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Abstract Background The endoplasmic reticulum (ER) regulates critical processes, including lipid synthesis, which are affected by transmembrane proteins localized in the ER membrane. One such protein, transmembrane protein 147 (TMEM147), has recently been implicated for its role in hepatocellular carcinoma (HCC) tumorigenesis; however, the mechanisms remain unclear. We investigated the role of TMEM147 in HCC and the underlying mechanisms. Methods TMEM147 expression was examined in human HCC cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of TMEM147 on the progression of HCC. Proteins interacting with TMEM147 were identified via RNA-seq, immunoprecipitation, and mass spectrometry analyses. Lipidomic analysis and enzyme-linked immunosorbent assay (ELISA) were employed to determine and analyze cholesterol and 27-hydroxycholesterol (27HC) contents. Extensive experimental techniques were used to study ferroptosis in HCC cells. The fatty acid content of macrophages affected by TMEM147 was quantified using ELISA. Macrophage phenotypes were determined using immunofluorescence assay and flow cytometric analysis. Results TMEM147 mRNA and protein levels were increased in HCC cells, and the increased TMEM147 expression was associated with a poor survival. TMEM147 promoted tumor cell proliferation and metastases in vitro and in vivo. The protein was found to interact with the key enzyme 7-dehydrocholesterol reductase (DHCR7), which affected cellular cholesterol homeostasis and increased the extracellular levels of 27HC in HCC cells. TMEM147 also promoted the expression of DHCR7 by enhancing the activity of signal transducer and activator of transcription 2. 27HC expression upregulated glutathione peroxidase 4 in HCC, leading to ferroptosis resistance and promotion of HCC proliferation. HCC cell-derived 27HC expression increased the lipid metabolism in macrophages and activated peroxisome proliferator-activated receptor-γ signaling, thereby activating M2 macrophage polarization and promoting HCC cell invasion and migration. Conclusions Our results indicate that TMEM147 confers ferroptosis resistance and M2 macrophage polarization, which are primarily dependent on the upregulation of cellular cholesterol homeostasis and 27HC secretion, leading to cancer growth and metastasis. These findings suggest that the TMEM147/STAT2/DHCR7/27HC axis in the tumor microenvironment may serve as a promising therapeutic target for HCC. Graphical Abstract

Introduction: Qi-Xian Decoction (QXD), a traditional Chinese medicine (TCM) formula consisting of eight herbs, has been clinically used to treat asthma. However, the underlying mechanisms have not been completely elucidated. This study aimed to combine metabolomics and network pharmacology to reveal the mechanism of action of QXD in asthma treatment.Methods: An ovalbumin (OVA)-induced asthma mouse model was constructed to evaluate the therapeutic effects of QXD. Serum metabolomics and network pharmacology were combined to study the mechanism of anti-asthma action as well as the potential target, and related biological functions were validated.Results: The QXD treatment has demonstrated significant protective effects in OVA-induced asthmatic mice, as evidenced by its ability to inhibit inflammation, IgE, mucus overproduction, and airway hyperreactivity (AHR). Metabolomic analysis has revealed a total of 140 differential metabolites associated with QXD treatment. In addition, network pharmacology has identified 126 genes that are linked to the effects of QXD, including TNF, IL-6, IL1β, STAT3, MMP9, EGFR, JUN, CCL2, TLR4, MAPK3 and MAPK8. Through comprehensive gene-metabolite interaction network analysis, seven key metabolites have been identified and associated with the potential anti-asthmatic effect of QXD, with palmitic acid (PA) being the most notable among them. In vitro validation studies have confirmed the gene-metabolite interaction involving PA, IL-6, and MAPK8. Furthermore, our research has demonstrated that QXD treatment can effectively inhibit PA-promoted IL-6 expression in MH-S cells and reduce PA concentration in OVA-induced asthmatic mice.Conclusion: The regulation of metabolic pathways by QXD was found to be associated with its anti-asthmatic action, which provides insight into the mechanism of QXD in treating asthma.

Abstract Colorectal cancer (CRC) is a gastrointestinal malignancy originating from either the colon or the rectum. A growing number of researches prove that the unfolded protein response (UPR) is closely related to the occurrence and progression of colorectal cancer. The UPR has three canonical endoplasmic reticulum (ER) transmembrane protein sensors: inositol requiring kinase 1 (IRE1), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6 (ATF6). Each of the three pathways is closely associated with CRC development. The three pathways are relatively independent as well as interrelated. Under ER stress, the activated UPR boosts the protein folding capacity to maximize cell adaptation and survival, whereas sustained or excessive ER triggers cell apoptosis conversely. The UPR involves different stages of CRC pathogenesis, promotes or hinders the progression of CRC, and will pave the way for novel therapeutic and diagnostic approaches. Meanwhile, the correlation between different signal branches in UPR and the switch between the adaptation and apoptosis pathways still need to be further investigated in the future.

BackgroundUnfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis.MethodsThe bioinformatics analysis was performed to examine the expression status of cancer associated genes in patients with stomach adenocarcinoma (STAD) and predict the targeting sites of miR-224-5p with LncRNA MIR503HG and TUSC3. Genes expressions were quantified by Real-Time qPCR, Western Blot and immunohistochemistry (IHC). Cell proliferation, viability, apoptosis and mobility were evaluated by MTT assay, trypan blue staining assay, flow cytometer and transwell assay, respectively. The binding sites were validated by dual-luciferase reporter gene system assay.ResultsLncRNA MIR503HG and TUSC3 were downregulated, but miR-224-5p was upregulated in GC tissues and cells, in contrast with their normal counterparts. Further gain- and loss-of-function experiments validated that the malignant phenotypes in GC cells, including cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and tumorigenesis, were negatively regulated by LncRNA MIR503HG. Mechanistically, LncRNA MIR503HG upregulated TUSC3 in GC cells through sponging miR-224-5p, resulting in the repression of GC progression. Finally, we validated that knock-down of ATF6, but not other two branches of UPR (PERK1 and IRE1), partially rescued cell proliferation and EMT in the GC cells with LncRNA MIR503HG overexpression.ConclusionsTargeting the LncRNA MIR503HG/miR-224-5p/TUSC3 signaling cascade suppressed ATF6-mediated UPR, resulting in the blockage of GC development.

BackgroundThe prognostic significance of the Naples prognostic score (NPS) in colorectal cancer remains uncertain. This study aims to investigate the correlation between the pretreatment NPS and long-term oncological outcomes in patients with colorectal cancer.MethodsA comprehensive literature search of electronic databases, including PubMed, Embase, and Web of Science, was conducted up to July 1st, 2024. The primary outcomes assessed were survival outcomes. Subgroup analysis and sensitivity analysis were performed during the pooled analysis.ResultsEight studies including 2571 patients were included. The pooled results indicated that patients in the high NPS group exhibited significantly worse overall survival (HR= 2.08 95%CI: 1.74-2.48; P

Abstract Background Insufficient evidence existed about the prognostic role of the advanced lung cancer inflammation index (ALI) for gastric cancer patients who underwent curative resection. The aim of this study was to identify the predictive ability of ALI for survival after curative gastrectomy. Methods We retrospectively analyzed 328 gastric cancer patients who received curative gastrectomy from the database of Chongqing University Cancer Hospital, and investigated the prognostic role of the preoperative ALI compared with clinicopathological variables and other serum biomarkers, such as preoperative neutrophil-to-lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and Lymphocyte-monocyte ratio (LMR). To minimize intergroup differences, propensity score matching (PSM) analysis was employed. Additionally, we performed a meta-analysis of four cohort studies published up to October 2023 following the PRISMA guidelines. Results In the overall cohort, patients in the low ALI group had a significantly worse overall survival compared to those in the high ALI group (P

Abstract Background ​The applicability of laparoscopy to nonmetastatic T4a patients with gastric cancer remains unclear due to the lack of high-quality evidence. The purpose of this study was to compare the survival rates of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for these patients through a meta-analysis of reconstructed individual participant data from propensity score-matched studies. Methods PubMed, Embase, Web of Science, Cochrane library and CNKI were examined for relevant studies without language restrictions through July 25, 2023. Individual participant data on overall survival (OS) and disease-free survival (DFS) were extracted from the published Kaplan-Meier survival curves. One-stage and two-stage meta-analyses were performed. In addition, data regarding surgical outcomes and recurrence patterns were also collected, which were meta-analyzed using traditional aggregated data. Results Six studies comprising 1860 patients were included for analysis. In the one-stage meta-analyses, the results demonstrated that LG was associated with a significantly better DFS (Random-effects model: P = 0.027; Restricted mean survival time [RMST] up to 5 years: P = 0.033) and a comparable OS (Random-effects model: P = 0.135; RMST up to 5 years: P = 0.053) than OG for T4a gastric cancer patients. Two-stage meta-analyses resulted in similar results, with a 13% reduced hazard of cancer-related death (P = 0.04) and 10% reduced hazard of overall mortality (P = 0.11) in the LG group. For secondary outcomes, the pooled results showed an association of LG with less estimated blood loss, faster postoperative recovery and more retrieved lymph nodes. Conclusion Laparoscopic surgery for patients with nonmetastatic T4a disease is associated with a potential survival benefit and improved surgical outcomes.

Abstract Background The incidence of colorectal cancer (CRC) has increased in recent years. Identification of accurate tumor markers has become the focus of CRC research. Early and frequent DNA methylation tends to occur in cancer. Thus, identifying accurate methylation biomarkers would improve the efficacy of CRC treatment. Neuroglobin (NGB) is involved in neurological and oncological diseases. However, there are currently no reports on epigenetic regulation involvement of NGB in CRC. Results NGB was downregulated or silenced in majority CRC tissues and cell lines. The hypermethylation of NGB was detected in tumor tissue, but no or a very low methylation frequency in normal tissues. Overexpression of NGB induced G2/M phase arrest and apoptosis, suppressed proliferation, migration, invasion in vitro, and inhibited CRC tumor growth and angiogenesis in vivo. Isobaric tag for relative and absolute quantitation (Itraq)-based proteomics identified approximately 40% proteins related to cell–cell adhesion, invasion, and tumor vessel formation in the tumor microenvironment, among which GPR35 was proved critical for NGB-regulated tumor angiogenesis suppression in CRC. Conclusions NGB, an epigenetically silenced factor, inhibits metastasis through the GPR35 in CRC. It is expected to grow into a potential cancer risk assessment factor and a valuable biomarker for early diagnosis and prognosis assessment of CRC.

The transition metal vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. As a well known vanadium compound, sodium orthovanadate (SOV) has shown promising antineoplastic activity in several human cancers. However, the effects of SOV on liver cancer are still unknown. In this study, for the first time, we showed that SOV could effectively suppress proliferation, induce G2/M cell cycle arrest and apoptosis, and diminish the mitochondrial membrane potential (MMP) of HCC cells in vitro. In addition, our in vitro results were recapitulated in vivo, showing that SOV exhibited a dose-dependent inhibition of growth of human HCC in an orthotopic model, evidenced by the reduction in tumor size, proliferation index and microvessel density, and increase in cell apoptosis. Most important, we found that SOV could inhibit autophagy in HCC cells in vitro and in vivo, which plays a prodeath role. Thus, our findings suggest that SOV could effectively suppress the growth of human HCC through the regulations of proliferation, cell cycle, apoptosis and autophagy, and thus may act as a potential therapeutic agent in HCC treatment. [ABSTRACT FROM AUTHOR]