenchers within the complexes, leading to varying degrees of fluorescence recovery. The array accurately and effectively distinguished four tea polyphenols and 16 tea varieties, thereby demonstrating the broad applicability of the multilocus distance-modulated IDA array in detecting polyhydroxy foods and natural medicines.

SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy.

BACKGROUND AND AIMS: RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood. METHODS: Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10△hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment. RESULTS: SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity. CONCLUSIONS: SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.

FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2.

BACKGROUND & AIMS: Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis. METHODS: PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment. RESULTS: ETV4 expression was positively related to higher tumour-node-metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signalling-induced HCC metastasis. CONCLUSIONS: ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis. IMPACT AND IMPLICATIONS: Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8+ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC.

The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases.

Aminoacyl-tRNA synthetases (ARSs) catalyze the ligation of amino acids to their cognate transfer RNAs and are indispensable enzymes for protein biosynthesis in all the cells. Previously, ARSs were considered simply as housekeeping enzymes, however, they are now known to be involved in a variety of physiological and pathological processes, such as tumorigenesis, angiogenesis, and immune response. In this review, we summarize the role of ARSs in the digestive system, including the esophagus, stomach, small intestine, colon, as well as the auxiliary organs such as the pancreas, liver, and the gallbladder. Furthermore, we specifically focus on the diagnostic and prognostic value of ARSs in cancers, aiming to provide new insights into the pathophysiological implications of ARSs in tumorigenesis.

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis.

Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored. Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub. Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis. Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.

Clinical outcomes of endoscopic treatment for gastric gastrointestinal stromal tumors: a single-center study of 240 cases in China.

BACKGROUND AND AIMS: Endoscopic resection (ER) gradually becomes an important treatment method for gastrointestinal stromal tumors (GISTs). The aim of this study is to evaluate the efficacy and safety of ER of gastric GISTs. METHODS: This retrospective study included 240 patients with gastric GISTs who underwent ER at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2010 to December 2019. The clinicopathologic, endoscopic and follow-up data of the patients were collected and analyzed. RESULTS: The mean maximum tumor diameter was 1.67 ± 1.00 cm (range 0.2-6.5 cm), of which 156 cases (65.00%) were small gastric GISTs (tumor diameter < 2 cm). A total of 43 patients (17.92%) had perioperative bleeding, including 40 cases (16.67%) of minor bleeding and three cases (1.25%) of major bleeding. Perioperative perforation occurred in 101 patients (42.08%), of which 51 patients (21.25%) were active perforation and 50 patients (20.83%) were passive perforation. The en bloc resection rate was 97.08% (233/240), and seven cases (2.92%) had piecemeal resection. There were three cases (1.92%) of small gastric GISTs at intermediate risk and one case (0.64%) at high risk. A total of 193 patients were followed up, and no tumor residual, recurrence or metastasis occurred within a median follow-up time of 30 months (range 1-127 months). CONCLUSIONS: Endoscopic treatment for gastric GISTs is safe and effective. Piecemeal resection does not seem to be related to the patient's prognosis. Endoscopic resection can be performed if patients are willing to remove small gastric GISTs.

MIG/CXCL9 exacerbates the progression of metabolic-associated fatty liver disease by disrupting Treg/Th17 balance.

CD4+CD25+ regulatory T (Treg) cells and Th17 cells play important roles in the progression of metabolic-associated fatty liver disease (MAFLD). However, the contribution of monokine induced by interferon-gamma (MIG)/CXCL9 to the Treg/Th17 imbalance in MAFLD is only partially understood. In the present study, we detected increased levels of MIG/CXCL9 and a Treg/Th17 imbalance in the setting of metabolic-associated steatohepatitis (MASH). Recombinant adeno-associated virus-mediated gene transfer and silencing of MIG/CXCL9 expression in mice alleviated MASH and increased the Treg/Th17 ratio. Furthermore, the percentage of Th17 cells, but not Treg cells, differentiated from splenic CD4+ T cells was significantly increased by administration of MIG/CXCL9. MIG/CXCL9 also promoted Th17 cell proliferation, and its effects were dose dependent. Levels of phosphorylated c-Jun N-terminal kinase (JNK) decreased dramatically when MIG/CXCL9 was inhibited in a murine MASH model. In cultured Treg cells, phosphorylated JNK levels decreased dose-dependently in response to MIG/CXCL9 inhibition, but increased in cultured Th17 cells. This effect was blocked in the presence of a JNK inhibitor. These findings underline the fundamental importance of MIG/CXCL9 in maintaining the Treg/Th17 balance in MAFLD and provide the foundations for a novel approach to preventing and treating MAFLD.

Robust antiviral responses to enterovirus 71 infection in human intestinal epithelial cells.

Enterovirus 71 (EV71) is a single-stranded RNA virus that belongs to Picornaviridae family. It causes the hand-foot-and-mouth disease and fatal neurological diseases in young children and infants. The mechanism of EV71 pathogenesis remains obscure. The intestinal tract is the initial site of EV71 replication, but no or only mild gastrointestinal symptoms are observed clinically, suggesting that host immune responses of the intestinal epithelium to EV71 may be unique, which, however, remains rarely investigated. In this study, we showed that human intestinal epithelial cells HT-29 were susceptible to EV71, and the infected cells exhibited cytopathic effects (CPEs) and were prone to apoptosis. TLR-7 and TLR-8 were induced significantly post infection and may be pivotal in the induction of IFN-ß and host innate immune responses against EV71. Among proinflammatory responses in EV71-infected intestinal epithelial cells, IL-6, CCL5, and IP10 were up-regulated and may play a key role in intestinal pathogenicity. We examined extrinsic and intrinsic apoptotic pathways and found that both were activated in EV71 infection. The mitochondria-mediated intrinsic pathway may also be activated through Bid cleaved by active caspase-8. Robust induction of IFN-ß in human intestinal epithelial cells contradicts the finding that IFN induction was suppressed in other types of the cells, suggesting that mild gastrointestinal symptoms may be the result of sufficient local antiviral inductions. Our study has demonstrated a unique way of antiviral responses in human gut different from other tissue cells in response to EV71, which may account for mild symptoms in intestinal tract. This finding will broaden our understanding of host defense mechanism and the pathogenesis of EV71 infection.